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Tarbell E, Jarvis JN. Using genetics, genomics, and transcriptomics to identify therapeutic targets in juvenile idiopathic arthritis. HGG ADVANCES 2025; 6:100424. [PMID: 40083163 PMCID: PMC11994403 DOI: 10.1016/j.xhgg.2025.100424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 03/10/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025] Open
Abstract
Despite progress in improving outcomes for oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), the field still faces considerable challenges. More than half of adults who have had JIA continue to have active disease and have developed functional limitations. Medication side effects are common and intrusive. Thus, the field continues to search for therapeutic agents that target specific aspects of disease pathobiology and will be accompanied by fewer and less intrusive side effects. We identified 28 candidate target genes that were associated with JIA according to Open Targets Genetics and were also differentially expressed in the CD4+ T cells of children with active JIA (when compared to healthy control subjects). Of the 28 candidates, the strongest new target to emerge was homeodomain-interacting protein kinase 1 (HIPK1), which suppresses T cell activation and is within the PTPN22 locus tagged by rs6679677. This locus includes an enhancer element that contacts the HIPK1 promoter, and HIPK1 shows decreased expression in JIA CD4+ T cells when compared to controls. Gene Ontology terms associated with HIPK1 were overrepresented among the differentially expressed genes between JIA and controls, and PML, a known coregulator of HIPK1, showed a similar suppressed gene expression profile. Two downstream transcription factors of HIPK1, TP53 and GATA4, showed enriched binding patterns near the promoters of JIA up-regulated genes. Taken together, these data suggest a pathogenic role for HIPK1 in JIA and make it a prime candidate for therapeutic modulation.
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Affiliation(s)
- Evan Tarbell
- Enhanced Pharmacodynamics, LLC, Buffalo, NY, USA.
| | - James N Jarvis
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
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Attrill MH, Shinko D, Viveiros TM, Milighetti M, de Gruijter NM, Jebson B, Kartawinata M, Rosser EC, Wedderburn LR, Pesenacker AM. Treg fitness signatures as a biomarker for disease activity in Juvenile Idiopathic Arthritis. J Autoimmun 2025; 152:103379. [PMID: 39954509 DOI: 10.1016/j.jaut.2025.103379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/06/2025] [Accepted: 02/01/2025] [Indexed: 02/17/2025]
Abstract
Juvenile Idiopathic Arthritis (JIA) is an autoimmune condition characterised by flares of joint inflammation. However, no reliable biomarker exists to predict the erratic disease course. Normally, regulatory T cells (Tregs) maintain tolerance, with altered Tregs associated with autoimmunity. Treg signatures have shown promise in monitoring other conditions, therefore a Treg gene/protein signature could offer novel biomarker potential for predicting disease activity in JIA. Machine learning on our nanoString Treg 48-gene signature on peripheral blood (PB) Tregs generated a model to distinguish active JIA (active joint count, AJC≥1) Tregs from healthy controls (HC, AUC = 0.9875 on test data). Biomarker scores from this model successfully differentiated inactive (AJC = 0) from active JIA PB Tregs. Moreover, scores correlated with clinical activity scores (cJADAS), and discriminated subclinical disease (AJC = 0, cJADAS≥0.5) from remission (cJADAS<0.5). To investigate altered protein expression as a surrogate measure for Treg fitness in JIA, we utilised spectral flow cytometry and unbiased clustering analysis. Three Treg clusters were of interest in active JIA PB, including TIGIThighCD226highCD25low Teff-like Tregs, CD39-TNFR2-Helioshigh, and a 4-1BBlowTIGITlowID2intermediate Treg cluster predominated in inactive JIA PB (AJC = 0). The ratio of these Treg clusters correlated to cJADAS, and higher ratios could potentially predict inactive individuals that flared by 9-month follow-up. Thus, we demonstrate altered Treg signatures and subsets as an important factor, and useful biomarker, for disease progression versus remission in JIA, revealing genes and proteins contributing to Treg fitness. Ultimately, PB Treg fitness measures could serve as routine biomarkers to guide disease and treatment management to sustain remission in JIA.
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Affiliation(s)
- Meryl H Attrill
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, London, NW3 2PP, UK; Infection, Immunity & Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, UCL, London, WC1N 1EH, UK
| | - Diana Shinko
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, London, NW3 2PP, UK
| | - Telma Martins Viveiros
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, London, NW3 2PP, UK
| | - Martina Milighetti
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, London, NW3 2PP, UK; Cancer Institute, UCL, London, WC1E 6DD, UK
| | - Nina M de Gruijter
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, London, WC1E 6JF, UK; Division of Medicine, UCL, London, WC1E 6JF, UK
| | - Bethany Jebson
- Infection, Immunity & Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, UCL, London, WC1N 1EH, UK; Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, London, WC1E 6JF, UK
| | - Melissa Kartawinata
- Infection, Immunity & Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, UCL, London, WC1N 1EH, UK; Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, London, WC1E 6JF, UK
| | - Elizabeth C Rosser
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, London, WC1E 6JF, UK; Division of Medicine, UCL, London, WC1E 6JF, UK
| | - Lucy R Wedderburn
- Infection, Immunity & Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, UCL, London, WC1N 1EH, UK; Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, London, WC1E 6JF, UK; NIHR Biomedical Research Centre at GOSH, London, WC1N 1EH, UK
| | - Anne M Pesenacker
- Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, London, NW3 2PP, UK.
