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Goossens Q, Locsin M, Ponder LA, Chan M, Ozmen GC, Prahalad S, Inan OT. Active Vibrational Achilles Tendon Sensing for Identifying and Characterizing Inflammatory Symptomatology in Enthesitis Related Arthritis. IEEE Trans Biomed Eng 2025; 72:645-654. [PMID: 39316483 DOI: 10.1109/tbme.2024.3466831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
OBJECTIVE This study explores the potential of active vibrational sensing as a digital biomarker to identify and characterize inflammatory symptomatology in the Achilles tendon and its entheses in juvenile idiopathic arthritis (JIA), particularly enthesitis related arthritis (ERA), a subcategory of JIA. METHODS Active vibrational data were non-invasively recorded using a miniature coin vibration motor and accelerometer. Twenty active vibration recordings from children diagnosed with JIA were used in the analysis. Machine learning algorithms were leveraged to classify the vibrational signatures according to the corresponding subject groups. Subjects were classified into symptomatic ERA (sxERA), asymptomatic ERA (asxERA), and asymptomatic JIA (non-ERA) (asxNERA) groups based on clinical evaluations and ILAR criteria. RESULTS Distinct vibrational signatures were observed during tiptoe standing, providing differentiation between subject groups. Feature-based and waveform-based approaches effectively classified the sxERA group against asxNERA and asxERA groups using leave-one-subject-out (LOSO-CV) and 3-fold cross-validation. For the 3-fold cross-validation, the mean accuracies for distinguishing sxERA from asxNERA were 81% (feature-based) and 81% (waveform-based), while the accuracies for discriminating sxERA against asxERA were 73% (feature-based) and 74% (waveform-based). CONCLUSION Active vibrational sensing demonstrates promise as a tool for identifying Achilles tendon inflammation in JIA, potentially aiding in early diagnosis and disease monitoring. SIGNIFICANCE Developing active vibrational sensing as a diagnostic modality could address challenges in diagnosing ERA and facilitate timely intervention and personalized care for JIA, potentially enhancing long-term patient outcomes.
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Glerup M, Tagkli A, Küseler A, Christensen AE, Verna C, Bilgrau AE, Nørholt SE, Herlin T, Pedersen TK, Stoustrup P. Incidence of Orofacial Manifestations of Juvenile Idiopathic Arthritis From Diagnosis to Adult Care Transition: A Population-Based Cohort Study. Arthritis Rheumatol 2023; 75:1658-1667. [PMID: 36806745 DOI: 10.1002/art.42481] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 12/29/2022] [Accepted: 02/14/2023] [Indexed: 02/23/2023]
Abstract
OBJECTIVE To estimate the cumulative incidences of orofacial conditions related to temporomandibular joint (TMJ) juvenile idiopathic arthritis (JIA) between diagnosis in childhood to transition into adult care, and to identify features in JIA associated with TMJ involvement. METHODS A population-based cohort analysis was conducted of patients with JIA involving longitudinal data on orofacial health from 2000 to 2018. Regardless of TMJ status, the patients were referred to the Regional Specialist Craniofacial Clinic of Western Denmark for routine orofacial examinations. Data collection included information about disease-specific background characteristics, TMJ involvement, JIA-induced dentofacial deformity, and orofacial symptoms and dysfunction. RESULTS A total of 613 patients were followed up with a mean clinical TMJ observation time of 4.0 years. From JIA onset to transition into adult care, the cumulative incidence of patients with JIA involvement of the TMJ was 30.1%. Furthermore, 20.6% of the cohort had developed arthritis-induced dentofacial deformity. A substantial proportion of the cohort experienced several events with orofacial symptoms (23.5%) and dentofacial dysfunction (52%). Young age at diagnosis (<9 years), female gender, and antinuclear antibody positivity were significantly associated with TMJ involvement. CONCLUSION Orofacial signs and symptoms were frequent findings in children and adolescents with JIA. TMJ involvement was seen in 30.1% of the cohort; and 20.6% of the total cohort developed JIA-related dentofacial deformity before transition into adult care. This is the first population-based study in the era of available biologic treatments to document these frequent orofacial complications in children with JIA.
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Affiliation(s)
- Mia Glerup
- Pediatric Rheumatology Clinic, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
| | | | | | | | - Carlalberta Verna
- Department of Pediatric Oral Health and Orthodontics, UZB University Center for Dental Medicine Basel, University of Basel, Basel, Switzerland
| | - Anders E Bilgrau
- Department of Mathematical Sciences, Aalborg University, Aalborg, Denmark
| | - Sven Erik Nørholt
- Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, and Section of Oral Surgery and Oral Pathology, Department of Dentistry and Oral Health, Aarhus University, Aarhus, Denmark
| | - Troels Herlin
- Pediatric Rheumatology Clinic, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
| | - Thomas K Pedersen
- Section of Orthodontics, Aarhus University, and Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, Aarhus, Denmark
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Goossens Q, Locsin M, Gharehbaghi S, Brito P, Moise E, Ponder LA, Inan OT, Prahalad S. Knee acoustic emissions as a noninvasive biomarker of articular health in patients with juvenile idiopathic arthritis: a clinical validation in an extended study population. Pediatr Rheumatol Online J 2023; 21:59. [PMID: 37340311 DOI: 10.1186/s12969-023-00842-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 06/03/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND Joint acoustic emissions from knees have been evaluated as a convenient, non-invasive digital biomarker of inflammatory knee involvement in a small cohort of children with Juvenile Idiopathic Arthritis (JIA). The objective of the present study was to validate this in a larger cohort. FINDINGS A total of 116 subjects (86 JIA and 30 healthy controls) participated in this study. Of the 86 subjects with JIA, 43 subjects had active knee involvement at the time of study. Joint acoustic emissions were bilaterally recorded, and corresponding signal features were used to train a machine learning algorithm (XGBoost) to classify JIA and healthy knees. All active JIA knees and 80% of the controls were used as training data set, while the remaining knees were used as testing data set. Leave-one-leg-out cross-validation was used for validation on the training data set. Validation on the training and testing set of the classifier resulted in an accuracy of 81.1% and 87.7% respectively. Sensitivity / specificity for the training and testing validation was 88.6% / 72.3% and 88.1% / 83.3%, respectively. The area under the curve of the receiver operating characteristic curve was 0.81 for the developed classifier. The distributions of the joint scores of the active and inactive knees were significantly different. CONCLUSION Joint acoustic emissions can serve as an inexpensive and easy-to-use digital biomarker to distinguish JIA from healthy controls. Utilizing serial joint acoustic emission recordings can potentially help monitor disease activity in JIA affected joints to enable timely changes in therapy.
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Affiliation(s)
- Quentin Goossens
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Technology Square Research Building, 85 Fifth St NW, Atlanta, GA, 30308, USA.
| | - Miguel Locsin
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30223, USA
| | - Sevda Gharehbaghi
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Technology Square Research Building, 85 Fifth St NW, Atlanta, GA, 30308, USA
| | - Priya Brito
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30223, USA
| | - Emily Moise
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Technology Square Research Building, 85 Fifth St NW, Atlanta, GA, 30308, USA
| | - Lori A Ponder
- Children's Healthcare of Atlanta, Atlanta, GA, 30223, USA
| | - Omer T Inan
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Technology Square Research Building, 85 Fifth St NW, Atlanta, GA, 30308, USA
| | - Sampath Prahalad
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30223, USA
- Children's Healthcare of Atlanta, Atlanta, GA, 30223, USA
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30223, USA
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Tanatar A, Akgün Ö, Çağlayan Ş, Bağlan E, Otar Yener G, Öztürk K, Çakan M, Sönmez HE, Sözeri B, Aktay Ayaz N. Withdrawal of biologic therapy in juvenile idiopathic arthritis due to remission: predictors of flare and outcomes. Expert Opin Biol Ther 2023; 23:305-313. [PMID: 36825474 DOI: 10.1080/14712598.2023.2185132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
OBJECTIVES To investigate patients who flared after discontinuation of biological disease-modifying anti-rheumatic agents (bDMARDs) and identify risk factors associated with flare. METHODS A multicenter study evaluating systemic and non-systemic juvenile idiopathic arthritis (sJIA and non-sJIA) patients whose bDMARDs were ceased after remission. RESULTS A total of 101 patients whose bDMARDs were ceased after remission was evaluated. Children with sJIA had the lowest risk of flare and 11.1% of 36 sJIA patients experienced flare after a median of 9 (4-24) months of bDMARDs cessation with three of them flaring in the first year. High leukocyte counts in sJIA patients were associated with inactive disease at 1-year after the start of treatment (p = 0.004). In the non-sJIA group, 46.1% patients experienced flare after a median of 7 (1-32) months of biologic cessation, and of these, 25 flared in the first year. Antinuclear antibody positivity (p = 0.02), earlier disease onset (p = 0.03), long disease duration (p = 0.01), and follow-up (p = 0.02) and extended time from diagnosis to first biological onset (p = 0.03) were more common among patients with flare. CONCLUSIONS When considering discontinuation of bDMARDs, it should be kept in mind that the risk of exacerbation requiring re-initiation therapy is quite significant within the first year after discontinuation of therapy.
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Affiliation(s)
- Ayşe Tanatar
- Faculty of Medicine, Department of Pediatric Rheumatology, Istanbul University, Fatih, Turkey
| | - Özlem Akgün
- Faculty of Medicine, Department of Pediatric Rheumatology, Istanbul University, Fatih, Turkey
| | - Şengül Çağlayan
- Department of Pediatric Rheumatology, University of Health Sciences, Ümraniye Research and Training Hospital, Ümraniye, Turkey
| | - Esra Bağlan
- Department of Pediatric Rheumatology, University of Health Sciences, Dr. Sami Ulus Maternity and Child Health and Diseases Research and Training Hospital, Altındağ, Turkey
| | - Gülçin Otar Yener
- Department of Pediatric Rheumatology, Şanlıurfa Research and Training Hospital, Haliliye, Turkey
| | - Kübra Öztürk
- Department of Pediatric Rheumatology, Istanbul Medeniyet University, Göztepe Prof. Dr. Süleyman Yalçın City Hospital, Kadıköy, Turkey
| | - Mustafa Çakan
- Department of Pediatric Rheumatology, University of Health Sciences, Ümraniye Research and Training Hospital, Ümraniye, Turkey
| | - Hafize Emine Sönmez
- Faculty of Medicine, Department of Pediatric Rheumatology, Kocaeli University, İzmit, Turkey
| | - Betül Sözeri
- Department of Pediatric Rheumatology, University of Health Sciences, Ümraniye Research and Training Hospital, Ümraniye, Turkey
| | - Nuray Aktay Ayaz
- Faculty of Medicine, Department of Pediatric Rheumatology, Istanbul University, Fatih, Turkey
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Oommen PT, Strauss T, Baltruschat K, Foeldvari I, Deuter C, Ganser G, Haas JP, Hinze C, Holzinger D, Hospach A, Huppertz HI, Illhardt A, Jung M, Kallinich T, Klein A, Minden K, Mönkemöller K, Mrusek S, Neudorf U, Dückers G, Niehues T, Schneider M, Schoof P, Thon A, Wachowsky M, Wagner N, Bloedt S, Hofer M, Tenbrock K, Schuetz C. Update of evidence- and consensus-based guidelines for the treatment of juvenile idiopathic arthritis (JIA) by the German Society of Pediatric and Juvenile Rheumatic Diseases (GKJR): New perspectives on interdisciplinary care. Clin Immunol 2022; 245:109143. [DOI: 10.1016/j.clim.2022.109143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/15/2022]
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McErlane F, Anderson C, Lawson-Tovey S, Lee B, Lee C, Lunt L, McDonagh JE, Smith AD, Smith N, Cleary G. Quality improvement in juvenile idiopathic arthritis: a mixed-methods implementation pilot of the CAPTURE-JIA dataset. Pediatr Rheumatol Online J 2022; 20:43. [PMID: 35717328 PMCID: PMC9206126 DOI: 10.1186/s12969-022-00697-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/26/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND A significant proportion of children and young people with juvenile idiopathic arthritis (JIA) do not achieve inactive disease during the first two years following diagnosis. Refinements to clinical care pathways have the potential to improve clinical outcomes but a lack of consistent and contemporaneous clinical data presently precludes standard setting and implementation of meaningful quality improvement programmes. This study was the first to pilot clinical data collection and analysis using the CAPTURE-JIA dataset, and to explore patient and clinician-reported feasibility and acceptability data. METHODS A multiphase mixed-methods approach enabled prospective collection of quantitative data to examine the feasibility and efficacy of dataset collection and of qualitative data informing the context and processes of implementation. An initial paper pilot informed the design of a bespoke electronic data collection system (the Agileware system), with a subsequent electronic pilot informing the final CAPTURE-JIA data collection tool. RESULTS Paper collection of patient data was feasible but time-consuming in the clinical setting. Phase 1 paper pilot data (121 patients) identified three themes: problematic data items (14/62 data items received >40% missing data), formatting of data collection forms and a clinician-highlighted need for digital data collection, informing Phase 2 electronic data collection tool development. Patients and families were universally supportive of the collection and analysis of anonymised patient data to inform clinical care. No apparent preference for paper / electronic data collection was reported by families. Phase 3 electronic pilot data (38 patients) appeared complete and the system reported to be easy to use. Analysis of the study dataset and a dummy longitudinal dataset confirmed that all eleven JIA national audit questions can be answered using the electronic system. CONCLUSIONS Multicentre CAPTURE-JIA data collection is feasible and acceptable, with a bespoke data collection system highlighted as the most satisfactory solution. The study is informing ongoing work towards a streamlined and flexible national paediatric data collection system to drive quality improvement in clinical care.