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Hamdi W, Migowa A, Ferjani HL, Makhloufi CD, Makhlouf Y, Nasef SI, Ziade N, Baraliakos X, Brunner H, Hassan M, Libe T, Palalane E, Hassan W, Sobh A, Seri A, Mosad D, Lishan H, Taha Y, Gacem O, Hashed S, Furia FF, Slimani S, Scott C, Hadef D. Pediatric Society of the African League Against Rheumatism juvenile idiopathic arthritis recommendations for enthesitis-related arthritis and juvenile psoriatic arthritis. Clin Rheumatol 2025; 44:901-922. [PMID: 39893309 DOI: 10.1007/s10067-025-07334-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/07/2025] [Accepted: 01/11/2025] [Indexed: 02/04/2025]
Abstract
The objective of this study is to develop evidence-based recommendations for the diagnosis and management of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) in the African context. The recommendations for ERA and JPsA were combined into a single document. The steering committee and task force identified 15 key questions and formulated 35 research questions. A comprehensive literature review, utilizing Medline and a manual search for African local data, was conducted to gather evidence. Following this synthesis, the task force developed draft recommendations and engaged in a Delphi process with an expert panel, including 17 African and three international experts, to reach a consensus and ensure alignment with global standards. The final recommendations were assigned a level of evidence and subsequently approved by the task force members, the expert panel, and the PAFLAR Board. Fifteen recommendations on the diagnosis and management of ERA and JPsA were developed, covering the role of the pediatric rheumatologist in multiple aspects of disease management, including diagnosis, monitoring of disease and extra-articular manifestations, determining treatment strategies, and guiding interventions. The level of evidence supporting these recommendations was variable, leading to the identification of a research agenda to address African particularities and answer pending questions. The final recommendations achieved a high level of agreement, with consensus ranging from 90 to 100%. These recommendations represent an important achievement for pediatric rheumatology in Africa, being the first of their kind, tailored specifically to the region. Developed through a rigorous methodology and collaboration between international and African experts, they aim to standardize care and address the unique challenges faced in African setting.
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Affiliation(s)
- Wafa Hamdi
- Department of Rheumatology, Faculty of Medicine of Tunis, Kassab Institute, Tunis El Manar University, UR17SP04, Tunis, Tunisia.
| | - Angela Migowa
- Department of Pediatrics, Aga Khan University Medical College East Africa, Nairobi, P.O. Box 30270, Nairobi, 00100, Kenya
| | - Hanene Lassoued Ferjani
- Department of Rheumatology, Faculty of Medicine of Tunis, Kassab Institute, Tunis El Manar University, UR17SP04, Tunis, Tunisia
| | - Chafia Dahou Makhloufi
- Department of Rheumatology, Faculty of Medicine of Algiers, Med Lamine Debaghine University Hospital, Bab El Oued, BD Said Touati, Algiers, Algeria
| | - Yasmine Makhlouf
- Department of Rheumatology, Tunis El Manar University Faculty of Medicine of Tunis, Mongi Slim Hospital, Tunis, Tunisia
| | - Samah Ismail Nasef
- Department of Rheumatology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Nelly Ziade
- Rheumatology Department, Saint Joseph University and Hotel-Dieu De France, Beirut, Lebanon
| | | | - Hermine Brunner
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Mohammed Hassan
- Rheumatology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Temesgen Libe
- College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | | | - Waleed Hassan
- Rheumatology and Rehabilitation Department, Benha University, Banha, Egypt
| | - Ali Sobh
- Department of Pediatrics, Mansoura University Children's Hospital, Mansoura University Faculty of Medicine, Mansoura, Egypt
| | - Ahmed Seri
- Clinical Immunology and Allergy Center, Royal Care International Hospital, Khartoum, Sudan
- Clinical Immunology and Allergy Department, Soba University Hospital, Al Khurtum, Sudan
| | - Doaa Mosad
- Department of Rheumatology and Rehabilitation, Mansoura University Hospitals, Mansoura University Faculty of Medicine, Mansoura, Egypt
| | - Hanna Lishan
- Rheumatology Unit, Department of Pediatrics and Child Health, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Yassmin Taha
- Pediatric Rheumatology Unit, Ahmed Gasim Children Hospital, Khartoum, Sudan
| | - Ourida Gacem
- Algiers Faculty of Medicine, Department of Pediatrics, El Biar Hospital Algiers, Algiers, Algeria
| | - Soad Hashed
- Tripoli Children's Hospital, University of Tripoli, Tripoli, Libya
| | - Francis Fredrick Furia
- School of Clinical Medicine, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania
| | | | - Christiaan Scott
- Pediatric Rheumatology, University of Ottawa, Ottawa, Ontario, Canada
- University of Cape Town, Cape Town, South Africa
| | - Djohra Hadef
- Department of Pediatrics, University Hospital Center of Batna Faculty of Medicine, Batna 2 University, Batna, Algeria
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Oshima A, Ebato T, Kaneko M, Shikama Y, Imagawa T. Clinical remission rate and drug withdrawal status in articular juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2025; 23:21. [PMID: 39994731 PMCID: PMC11853753 DOI: 10.1186/s12969-025-01075-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/16/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND The clinical remission rate of articular juvenile idiopathic arthritis (JIA) differs according to the disease categories. At present, there is no consensus regarding drug withdrawal after remission is achieved. OBJECTIVES To clarify the clinical remission rate and drug withdrawal status of patients with juvenile idiopathic arthritis (JIA). METHODS We conducted a retrospective observational study in patients who developed articular JIA by 2017 and were followed up (2013-2022). The Wallace criteria were used as remission criteria. RESULTS Forty-nine patients were included, i.e., 16 (33%) with polyarticular JIA (PJIA) and 33 (67%) with oligoarticular JIA (OJIA). Rheumatoid factor-positive (RF +) PJIA had significantly higher biological disease-modifying antirheumatic drug (bDMARD) introduction rates (86%, p < 0.01). The rate of clinical remission off medication was significantly higher in OJIA (67%). Numerous cases of RF + PJIA (50%), RF-negative (RF -) PJIA (25%), and OJIA (30%) flared within 2 years after conventional synthetic disease-modifying antirheumatic drug withdrawal. Patients with RF - PJIA and OJIA (two cases each) discontinued bDMARDs. Both RF - PJIA cases (100%) and half of OJIA cases (50%) flared within 2 years after bDMARD withdrawal. In one case of OJIA, remission was maintained after withdrawal of all drugs. CONCLUSIONS OJIA had the highest rate of clinical remission off medication (67%) versus others. In OJIA, it was possible to discontinue all drugs in some patients with OJIA receiving bDMARDs. In PJIA requiring bDMARDs, withdrawal of bDMARDs was difficult all two cases.
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Affiliation(s)
- Akira Oshima
- Department of Infectious Disease & Immunology, Kanagawa Children's Medical Center, Yokohama, 232-8555, Japan.
| | - Takasuke Ebato
- Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, 252-0375, Japan
| | - Masanori Kaneko
- Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, 252-0375, Japan
| | - Yoshiaki Shikama
- Department of Infectious Disease & Immunology, Kanagawa Children's Medical Center, Yokohama, 232-8555, Japan
| | - Tomoyuki Imagawa
- Department of Infectious Disease & Immunology, Kanagawa Children's Medical Center, Yokohama, 232-8555, Japan
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Ebato T, Kishi T, Akamine K, Nozawa T, Imagawa T, Bando Y, Miyamae T. Evaluation of medication withdrawal in patients with non-systemic juvenile idiopathic arthritis in Japan using a web-based survey. Mod Rheumatol 2024; 34:1231-1237. [PMID: 38441307 DOI: 10.1093/mr/roae016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/15/2024] [Indexed: 10/17/2024]
Abstract
OBJECTIVES Although treatments for juvenile idiopathic arthritis (JIA) have seen considerable advancements, there remains a lack of clear guidelines on withdrawing medications. This study aimed to investigate the current strategies for discontinuing non-systemic JIA treatment. METHODS A web-based questionnaire was distributed to members of the Pediatric Rheumatology Association of Japan. RESULTS According to 126 responses, the most significant factors influencing JIA treatment tapering were the duration of clinically inactive disease, medication toxicity, and a history of arthritis flares. Respondents were often cautious about discontinuing medication if symptoms, e.g. 'morning stiffness' or 'intermittent joint pain', persisted. Among subtypes, oligoarticular JIA was more amenable to treatment tapering, whereas rheumatoid factor-positive polyarticular JIA proved less amenable. Most respondents started medication tapering after a continuous clinical inactive duration exceeding 12 months, and >50% of them required >6 months to achieve treatment discontinuation. Additionally, 40% of the respondents consistently underwent imaging before treatment tapering. CONCLUSIONS The relative risks of treatment continuation and withdrawal should be considered, and decisions should be made accordingly. To obtain improved understanding of and more robust evidence for the optimal strategies for safely discontinuing JIA treatment, it is crucial to continue investigations including long-term outcomes.
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Affiliation(s)
- Takasuke Ebato
- Department of Pediatrics, Kitasato University, Kanagawa, Japan
| | - Takayuki Kishi
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Keiji Akamine
- Department of Nephrology and Rheumatology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Tomo Nozawa
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan
| | - Tomoyuki Imagawa
- Department of Infection and Immunology, Kanagawa Children's Medical Center, Kanagawa, Japan
| | - Yuki Bando
- Department of Pediatrics, Kitasato University Medical Center, Saitama, Japan
| | - Takako Miyamae
- Department of Pediatric Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
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Ren T, Guan JH, Li Y, Li NN, Li Z. Evolution of treatment options for juvenile idiopathic arthritis. World J Orthop 2024; 15:831-835. [PMID: 39318493 PMCID: PMC11417629 DOI: 10.5312/wjo.v15.i9.831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/27/2024] [Accepted: 08/19/2024] [Indexed: 09/12/2024] Open
Abstract
A recent study published in World J Clin Cases addressed the optimal non-steroidal anti-inflammatory drugs (NSAIDs) for juvenile idiopathic arthritis (JIA). Herein, we outline the progress in drug therapy of JIA. NSAIDs have traditionally been the primary treatment for all forms of JIA. NSAIDs are symptom-relief medications, and well tolerated by patients. Additionally, the availability of selective NSAIDs further lower the gastrointestinal adverse reactions compared with traditional NSAIDs. Glucocorticoid is another kind of symptom-relief medications with potent anti-inflammatory effect. However, the frequent adverse events limit the clinical use. Both NSAIDs and glucocorticoid fail to ease or prevent joint damage, and the breakthrough comes along with the disease-modifying antirheumatic drugs (DMARDs). DMARDs can prevent disease progression and reduce joint destruction. Particularly, the emergence of biologic DMARDs (bDMARDs) has truly revolutionized the therapeutics of JIA, compared with conventional synthetic DMARDs. As a newly developed class of drugs, the places of most bDMARDs in the management of JIA remain to be well established. Nevertheless, the continuous evolution of bDMARDs raises hopes of improving long-term disease outcomes for JIA.