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Affiliation(s)
- Flora McErlane
- Paediatric Rheumatology, Great North Children's Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. .,Institute of Population and Health Sciences, Medical School, Newcastle University, Newcastle upon Tyne, UK.
| | | | - Saskia Lawson-Tovey
- grid.5379.80000000121662407Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK ,grid.498924.a0000 0004 0430 9101National Institute of Health Research Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK
| | | | - Chris Lee
- Appligo Ltd, https://www.agileware.io/about
| | - Laura Lunt
- grid.498924.a0000 0004 0430 9101National Institute of Health Research Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK ,grid.5379.80000000121662407Versus Arthritis Centre for Epidemiology, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK
| | - Janet E. McDonagh
- grid.498924.a0000 0004 0430 9101National Institute of Health Research Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK ,grid.5379.80000000121662407Versus Arthritis Centre for Epidemiology, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK ,grid.415910.80000 0001 0235 2382Department of Paediatric and Adolescent Rheumatology, Royal Manchester Children’s Hospital, Manchester University Hospitals NHS Trust, Manchester, UK
| | - Andrew D. Smith
- grid.498924.a0000 0004 0430 9101National Institute of Health Research Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK ,grid.5379.80000000121662407Versus Arthritis Centre for Epidemiology, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK
| | - Nicola Smith
- grid.1006.70000 0001 0462 7212Musculoskeletal Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Gavin Cleary
- grid.413582.90000 0001 0503 2798Department of Rheumatology, Alder Hey Children’s Hospital, Liverpool, UK
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Ong MS, Ringold S, Kimura Y, Schanberg LE, Tomlinson GA, Natter MD. Improved Disease Course Associated With Early Initiation of Biologics in Polyarticular Juvenile Idiopathic Arthritis: Trajectory Analysis of a Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans Study. Arthritis Rheumatol 2021; 73:1910-1920. [PMID: 34105303 DOI: 10.1002/art.41892] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 06/01/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To investigate the effects of early introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) on the disease course in untreated polyarticular juvenile idiopathic arthritis (JIA). METHODS We analyzed data on patients with polyarticular JIA participating in the Start Time Optimization of Biologics in Polyarticular JIA (STOP-JIA) study (n = 400) and a comparator cohort (n = 248) from the Childhood Arthritis and Rheumatology Research Alliance Registry. Latent class trajectory modeling (LCTM) was applied to identify subgroups of patients with distinct disease courses based on disease activity (clinical Juvenile Arthritis Disease Activity Score in 10 joints) over 12 months from baseline. RESULTS In the STOP-JIA study, 198 subjects (49.5%) received bDMARDs within 3 months of baseline assessment. LCTM analyses generated 3 latent classes representing 3 distinct disease trajectories, characterized by slow, moderate, or rapid disease activity improvement over time. Subjects in the rapid improvement trajectory attained inactive disease within 6 months from baseline. Odds of being in the rapid improvement trajectory versus the slow improvement trajectory were 3.6 times as high (95% confidence interval 1.32-10.0; P = 0.013) for those treated with bDMARDs ≤3 months from baseline compared with subjects who started bDMARDs >3 months after baseline, after adjusting for demographic characteristics, clinical attributes, and baseline disease activity. Shorter disease duration at first rheumatology visit approached statistical significance as a predictor of favorable trajectory without bDMARD treatment. CONCLUSION Starting bDMARDs within 3 months of baseline assessment is associated with more rapid achievement of inactive disease in subjects with untreated polyarticular JIA. These results demonstrate the utility of trajectory analysis of disease course as a method for determining treatment efficacy.
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Affiliation(s)
- Mei Sing Ong
- Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
| | | | - Yukiko Kimura
- Joseph M. Sanzari Children's Hospital and Hackensack Meridian School of Medicine, Hackensack, New Jersey
| | | | | | - Marc D Natter
- Boston Children's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts
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Update on the treatment of nonsystemic juvenile idiopathic arthritis including treatment-to-target: is (drug-free) inactive disease already possible? Curr Opin Rheumatol 2021; 32:403-413. [PMID: 32657803 DOI: 10.1097/bor.0000000000000727] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE OF REVIEW This review concerns the outcome for nonsystemic juvenile idiopathic arthritis (JIA) with emphasis on treatment-to-target (T2T) and treatment strategies aiming at inactive disease by giving an overview of recent articles. RECENT FINDINGS More efficacious therapies and treatment strategies/T2T with inactive disease as target, have improved the outcome for JIA significantly. Recent studies regarding treatment strategies have shown 47-68% inactive disease after 1 year. Moreover, probability of attaining inactive disease at least once in the first year seems even higher in recent cohort-studies, reaching 80%, although these studies included relatively high numbers of oligoarticular JIA patients. However, 26-76% of patients flare upon therapy withdrawal and prediction of flares is still difficult. SUMMARY Remission can be achieved and sustained in (some) JIA patients, regardless of initial treatment. Cornerstone principles in the management of nonsystemic JIA treatment are early start of DMARD therapy, striving for inactive disease and T2T by close and repeated monitoring of disease activity. T2T and tight control appear to be more important than a specific drug in JIA. Next to inactive disease, it is important that patients/parents are involved in personal targets, like reduction of pain and fatigue. Future studies should focus on predictors (based on imaging-methods or biomarkers) for sustained drug-free remission and flare.