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Affiliation(s)
- Tao Ren
- Department of Colorectal Surgery, Taihe County People’s Hospital of Anhui Province, Fuyang 236600, Anhui Province, China
| | - Jia-Hui Guan
- Department of Colorectal Surgery, Taihe County People’s Hospital of Anhui Province, Fuyang 236600, Anhui Province, China
| | - Yu Li
- Department of Pharmacy, Taihe County People’s Hospital of Anhui Province, Fuyang 236600, Anhui Province, China
| | - Nan-Nan Li
- University of Science and Technology of China, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Zheng Li
- Jiangsu Engineering Research Center of Cardiovascular Drugs Targeting Endothelial Cells, College of Health Sciences, School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, China
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Glerup M, Kessel C, Foell D, Berntson L, Fasth A, Myrup C, Nordal E, Rypdal V, Rygg M, Arnstad ED, Peltoniemi S, Aalto K, Schleifenbaum S, Høllsberg MN, Bilgrau AE, Herlin T. Inflammatory biomarkers predicting long-term remission and active disease in juvenile idiopathic arthritis: a population-based study of the Nordic JIA cohort. RMD Open 2024; 10:e004317. [PMID: 39242113 PMCID: PMC11381635 DOI: 10.1136/rmdopen-2024-004317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 08/20/2024] [Indexed: 09/09/2024] Open
Abstract
OBJECTIVES To assess the ability of baseline serum biomarkers to predict disease activity and remission status in juvenile idiopathic arthritis (JIA) at 18-year follow-up (FU) in a population-based setting. METHODS Clinical data and serum levels of inflammatory biomarkers were assessed in the longitudinal population-based Nordic JIA cohort study at baseline and at 18-year FU. A panel of 16 inflammatory biomarkers was determined by multiplexed bead array assay. We estimated both univariate and multivariate logistic regression models on binary outcomes of disease activity and remission with baseline variables as explanatory variables. RESULTS Out of 349 patients eligible for the Nordic JIA cohort study, 236 (68%) had available serum samples at baseline. We measured significantly higher serum levels of interleukin 1β (IL-1β), IL-6, IL-12p70, IL-13, MMP-3, S100A9 and S100A12 at baseline in patients with active disease at 18-year FU than in patients with inactive disease. Computing receiver operating characteristics illustrating the area under the curve (AUC), we compared a conventional prediction model (gender, age, joint counts, erythrocyte sedimentation rate, C reactive protein) with an extended model that also incorporated the 16 baseline biomarkers. Biomarker addition significantly improved the ability of the model to predict activity/inactivity at the 18-year FU, as evidenced by an increase in the AUC from 0.59 to 0.80 (p=0.02). Multiple regression analysis revealed that S100A9 was the strongest predictor of inactive disease 18 years after disease onset. CONCLUSION Biomarkers indicating inflammation at baseline have the potential to improve evaluation of disease activity and prediction of long-term outcomes.
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Affiliation(s)
- Mia Glerup
- Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Christoph Kessel
- Department of Paediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany
| | - Dirk Foell
- Department of Paediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany
| | - Lillemor Berntson
- Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
| | - Anders Fasth
- Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Charlotte Myrup
- Department of Paediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ellen Nordal
- Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway
- Department of Clinical Medicine, UiT–The Arctic University of Norway, Tromsø, Norway
| | - Veronika Rypdal
- Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway
- Department of Clinical Medicine, UiT–The Arctic University of Norway, Tromsø, Norway
| | - Marite Rygg
- Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pediatrics, St Olavs Hospital, Trondheim, Norway
| | - Ellen Dalen Arnstad
- Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway
- Department of Paediatrics, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Suvi Peltoniemi
- Clinic of Rheumatology, Helsinki University Hospital, Helsinki, Finland
| | - Kristiina Aalto
- Department of Paediatrics, New Children's Hospital, Helsinki University Hospital, Helsinki, Finland
- Paediatric Research Centre, University of Helsinki, Helsinki, Finland
| | - Susanne Schleifenbaum
- Department of Paediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany
| | - Malene Noer Høllsberg
- Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | - Troels Herlin
- Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Nordic Study Group of Paediatric Rheumatology (NoSPeR)
- Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Paediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany
- Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
- Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Paediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway
- Department of Clinical Medicine, UiT–The Arctic University of Norway, Tromsø, Norway
- Department of Clinical and Molecular Medicine, NTNU–Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pediatrics, St Olavs Hospital, Trondheim, Norway
- Department of Paediatrics, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
- Clinic of Rheumatology, Helsinki University Hospital, Helsinki, Finland
- Department of Paediatrics, New Children's Hospital, Helsinki University Hospital, Helsinki, Finland
- Paediatric Research Centre, University of Helsinki, Helsinki, Finland
- Department of Mathematical Sciences, Aalborg University, Aalborg, Denmark
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Ozen S, Aksentijevich I. The past 25 years in paediatric rheumatology: insights from monogenic diseases. Nat Rev Rheumatol 2024; 20:585-593. [PMID: 39112602 DOI: 10.1038/s41584-024-01145-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2024] [Indexed: 08/29/2024]
Abstract
The past 25 years have seen major novel developments in the field of paediatric rheumatology. The concept of autoinflammation was introduced to this field, and medicine more broadly, with studies of familial Mediterranean fever, the most common autoinflammatory disease globally. New data on the positive evolutionary selection of familial Mediterranean fever-associated genetic variants might be pertinent to mild gain-of-function variants reported in other disease-associated genes. Genetic studies have unveiled the complexity of human heritability to inflammation and flourishing data from rare monogenic disorders have contributed to a better understanding of general disease mechanisms in paediatric rheumatic conditions. Beyond genomics, the application of other 'omics' technologies, including transcriptomics, proteomics and metabolomics, has generated an enormous dataset that can be applied to the development of new therapies and in the practice of precision medicine. Novel biomarkers for monitoring disease activity and progression have also emerged. A surge in the development of targeted biologic therapies has led to durable remission and improved prognosis for many diseases that in the past caused major complications. Last but not least, the COVID-19 pandemic has affected paediatric rheumatology practice and has sparked new investigations into the link between viral infections and unregulated inflammatory responses in children.
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Affiliation(s)
- Seza Ozen
- Department of Paediatric Rheumatology, Hacettepe University, Ankara, Turkey.
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Wibrand C, Kyvsgaard N, Herlin T, Glerup M. Methotrexate Intolerance in Juvenile Idiopathic Arthritis: Definition, Risks, and Management. Paediatr Drugs 2024; 26:479-498. [PMID: 39044097 PMCID: PMC11335943 DOI: 10.1007/s40272-024-00643-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/19/2024] [Indexed: 07/25/2024]
Abstract
Juvenile idiopathic arthritis is the most common rheumatic disorder in childhood and adolescence posing a significant threat of short-term and long-term disability if left untreated. Methotrexate is a folic acid analog with various immunomodulatory properties. It has demonstrated significant efficacy for the treatment of juvenile idiopathic arthritis, often considered the preferred first-line disease-modifying anti-rheumatic drug given as monotherapy or in combination with biological drugs. Despite this, there is a considerable risk for treatment disruptions owing to the high prevalence of methotrexate intolerance, with symptoms such as nausea, stomach ache, vomiting, and behavioral symptoms. Many different risk factors for the intolerance have been proposed including gender, age, disease activity, treatment duration, dosing and administration, and genetic and psychological factors. As the studies have shown contradictory results, many questions are left unanswered. Therefore, a consensus regarding outcome measures and reporting is crucial. In this review, we describe the identification and assessment of methotrexate intolerance and evaluate potential risk factors, genetic associations as well as management strategies.
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Affiliation(s)
- Camilla Wibrand
- Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Nini Kyvsgaard
- Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Troels Herlin
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Institute of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark.
| | - Mia Glerup
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Institute of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
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10
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Oliveira Ramos F, Zinterl C, Fonseca JE. A lifelong journey: Long-term perspectives on Juvenile Idiopathic Arthritis. Best Pract Res Clin Rheumatol 2024; 38:101984. [PMID: 39068102 DOI: 10.1016/j.berh.2024.101984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
Juvenile Idiopathic Arthritis (JIA) represents a diverse group of chronic inflammatory conditions that begin in childhood or adolescence and continue into adulthood, with varying severity and outcomes. This review discusses the complexities of transitioning JIA patients emphasizing that inadequate transition from pediatric to adult care leads to loss of follow-up, treatment discontinuation, and increased disease activity. Furthermore, challenges in disease classification hinder continuity of care across lifespan. It is also pointed out that predicting long-term outcomes in JIA remains complex due to heterogeneity and evolving phenotypes. Factors such as disease category, joint involvement, and treatment influence disease activity, functional disability, and quality of life. Despite advancements in treatment strategies, a substantial proportion of patients experience long-term disability and joint damage. Finally, it is underscored that optimising long-term outcomes in adults with JIA requires a multifaceted approach encompassing structured transition processes, personalised treatment strategies, and comprehensive management of comorbidities. Further research is needed to refine predictive models, enhance disease monitoring tools, and understand the complex interplay between disease activity, treatment response, and long-term outcomes.