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Armaroli G, Klein A, Ganser G, Ruehlmann MJ, Dressler F, Hospach A, Minden K, Trauzeddel R, Foeldvari I, Kuemmerle-Deschner J, Weller-Heinemann F, Urban A, Horneff G. Long-term safety and effectiveness of etanercept in JIA: an 18-year experience from the BiKeR registry. Arthritis Res Ther 2020; 22:258. [PMID: 33121528 PMCID: PMC7597050 DOI: 10.1186/s13075-020-02326-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 09/22/2020] [Indexed: 01/22/2023] Open
Abstract
Background At present, etanercept represents the most commonly prescribed biologic agent for juvenile idiopathic arthritis (JIA) treatment. Children and adolescents with JIA are often treated with etanercept over long periods, sometimes even into adulthood. The objectives of this analysis were to determine the long-term safety of etanercept compared to a biologic-naïve cohort and to assess the long-term treatment response upon continuous etanercept exposure using data from the German biologics registry (BiKeR). Methods JIA patients newly exposed to etanercept were documented in the BiKeR registry from January 2001 to March 2019, and baseline characteristics, effectiveness, and safety parameters were analysed. Response to treatment was assessed according to 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), JADAS-defined minimal disease activity and remission, JIA-American College of Rheumatology (ACR) improvement criteria, and ACR-inactive disease definition. Safety assessments were based on adverse event (AE) reports. Results A total of 2725 new etanercept users with a diagnosis of JIA were registered. Of these, etanercept was received as a first-line biologic by 95.8% and as monotherapy without concomitant methotrexate by 31.5%. After nine years on continuous treatment, 68.1% of patients presented minimal disease activity, 43.1% JADAS-defined remission on drug, and 36.6% ACR-inactive disease. JIA-ACR30/50/70/90 response rates were still 82/79/71/54% after nine years of treatment. Overall, 2053 AEs (34.3/100PY), including 226 serious AEs (SAE, 3.8/100PY), were observed upon etanercept, compared to 1345 AEs [35.6/100PY; p = 0.3] and 52 SAEs (1.4/100PY; p = 0.0001) in the biologic-naïve cohort. Respective exposure-adjusted rates for etanercept and biologic-naïve patients were 0.9/100PY and 0.2/100PY (p = 0.0001) for serious infections, 0.4/100PY and 0.1/100PY (p = 0.01) for zoster reactivation, 0.3/100PY and 0.03/100PY (p = 0.015) for inflammatory bowel disease, and 1.9/100PY and 1.4/100PY (p = 0.09) for uveitis. Three and two malignancies were documented in the etanercept and biologic-naïve groups, as well as three and one deaths, respectively. Conclusions No new safety signal was observed, especially no increased risk for malignancies or autoimmune disorders other than inflammatory bowel disease. However, SAEs and serious infections, though infrequent, were more often reported on etanercept than in biologic-naïve patients. In addition, etanercept demonstrated a long-term maintenance of clinical benefits up to nine years of continuous treatment.
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Affiliation(s)
- Giulia Armaroli
- Division of Paediatric Rheumatology, Sankt Augustin Asklepios Children's Hospital, 53757 Sankt Augustin, Germany.
| | - Ariane Klein
- Division of Paediatric Rheumatology, Sankt Augustin Asklepios Children's Hospital, 53757 Sankt Augustin, Germany.,Cologne University, Medical School, Cologne, Germany
| | - Gerd Ganser
- Division of Paediatric Rheumatology, Northwest German Rheumatology Center, St. Josef Stift, Sendenhorst, Germany
| | | | - Frank Dressler
- Division of Paediatric Pulmonology, Allergology and Immunology, Hannover Medical School, Hannover, Germany
| | - Anton Hospach
- Division of Paediatric Rheumatology, Olgahospital, Stuttgart, Germany
| | - Kirsten Minden
- German Rheumatism Research Center, Charité University Hospital, Berlin, Germany
| | - Ralf Trauzeddel
- Department of Paediatrics, Berlin-Buch Helios Hospital, Berlin, Germany
| | - Ivan Foeldvari
- Paediatric Rheumatology Medical Center, Hamburg, Germany
| | | | | | - Andreas Urban
- Department of Paediatrics, St. Marien Hospital, Amberg, Germany
| | - Gerd Horneff
- Division of Paediatric Rheumatology, Sankt Augustin Asklepios Children's Hospital, 53757 Sankt Augustin, Germany.,Cologne University, Medical School, Cologne, Germany
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Sengler C, Niewerth M, Minden K. Rheumatische Erkrankungen im Kindes- und Jugendalter: Wichtigkeit einer frühzeitigen multiprofessionellen Versorgung. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020; 63:846-855. [DOI: 10.1007/s00103-020-03173-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Jones AP, Clayton D, Nkhoma G, Sherratt FC, Peak M, Stones SR, Roper L, Young B, McErlane F, Moitt T, Ramanan AV, Foster HE, Williamson PR, Deepak S, Beresford MW, Baildam EM. Different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis: the SIRJIA mixed-methods feasibility study. Health Technol Assess 2020; 24:1-152. [PMID: 32758350 PMCID: PMC7443738 DOI: 10.3310/hta24360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND In the UK, juvenile idiopathic arthritis is the most common inflammatory disorder in childhood, affecting 10 : 100,000 children and young people aged < 16 years each year, with a population prevalence of around 1 : 1000. Corticosteroids are commonly used to treat juvenile idiopathic arthritis; however, there is currently a lack of consensus as to which corticosteroid induction regimen should be used with various disease subtypes and severities of juvenile idiopathic arthritis. OBJECTIVE The main study objective was to determine the feasibility of conducting a randomised controlled trial to compare the different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis. DESIGN This was a mixed-methods study. Work packages included a literature review; qualitative interviews with children and young people with juvenile idiopathic arthritis and their families; a questionnaire survey and screening log to establish current UK practice; a consensus meeting with health-care professionals, children and young people with juvenile idiopathic arthritis, and their families to establish the primary outcome; a feasibility study to pilot data capture and to collect data for future sample size calculations; and a final consensus meeting to establish the final protocol. SETTING The setting was rheumatology clinics across the UK. PARTICIPANTS Children, young people and their families who attended clinics and health-care professionals took part in this mixed-methods study. INTERVENTIONS This study observed methods of prescribing corticosteroids across the UK. MAIN OUTCOME MEASURES The main study outcomes were the acceptability of a future trial for children, young people, their families and health-care professionals, and the feasibility of delivering such a trial. RESULTS Qualitative interviews identified differences in the views of children, young people and their families on a randomised controlled trial and potential barriers to recruitment. A total of 297 participants were screened from 13 centres in just less than 6 months. In practice, all routes of corticosteroid administration were used, and in all subtypes of juvenile idiopathic arthritis. Intra-articular corticosteroid injection was the most common treatment. The questionnaire surveys showed the varying clinical practice across the UK, but established intra-articular corticosteroids as the treatment control for a future trial. The primary outcome of choice for children, young people, their families and health-care professionals was the Juvenile Arthritis Disease Activity Score, 71-joint count. However, results from the feasibility study showed that, owing to missing blood test data, the clinical Juvenile Arthritis Disease Activity Score should be used. The Juvenile Arthritis Disease Activity Score, 71-joint count, and the clinical Juvenile Arthritis Disease Activity Score are composite disease activity scoring systems for juvenile arthritis. Two final trial protocols were established for a future randomised controlled trial. LIMITATIONS Fewer clinics were included in this feasibility study than originally planned, limiting the ability to draw strong conclusions about these units to take part in future research. CONCLUSIONS A definitive randomised controlled trial is likely to be feasible based on the findings from this study; however, important recommendations should be taken into account when planning such a trial. FUTURE WORK This mixed-methods study has laid down the foundations to develop the evidence base in this area and conducting a randomised control trial to compare different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis is likely to be feasible. STUDY REGISTRATION Current Controlled Trials ISRCTN16649996. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 36. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Ashley P Jones