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Affiliation(s)
- Filipa Oliveira Ramos
- Unidade de Reumatologia Pediátrica, Hospital Universitário Santa Maria, ULS Santa Maria, Centro Académico de Medicina de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Portugal.
| | - Carolina Zinterl
- Unidade de Reumatologia Pediátrica, Hospital Universitário Santa Maria, ULS Santa Maria, Centro Académico de Medicina de Lisboa, Portugal
| | - João Eurico Fonseca
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Portugal; Serviço de Reumatologia, ULS Santa Maria, Centro Académico de Medicina de Lisboa, Portugal
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11
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Brunner HI, Schulert GS, Sproles A, Thornton S, Cornejo GV, Antón J, Cuttica R, Henrickson M, Foeldvari I, Kingsbury DJ, Askelson M, Liu J, Mukherjee S, Wong RL, Lovell DJ, Martini A, Ruperto N, Grom AA. S100 proteins as potential predictive biomarkers of abatacept response in polyarticular juvenile idiopathic arthritis. Arthritis Res Ther 2024; 26:125. [PMID: 38918871 PMCID: PMC11197242 DOI: 10.1186/s13075-024-03347-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 05/26/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. RESULTS At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. CONCLUSION Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
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Affiliation(s)
- Hermine I Brunner
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Grant S Schulert
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Alyssa Sproles
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Sherry Thornton
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | | | - Jordi Antón
- Pediatric Rheumatology Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain
| | - Ruben Cuttica
- Ruben Cuttica MD, Pediatric Rheumatology, Hospital General de Niños Pedro de Elizalde, Buenos Aires, Argentina
| | - Michael Henrickson
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ivan Foeldvari
- Hamburg Centre for Pediatric and Adolescent Rheumatology, Schön Klinik Hamburg Eilbek, Hamburg, Germany
| | - Daniel J Kingsbury
- Division of Rheumatology, Randall Children's Hospital at Legacy Emanuel, Portland, OR, USA
| | | | - Jinqi Liu
- Translational Medicine, Bristol Myers Squibb, Princeton, NJ, USA
| | | | - Robert L Wong
- Bristol Myers Squibb, Immunology and Fibrosis, Princeton, NJ, USA
| | - Daniel J Lovell
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Alberto Martini
- Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DiNOGMI), Università degli Studi di Genova, Genoa, Italy
| | - Nicolino Ruperto
- IRCCS Istituto Giannina Gaslini, Gaslini Trial Centre/Servizio di Sperimentazioni Cliniche Pediatriche, PRINTO, Genoa, Italy
| | - Alexei A Grom
- Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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12
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Tan J, Renton WD, Whittle SL, Takken T, Johnston RV, Tiller G, Munro J, Buchbinder R. Methotrexate for juvenile idiopathic arthritis. Cochrane Database Syst Rev 2024; 2:CD003129. [PMID: 38334147 PMCID: PMC10853975 DOI: 10.1002/14651858.cd003129.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2024]
Abstract
BACKGROUND Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used disease-modifying antirheumatic drug (DMARD). This is an update of a 2001 Cochrane review. It supports a living guideline for children and young people with JIA. OBJECTIVES To assess the benefits and harms of methotrexate for children and young people with juvenile idiopathic arthritis. SEARCH METHODS The Australian JIA Living Guideline Working Group created a registry of all randomised controlled trials (RCTs) of JIA by searching CENTRAL, MEDLINE, Embase, and trials registries. The date of the most recent search of online databases was 1 February 2023. SELECTION CRITERIA We searched for RCTs that compared methotrexate with placebo, no treatment, or another DMARD (with or without concomitant therapies) in children and young people (aged up to 18 years) with JIA. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. The main comparison was methotrexate versus placebo. Our outcomes were treatment response, sustained clinically inactive disease, function, pain, participant global assessment of well-being, serious adverse events, and withdrawals due to adverse events. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS We identified three new trials in this update, bringing the total number of included RCTs to five (575 participants). Three trials evaluated oral methotrexate versus placebo, one evaluated methotrexate plus intra-articular glucocorticoid (IAGC) therapy versus IAGC therapy alone, and one evaluated methotrexate versus leflunomide. Doses of methotrexate ranged from 5 mg/m2/week to 15 mg/m2/week in four trials, and participants in the methotrexate group of the remaining trial received 0.5 mg/kg/week. Trial size varied from 31 to 226 participants. The average age of participants ranged from four to 10 years. Most participants were females and most had nonsystemic JIA. The study that evaluated methotrexate plus IAGC therapy versus IAGC therapy alone recruited children and young people with the oligoarticular disease subtype of JIA. Two placebo-controlled trials and the trial of methotrexate versus leflunomide were adequately randomised and blinded, and likely not susceptible to important biases. One placebo-controlled trial may have been susceptible to selection bias due to lack of adequate reporting of randomisation methods. The trial investigating the addition of methotrexate to IAGC therapy was susceptible to performance and detection biases. Methotrexate versus placebo Methotrexate compared with placebo may increase the number of children and young people who achieve treatment response up to six months (absolute difference of 163 more per 1000 people; risk ratio (RR) 1.67, 95% confidence interval (CI) 1.21 to 2.31; I2 = 0%; 3 trials, 328 participants; low-certainty evidence). However, methotrexate compared with placebo may have little or no effect on pain as measured on an increasing scale of 0 to 100 (mean difference (MD) -1.10 points, 95% CI -9.09 to 6.88; 1 trial, 114 participants), improvement in participant global assessment of well-being (absolute difference of 92 more per 1000 people; RR 1.23, 95% CI 0.88 to 1.72; 1 trial, 176 participants), occurrence of serious adverse events (absolute difference of 5 fewer per 1000 people; RR 0.63, 95% CI 0.04 to 8.97; 3 trials, 328 participants), and withdrawals due to adverse events (RR 3.46, 95% CI 0.60 to 19.79; 3 trials, 328 participants) up to six months. We could not estimate the absolute difference for withdrawals due to adverse events because there were no withdrawals in the placebo group. All outcomes were reported within six months of randomisation. We downgraded the certainty of the evidence to low for all outcomes due to indirectness (suboptimal dosing of methotrexate and diverse outcome measures) and imprecision (few participants and low event rates). No trials reported function or the number of participants with sustained clinically inactive disease. Serious adverse events included liver derangement, abdominal pain, and inadvertent overdose. Methotrexate plus intra-articular corticosteroid therapy versus intra-articular corticosteroid therapy alone Methotrexate plus IAGC therapy compared with IAGC therapy alone may have little or no effect on the probability of sustained clinically inactive disease or the rate of withdrawals due to adverse events up to 12 months in children and young people with the oligoarticular subtype of JIA (low-certainty evidence). We could not calculate the absolute difference in withdrawals due to adverse events because there were no withdrawals in the control group. We are uncertain if there is any difference between the interventions in the risk of severe adverse events, because none were reported. The study did not report treatment response, function, pain, or participant global assessment of well-being. Methotrexate versus an alternative disease-modifying antirheumatic drug Methotrexate compared with leflunomide may have little or no effect on the probability of treatment response or on function, participant global assessment of well-being, risk of serious adverse events, and rate of withdrawals due to adverse events up to four months. We downgraded the certainty of the evidence for all outcomes to low due to imprecision. The study did not report pain or sustained clinically inactive disease. AUTHORS' CONCLUSIONS Oral methotrexate (5 mg/m2/week to 15 mg/m2/week) compared with placebo may increase the number of children and young people achieving treatment response but may have little or no effect on pain or participant global assessment of well-being. Oral methotrexate plus IAGC injections compared to IAGC injections alone may have little or no effect on the likelihood of sustained clinically inactive disease among children and young people with oligoarticular JIA. Similarly, methotrexate compared with leflunomide may have little or no effect on treatment response, function, and participant global assessment of well-being. Serious adverse events due to methotrexate appear to be rare. We will update this review as new evidence becomes available to inform the living guideline.
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Affiliation(s)
- Joachim Tan
- Department of Rheumatology, Children's Health Queensland, South Brisbane, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - William D Renton
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
- Rheumatology Unit, Department of General Medicine, The Royal Children's Hospital, Melbourne, Australia
- Department of Paediatric Rheumatology, Monash Children's Hospital, Melbourne, Australia
| | - Samuel L Whittle
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
- Department of Rheumatology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Australia
| | - Tim Takken
- Child Development and Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | - Renea V Johnston
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Georgina Tiller
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
- Rheumatology Unit, Department of General Medicine, The Royal Children's Hospital, Melbourne, Australia
- Department of Paediatric Rheumatology, Monash Children's Hospital, Melbourne, Australia
| | - Jane Munro
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
- Rheumatology Unit, Department of General Medicine, The Royal Children's Hospital, Melbourne, Australia
| | - Rachelle Buchbinder
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
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13
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Shoop-Worrall SJW, Lawson-Tovey S, Wedderburn LR, Hyrich KL, Geifman N. Towards stratified treatment of JIA: machine learning identifies subtypes in response to methotrexate from four UK cohorts. EBioMedicine 2024; 100:104946. [PMID: 38194741 PMCID: PMC10792564 DOI: 10.1016/j.ebiom.2023.104946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. METHODS Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year. Clusters of MTX 'response' were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. FINDINGS The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65-0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. INTERPRETATION Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis of a stratified medicine programme in early JIA. FUNDING Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and the National Institute for Health Research.
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Affiliation(s)
- Stephanie J W Shoop-Worrall
- Centre for Epidemiology Versus Arthritis, The University of Manchester, UK; Centre for Health Informatics, The University of Manchester, UK.
| | - Saskia Lawson-Tovey
- Centre for Genetics and Genomics Versus Arthritis, The University of Manchester, UK; National Institute for Health Research Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
| | - Lucy R Wedderburn
- Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH and GOSH, London, UK; Infection, Immunity and Inflammation Research & Teaching Department, UCL GOS Institute of Child Health, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK.
| | - Kimme L Hyrich
- Centre for Epidemiology Versus Arthritis, The University of Manchester, UK; National Institute for Health Research Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
| | - Nophar Geifman
- Faculty of Health and Medical Sciences, School of Health Sciences, The University of Surrey, Surrey, UK.