- Liverpool Clinical Trials Centre, University of Liverpool, a member of the Liverpool Health Partners, Liverpool, UK
| | - Dannii Clayton
- Liverpool Clinical Trials Centre, University of Liverpool, a member of the Liverpool Health Partners, Liverpool, UK
| | - Gloria Nkhoma
- Liverpool Clinical Trials Centre, University of Liverpool, a member of the Liverpool Health Partners, Liverpool, UK
| | | | - Matthew Peak
- Alder Hey Children's NHS Foundation Trust, a member of the Liverpool Health Partners, Liverpool, UK
| | | | - Louise Roper
- School of Psychology, University of Liverpool, Liverpool, UK
| | - Bridget Young
- School of Psychology, University of Liverpool, Liverpool, UK
| | - Flora McErlane
- Paediatric Rheumatology, Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK
| | - Tracy Moitt
- Liverpool Clinical Trials Centre, University of Liverpool, a member of the Liverpool Health Partners, Liverpool, UK
| | - Athimalaipet V Ramanan
- Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Helen E Foster
- Paediatric Rheumatology, Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK
| | - Paula R Williamson
- Liverpool Clinical Trials Centre, University of Liverpool, a member of the Liverpool Health Partners, Liverpool, UK
| | - Samundeeswari Deepak
- Paediatric Rheumatology, Nottingham Children's Hospital, Queen's Medical Centre, Nottingham, UK
| | - Michael W Beresford
- Faculty of Health and Life Science, University of Liverpool and Alder Hey Children's NHS Foundation Trust, members of Liverpool Health Partners, Liverpool, UK
| | - Eileen M Baildam
- Alder Hey Children's NHS Foundation Trust, a member of the Liverpool Health Partners, Liverpool, UK
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12
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Klein A, Minden K, Hospach A, Foeldvari I, Weller-Heinemann F, Trauzeddel R, Huppertz HI, Horneff G. Treat-to-target study for improved outcome in polyarticular juvenile idiopathic arthritis. Ann Rheum Dis 2020; 79:969-974. [PMID: 32299797 DOI: 10.1136/annrheumdis-2019-216843] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 03/07/2020] [Accepted: 03/15/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Juvenile idiopathic arthritis is one of the most prevalent chronic inflammatory diseases in children. Evidence suggests that early effective treatment minimises the burden of disease during childhood and in further life. We hypothesise that a guided treat-to-target (T2T) approach is superior to routine care in polyarticular juvenile idiopathic arthritis (pJIA) in terms of reaching a clinical remission after 12 months of treatment. METHODS Patients with early and active pJIA were enrolled. Targets for treatment were the following: Recognisable Juvenile Arthritis Disease Activity Score (JADAS) improvement after 3 months, acceptable disease at 6 months, minimal disease activity at 9 months and as primary endpoint remission after 12 months. Initially, patients received methotrexate. Failure to meet a defined target required treatment modification at the specified intervals. The choice of biologics was not influenced by the protocol. Finally, T2T patients were compared with a cohort of matched controls of patients with pJIA with unguided therapy documented by BIKER. RESULTS Sixty-three patients were enrolled. Treatment targets after 3/6/9 and 12 months were reached by 73%/75%/77% and 48% of patients. Fifty-four patients completed the protocol. Compared with matched controls, on T2T guidance significantly more patients reached JADAS remission (48% vs 32%; OR 1.96 (1.1-3.7); p=0.033) and JADAS minimal disease activity (JADAS-MDA) (76% vs 59%; OR 2.2 (1.1-4.4); p=0.028). Patients from the T2T cohort received a biologic significantly more frequent (50% vs 9% after 12 months; OR 9.8 (4.6-20.8); p<0.0001). CONCLUSION The T2T concept was feasible and superior to unguided treatment. High rates of patients reached JADAS-MDA and JADA remission after 12 months. Approximately half of the patients achieved their therapy goals without a biologic.
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Affiliation(s)
- Ariane Klein
- Department of Pediatrics, Asklepios Kinderklinik Sankt Augustin, Sankt Augustin, Germany
- Department of Pediatric and Adolescents Medicine, Medical Faculty, Medical faculty, University Hospital of Cologne, Cologne, Germany
| | - Kirsten Minden
- Klinik für Innere Medizin mit SP Rheumatologie und Immunologie, Charité Universitätsmedizin Berlin, Berlin, Germany
- Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany
| | - Anton Hospach
- Paediatrics, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany
| | - Ivan Foeldvari
- Klinikum Eilbek, Hamburger Zentrum für Kinder- und Jugendrheumatologie, Hamburg, Germany
| | | | | | | | - Gerd Horneff
- Department of Pediatrics, Asklepios Kinderklinik Sankt Augustin, Sankt Augustin, Germany
- Department of Pediatric and Adolescents Medicine, Medical Faculty, Medical faculty, University Hospital of Cologne, Cologne, Germany
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13
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Halyabar O, Mehta J, Ringold S, Rumsey DG, Horton DB. Treatment Withdrawal Following Remission in Juvenile Idiopathic Arthritis: A Systematic Review of the Literature. Paediatr Drugs 2019; 21:469-492. [PMID: 31673960 PMCID: PMC7301222 DOI: 10.1007/s40272-019-00362-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Early diagnosis and treatment of juvenile idiopathic arthritis (JIA) with conventional and biologic disease-modifying anti-rheumatic drugs have vastly improved outcomes for children with these diseases. Currently, a large proportion of children with JIA are able to achieve clinical inactive disease and remission. With this success, important questions have arisen about when medications can be stopped and how to balance the risks and benefits of continuing medications versus the potential for flare after stopping. AIM The aim was to conduct a systematic review of the available literature to summarize current evidence about medication withdrawal for JIA in remission. METHODS We conducted a systematic literature search in PubMed and Embase from 1990 to 2019. References were first screened by title and then independently screened by title and abstract by two authors. A total of 77 original papers were selected for full-text review. Data were extracted from 30 papers on JIA and JIA-associated uveitis, and the quality of the evidence was evaluated using National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) tools. Studies on biochemical and radiologic biomarkers were also reviewed and summarized. RESULTS Most studies investigating treatment withdrawal in JIA have been observational and of poor or fair quality; interpretations of these studies have been limited by differences in study populations, disease and remission durations, the medications withdrawn, approaches to withdrawal, and definitions of disease outcomes. Overall the data suggest that flares are common after stopping JIA medications, particularly biologic medications. Clinical characteristics associated with increased risks of flare have not been consistently identified. Biochemical biomarkers and ultrasound findings have been shown to predict outcomes after stopping medications, but to date, no such predictor has been consistently validated across JIA populations. Studies have also not identified optimal strategies for withdrawing medication for well-controlled JIA. Promising withdrawal strategies include discontinuing methotrexate before biologic medications in children receiving combination therapy, dose reduction for children on biologics, and treat-to-target approaches to withdrawal. These and other strategies require further investigation in larger, high-quality studies. CONCLUSIONS The published literature on treatment withdrawal in JIA has varied in design and quality, yielding little conclusive evidence thus far on the management of JIA in remission. Given the importance of this question, international collaborative efforts are underway to study clinical and biologic predictors of successful medication withdrawal in JIA. These efforts may ultimately support the development of personalized approaches to withdrawing medication in children with JIA in remission.
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Affiliation(s)
- Olha Halyabar
- Department of Pediatrics, Boston Children’s
Hospital, Boston, Massachusetts, USA
| | - Jay Mehta
- Department of Pediatrics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Sarah Ringold
- Department of Pediatrics, Seattle Children’s
Hospital, Seattle, Washington, USA
| | - Dax G. Rumsey
- Department of Pediatrics, University of Alberta, Edmonton,
Alberta, Canada
| | - Daniel B. Horton
- Department of Pediatrics, Rutgers Robert Wood Johnson
Medical School, New Brunswick, NJ, USA,Rutgers Center for Pharmacoepidemiology and Treatment
Science, Institute for Health, Health Care Policy and Aging Research, New Brunswick,
NJ, USA,Department of Biostatistics and Epidemiology, Rutgers
School of Public Health, Piscataway, NJ, USA
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14
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Predicting disease outcomes in juvenile idiopathic arthritis: challenges, evidence, and new directions. THE LANCET CHILD & ADOLESCENT HEALTH 2019; 3:725-733. [PMID: 31331873 DOI: 10.1016/s2352-4642(19)30188-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/18/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Abstract
The aims of treating juvenile idiopathic arthritis are to elicit treatment response toward remission, while preventing future flares. Understanding patient and disease characteristics that predispose young people with this condition to these outcomes would allow the forecasting of disease process and the tailoring of therapies. The strongest predictor of remission is disease category, particularly oligoarthritis, although a few additional clinical predictors of treatment response have been identified. Novel evidence using biomarkers, such as S100 proteins and novel single nucleotide polymorphism data, could add value to clinical models. The future aim of personalised medicine in the treatment of juvenile idiopathic arthritis will be aided with international collaborations, allowing for the analysis of larger datasets with novel biomarker data. Combined clinical and biomarker panels will probably be required for predicting outcomes in such a complex disease.
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15
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Patwardhan A. The Utility and Experience with Disease Biomarkers in Juvenile Onset Arthritis vs. Adult Onset Arthritis. Cureus 2019; 11:e5131. [PMID: 31341750 PMCID: PMC6649876 DOI: 10.7759/cureus.5131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Juvenile idiopathic arthritis (JIA) is the most common but extremely heterogeneous group of rheumatic diseases of childhood. There are no reliable, well-researched and published biomarkers for diagnosis or monitoring in juvenile idiopathic arthritis as there are for rheumatoid arthritis (RA) in adults. Biomarkers are not utilized in classifying JIA as they are in adult RA, making the JIA classifications less clinically effective and informative. The situation presents a lost opportunity for early aggressive therapy in JIA patients. Various researchers have used diverse biomarkers anecdotally in JIA and more systematically in RA patients and have drawn inferences on their utility from their experiences. The experience with biomarkers from RA patients cannot necessarily be extrapolated for JIA patients because they are dissimilar diseases. This article reconnoiters the comparative utility of various arthritis biomarkers in adult as well as in JIA patients. In contrast to RA, JIA is in itself a diverse group of arthritis with clinically overlapping subgroups with diverse etiology. The difference in the etiopathogenesis of arthritis subgroups demands identifying subgroup-specific biomarkers for diagnosis/monitoring and subgroup-specific therapies for management. The diagnostic/prognostic value of the individual biomarker could be different in different types of arthritis and in different types of hosts. Understanding the utility of individual biomarkers and careful selection of the assay are important to achieve the best disease outcomes.
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16
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Diener C, Horneff G. Comparison of adverse events of biologicals for treatment of juvenile idiopathic arthritis: a systematic review. Expert Opin Drug Saf 2019; 18:719-732. [PMID: 31204508 DOI: 10.1080/14740338.2019.1632288] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Objectives: Treatment of juvenile idiopathic arthritis has changed rapidly since the introduction of various biologics almost twenty years ago. Many clinical trials have been performed to monitor efficacy and safety of new agents. The aim of this review is to summarize safety concerns, which were observed during prospective clinical trials. Methods: Since etanercept was the first biologic approved and remains the most frequently used, as first biologic in polyarticular JIA patients, the authors calculated the relative risk of the adverse events for all examined biologicals and compared the values with the value of etanercept. Results: Relative rates for all adverse events showed similar rates for etanercept, infliximab, golimumab, and tocilizumab, whereas adalimumab showed higher rates and abatacept lower rates. Comparison of rates for serious adverse events demonstrated, that rates seemed comparable for etanercept, adalimumab, infliximab, and tocilizumab. Again, abatacept showed a lower rate, whereas golimumab seems to have a higher relative risk for serious adverse events. Rate of infection was lowest in patients treated with abatacept or tocilizumab, patients treated with etanercept, adalimumab and Infliximab again had similar rates. Conclusion: The safety profiles of actually approved biologics are highly acceptable. However, further observation, especially long-term observation through registry studies, is required.
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Affiliation(s)
- C Diener
- a Department of General Paediatrics, Asklepios Klinik Sankt Augustin , Sankt Augustin , Germany
| | - G Horneff
- a Department of General Paediatrics, Asklepios Klinik Sankt Augustin , Sankt Augustin , Germany.,b Department of Paediatric and Adolescents Medicine, Medical Faculty, University Hospital of Cologne , Cologne , Germany
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17
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Hoeppli RE, Pesenacker AM. Targeting Tregs in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis-Insights From Other Diseases. Front Immunol 2019; 10:46. [PMID: 30740105 PMCID: PMC6355674 DOI: 10.3389/fimmu.2019.00046] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/09/2019] [Indexed: 12/22/2022] Open
Abstract
Regulatory T cells (Tregs) are believed to be dysfunctional in autoimmunity. Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) result from a loss of normal immune regulation in specific tissues such as joints or muscle and skin, respectively. Here, we discuss recent findings in regard to Treg biology in oligo-/polyarticular JIA and JDM, as well as what we can learn about Treg-related disease mechanism, treatment and biomarkers in JIA/JDM from studies of other diseases. We explore the potential use of Treg immunoregulatory markers and gene signatures as biomarkers for disease course and/or treatment success. Further, we discuss how Tregs are affected by several treatment strategies already employed in the therapy of JIA and JDM and by alternative immunotherapies such as anti-cytokine or co-receptor targeting. Finally, we review recent successes in using Tregs as a treatment target with low-dose IL-2 or cellular immunotherapy. Thus, this mini review will highlight our current understanding and identify open questions in regard to Treg biology, and how recent findings may advance biomarkers and new therapies for JIA and JDM.
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Affiliation(s)
- Romy E Hoeppli
- Department of Surgery, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Anne M Pesenacker
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
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18
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Lovell DJ, Johnson AL, Huang B, Gottlieb BS, Morris PW, Kimura Y, Onel K, Li SC, Grom AA, Taylor J, Brunner HI, Huggins JL, Nocton JJ, Haines KA, Edelheit BS, Shishov M, Jung LK, Williams CB, Tesher MS, Costanzo DM, Zemel LS, Dare JA, Passo MH, Ede KC, Olson JC, Cassidy EA, Griffin TA, Wagner-Weiner L, Weiss JE, Vogler LB, Rouster-Stevens KA, Beukelman T, Cron RQ, Kietz D, Schikler K, Schmidt KM, Mehta J, Wahezi DM, Ting TV, Verbsky JW, Eberhard BA, Spalding S, Chen C, Giannini EH. Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease. Arthritis Rheumatol 2018; 70:1508-1518. [PMID: 29604189 DOI: 10.1002/art.40509] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 03/20/2018] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease. METHODS In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified.
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Affiliation(s)
- Daniel J Lovell
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Anne L Johnson
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Bin Huang
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Beth S Gottlieb
- The Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, New York
| | | | - Yukiko Kimura
- Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, New Jersey
| | - Karen Onel
- Hospital for Special Surgery, Weill Cornell Medicine, New York, New York
| | - Suzanne C Li
- Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, New Jersey
| | - Alexei A Grom
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Janalee Taylor
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | | | | | | | - Kathleen A Haines
- Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, New Jersey
| | | | | | | | | | - Melissa S Tesher
- University of Chicago, Comer Children's Hospital, Chicago, Illinois
| | - Denise M Costanzo
- The Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, New York
| | | | - Jason A Dare
- University of Arkansas for Medical Science, Little Rock
| | | | - Kaleo C Ede
- Phoenix Children's Hospital, Phoenix, Arizona
| | | | | | | | | | - Jennifer E Weiss
- Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, New Jersey
| | | | | | | | | | - Daniel Kietz
- Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | | | | | - Jay Mehta
- Children's Hospital at Montefiore, Bronx, New York
| | | | - Tracy V Ting
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | | | - B Anne Eberhard
- Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, New Jersey
| | | | - Chen Chen
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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19
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Long E, Foster HE, Hughes M, Wauchope E, McErlane F. 37. Time to Methotrexate or Etanercept Treatment in Children with Juvenile Idiopathic Arthritis: An Audit of Current Practice. Rheumatology (Oxford) 2017. [DOI: 10.1093/rheumatology/kex390.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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21
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Becker I, Horneff G. Risk of Serious Infection in Juvenile Idiopathic Arthritis Patients Associated With Tumor Necrosis Factor Inhibitors and Disease Activity in the German Biologics in Pediatric Rheumatology Registry. Arthritis Care Res (Hoboken) 2017; 69:552-560. [DOI: 10.1002/acr.22961] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 06/06/2016] [Accepted: 06/21/2016] [Indexed: 01/01/2023]
Affiliation(s)
| | - Gerd Horneff
- Asklepios Clinic Sankt AugustinSankt Augustin Germany
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22
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The challenge of trial design in paediatric rheumatology. Nat Rev Rheumatol 2016; 12:242. [DOI: 10.1038/nrrheum.2016.22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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23
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McErlane F, Foster HE, Carrasco R, Baildam EM, Chieng SEA, Davidson JE, Ioannou Y, Wedderburn LR, Thomson W, Hyrich KL. Trends in paediatric rheumatology referral times and disease activity indices over a ten-year period among children and young people with Juvenile Idiopathic Arthritis: results from the childhood arthritis prospective Study. Rheumatology (Oxford) 2016; 55:1225-34. [PMID: 27016664 PMCID: PMC4911538 DOI: 10.1093/rheumatology/kew021] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Indexed: 11/28/2022] Open
Abstract
Objectives. The medical management of JIA has advanced significantly over the past 10 years. It is not known whether these changes have impacted on outcomes. The aim of this analysis was to identify and describe trends in referral times, treatment times and 1-year outcomes over a 10-year period among children with JIA enrolled in the Childhood Arthritis Prospective Study. Methods. The Childhood Arthritis Prospective Study is a prospective inception cohort of children with new-onset inflammatory arthritis. Analysis included all children recruited in 2001–11 with at least 1 year of follow-up, divided into four groups by year of diagnosis. Median referral time, baseline disease pattern (oligoarticular, polyarticular or systemic onset) and time to first definitive treatment were compared between groups. Where possible, clinical juvenile arthritis disease activity score (cJADAS) cut-offs were applied at 1 year. Results. One thousand and sixty-six children were included in the analysis. The median time from symptom onset and referral to first paediatric rheumatology appointment (22.7–24.7 and 3.4–4.7 weeks, respectively) did not vary significantly (∼20% seen within 10 weeks of onset and ∼50% within 4 weeks of referral). For oligoarticular and polyarticular disease, 33.8–47 and 25.4–34.9%, respectively, achieved inactive disease by 1 year, with ∼30% in high disease activity at 1 year. A positive trend towards earlier definitive treatment reached significance in oligoarticular and polyarticular pattern disease. Conclusion. Children with new-onset JIA have a persistent delay in access to paediatric rheumatology care, with one-third in high disease activity at 1 year and no significant improvement over the past 10 years. Contributing factors may include service pressures and poor awareness. Further research is necessary to gain a better understanding and improve important clinical outcomes.
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Affiliation(s)
- Flora McErlane
- Paediatric Rheumatology, Great North Children's Hospital, Newcastle Hospitals NHS Foundation Trust
| | - Helen E Foster
- Paediatric Rheumatology, Great North Children's Hospital, Newcastle Hospitals NHS Foundation Trust, Rheumatology, Institute Cellular Medicine, Newcastle University, Newcastle upon Tyne
| | - Roberto Carrasco
- Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester
| | - Eileen M Baildam
- Paediatric Rheumatology, Alder Hey Children's Hospital, Liverpool
| | | | - Joyce E Davidson
- Paediatric Rheumatology, Royal Hospital for Children, Glasgow, Paediatric Rheumatology, Royal Hospital for Sick Children, Edinburgh
| | - Yiannis Ioannou
- Arthritis Research UK Centre for Adolescent Rheumatology, Division of Medicine, University College London (UCL)
| | - Lucy R Wedderburn
- Infection, Inflammation and Rheumatology Section, and Arthritis Research UK Centre for Adolescent Rheumatology, UCL Institute of Child Health, London
| | - Wendy Thomson
- Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester, Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute for Inflammation and Repair Faculty of Medical and Human Sciences, University of Manchester, and
| | - Kimme L Hyrich
- Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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Horneff G. Safety of biologic therapies for the treatment of juvenile idiopathic arthritis. Expert Opin Drug Saf 2016; 14:1111-26. [PMID: 26084637 DOI: 10.1517/14740338.2015.1042453] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION The introduction of biological therapies opened a new era of treatment of juvenile idiopathic arthritis. After 15 years of experience with the first biologics for treatment of pediatric rheumatic disease, long-term safety effects are of great interest. AREAS COVERED This review summarizes published knowledge about safety aspects from clinical trials as well as from biologic registries in juvenile idiopathic arthritis patients. Beside infusion and injection reactions, the occurrence and aggravation of infections, the occurrence of a second autoimmune diseases, including uveitis, psoriasis, chronic inflammatory bowel disease, multiple sclerosis, diabetes mellitus, as well as cytopenias and the development of malignancies are major concerns regarding treatment with biologics. EXPERT OPINION The safety profiles of approved biologics, the TNF-α inhibitors etanercept and adalimumab, and the IL-6-inhibitor tocilizumab are highly acceptable. This conclusion is not easily expandable to the IL-1 inhibitor canakinumab as well as the T-cell-activation-inhibitor abatacept due to lack of experience; however, both have showed an excellent safety profile so far. An increase in knowledge about risk profiles in national and international collaborations, with national as well as international registries, is necessary.
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Affiliation(s)
- Gerd Horneff
- Centre for Paediatric Rheumatology, Department of Paediatrics, Asklepios Clinic Sankt Augustin , Arnold-Janssen-Str. 29, 53757 Sankt Augustin , Germany +0049 2241 249 201 ; +0049 2241 249 203 ;
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Turnier JL, Brunner HI. Tocilizumab for treating juvenile idiopathic arthritis. Expert Opin Biol Ther 2016; 16:559-66. [DOI: 10.1517/14712598.2016.1150997] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Hügle B, Horneff G. The role of synthetic drugs in the biologic era: therapeutic strategies for treating juvenile idiopathic arthritis. Expert Opin Pharmacother 2016; 17:703-14. [PMID: 26678914 DOI: 10.1517/14656566.2016.1133592] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Juvenile idiopathic arthritis is the most frequent chronic rheumatic disease in childhood. Synthetic disease modifying drugs (DMARDs) have been used in its treatment since the 1980s and have led to substantial improvement of quality of life and disease outcome. Recent pharmacological research has focused on newer medications, especially biologic agents. AREAS COVERED Synthetic DMARDS, especially methotrexate, rightfully remain the first-line treatment of most categories of juvenile arthritis, as attested by several international guidelines. A substantial body of evidence supports these medications, and recent research tries to clarify their optimal use in the clinical setting, both as monotherapy and in combination with biologics. In addition, new forms of synthetic DMARDs are in the research pipeline, or are already used for rheumatoid arthritis. EXPERT OPINION Methotrexate remains the preferred first-line medication for polyarticular arthritis, with leflunomide as a viable alternative in case of intolerance or toxicity, despite lack of approval in Europe and the US. Sulfasalazine and hydroxychloroquine are used only rarely in clinical practice, considered in combination with methotrexate if biologics are not available. New synthetic DMARDS are in the research pipeline for JIA, in the form of small molecules.
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Affiliation(s)
- Boris Hügle
- a German Center for Pediatric Rheumatology , Garmisch-Partenkirchen , Germany
| | - Gerd Horneff
- b Department of Pediatrics , Asklepios Clinic Sankt Augustin , Sankt Augustin , Germany
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Funk RS, Becker ML. Disease modifying anti-rheumatic drugs in juvenile idiopathic arthritis: striving for individualized therapy. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2016. [DOI: 10.1080/23808993.2016.1133234] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Berard RA, Laxer RM. Early aggressive therapy for patients with juvenile idiopathic arthritis: are we there yet? J Rheumatol 2015; 41:2343-6. [PMID: 25452178 DOI: 10.3899/jrheum.141051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Roberta A Berard
- Pediatric Rheumatologist, Children's Hospital, London Health Sciences Centre; Assistant Professor of Pediatrics, Western University
| | - Ronald M Laxer
- Professor of Pediatrics and Medicine, University of Toronto, Staff Rheumatologist, The Hospital for Sick Children, Toronto, Ontario, Canada.
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Yun D, Stein SL. Review of the cutaneous manifestations of autoimmune connective tissue diseases in pediatric patients. World J Dermatol 2015; 4:80-94. [DOI: 10.5314/wjd.v4.i2.80] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 02/25/2015] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
Autoimmune connective tissue diseases are chronic inflammatory disorders associated with complex genetic and environmental interplay resulting in a variety of cutaneous and systemic manifestations. Pediatric onset of these disorders carries a unique diagnostic pressure for the clinician due to the potential years of disease burden and complications. Mortality and morbidity from these disorders has fallen dramatically over the past fifty years due to increasing awareness of these disease sequelae and utilization of systemic treatment modalities when necessary. This review highlights the clinical features that are unique to pediatric presentations of lupus erythematosus, juvenile idiopathic arthritis, juvenile dermatomyositis, juvenile onset systemic sclerosis and morphea. Each of these disorders has a distinct appearance corresponding to a particular cutaneous and systemic clinical course and prognosis. Awareness of the associated potential systemic complications can also alert the clinician to make astute management decisions when confronted with a probable rheumatologic case. Cutaneous symptoms may predate onset of systemic symptoms and by keeping the rheumatologic differential diagnoses in mind, the dermatologist can play a key role in potentially offsetting autoimmune disease burden in children.
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