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14
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İşgüder R, Kızıldağ Z, Torun R, Aydın T, Makay B, Ünsal E. Risk of flare in juvenile idiopathic arthritis: Is it related to the methotrexate treatment strategy or patient characteristics? Arch Rheumatol 2023; 38:602-610. [PMID: 38125067 PMCID: PMC10728747 DOI: 10.46497/archrheumatol.2023.10035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 02/23/2023] [Indexed: 12/23/2023] Open
Abstract
Objectives The study aimed to determine the factors that increase the risk of disease flare in patients with juvenile idiopathic arthritis who stopped methotrexate (MTX) monotherapy following inactive disease (ID). Patients and methods In the retrospective study, files of all juvenile idiopathic arthritis cases between April 1992 and June 2022 were examined. Patients who stopped MTX monotherapy following ID were evaluated. Patients with disease flare and persistent ID were compared. Juvenile idiopathic arthritis subgroup, age of symptom onset, autoantibodies, acute phase reactants, MTX method of use, and withdrawal strategy were recorded. Systemic juvenile idiopathic arthritis patients were excluded from the study due to different clinical symptoms, diagnosis, and treatment methods. Results Files of 1,036 patients were evaluated, and 107 patients (88 females, 19 males; mean age: 5.9±4.2 years; range, 0.8-16.5 years) were included in the study. The median age at symptom onset was 4.8 (interquartile range [IQR]: 2-7.6) years. In terms of juvenile idiopathic arthritis subgroups, 52 (48.6%) had oligoarticular juvenile idiopathic arthritis, 43 (40.2%) had polyarticular juvenile idiopathic arthritis, and 12 (11.2%) had juvenile psoriatic arthritis. The patients reached ID in nine (IQR: 4.8-17.7) months after starting MTX, and MTX treatment was discontinued after one (IQR: 0.7-1.3) year following ID. The disease flare developed in 59 (55%) of the cases. The ID continued in 48 (45%) patients. In multivariate analysis, the risk of flare was associated with younger symptom onset (odds ratio [OR]=2.2, p=0.006), antinuclear antibody positivity (OR=1.6, p=0.03), higher erythrocyte sedimentation rate (OR=1.01, p=0.04), and C-reactive protein (OR=1, p=0.02) at the MTX onset. No difference was observed between the two groups regarding MTX dose, route of administration, prior and concomitant treatments, time to reach ID, and time and method of MTX discontinuation. Conclusion In this study, the risk of flare was associated with patient's characteristics, rather than the administration and discontinuation method of MTX.
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Affiliation(s)
- Rana İşgüder
- Department of Pediatrics, Division of Pediatric Rheumatology, Dokuz Eylül University Faculty of Medicine, Izmir, Türkiye
| | - Zehra Kızıldağ
- Department of Pediatrics, Division of Pediatric Rheumatology, Dokuz Eylül University Faculty of Medicine, Izmir, Türkiye
| | - Rüya Torun
- Department of Pediatrics, Division of Pediatric Rheumatology, Dokuz Eylül University Faculty of Medicine, Izmir, Türkiye
| | - Tuncay Aydın
- Department of Pediatrics, Division of Pediatric Rheumatology, Dokuz Eylül University Faculty of Medicine, Izmir, Türkiye
| | - Balahan Makay
- Department of Pediatrics, Division of Pediatric Rheumatology, Dokuz Eylül University Faculty of Medicine, Izmir, Türkiye
| | - Erbil Ünsal
- Department of Pediatrics, Division of Pediatric Rheumatology, Dokuz Eylül University Faculty of Medicine, Izmir, Türkiye
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15
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Hinze CH, Foell D, Kessel C. Treatment of systemic juvenile idiopathic arthritis. Nat Rev Rheumatol 2023; 19:778-789. [PMID: 37923864 DOI: 10.1038/s41584-023-01042-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2023] [Indexed: 11/06/2023]
Abstract
Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory disease with hallmarks of severe systemic inflammation, which can be accompanied by arthritis. Contemporary scientific insights set this paediatric disorder on a continuum with its counterpart, adult-onset Still disease (AOSD). Patients with sJIA are prone to complications, including life-threatening hyperinflammation (macrophage activation syndrome (sJIA-MAS)) and sJIA-associated lung disease (sJIA-LD). Meanwhile, the treatment arsenal in sJIA has expanded markedly. State-of-the-art therapeutic approaches include biologic agents that target the IL-1 and IL-6 pathways. Beyond these, a range of novel agents are on the horizon, some of them already being used on a compassionate use basis, including JAK inhibitors and biologic agents that target IL-18, IFNγ, or IL-1β and IL-18 simultaneously. However, sJIA, sJIA-MAS and sJIA-LD still pose challenging conundrums to rheumatologists treating paediatric and adult patients worldwide. Although national and international consensus treatment plans exist for the treatment of 'classic' sJIA, the treatment approaches for early sJIA without arthritis, and for refractory or complicated sJIA, are not well defined. Therefore, in this Review we outline current approaches for the treatment of sJIA and provide an outlook on knowledge gaps.
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Affiliation(s)
- Claas H Hinze
- Department of Paediatric Rheumatology and Immunology, Münster University Hospital, Münster, Germany
| | - Dirk Foell
- Department of Paediatric Rheumatology and Immunology, Münster University Hospital, Münster, Germany.
| | - Christoph Kessel
- Department of Paediatric Rheumatology and Immunology, Münster University Hospital, Münster, Germany
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16
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Foell D, Saers M, Park C, Brix N, Glerup M, Kessel C, Wittkowski H, Hinze C, Berntson L, Fasth A, Myrup C, Nordal E, Rygg M, Hasle H, Albertsen BK, Herlin T, Holzinger D, Niederberger C, Schlüter B. A novel serum calprotectin (MRP8/14) particle-enhanced immuno-turbidimetric assay (sCAL turbo) helps to differentiate systemic juvenile idiopathic arthritis from other diseases in routine clinical laboratory settings. Mol Cell Pediatr 2023; 10:14. [PMID: 37878193 PMCID: PMC10600080 DOI: 10.1186/s40348-023-00168-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/09/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND Differential diagnosis in children with signs of unprovoked inflammation can be challenging. In particular, differentiating systemic juvenile idiopathic arthritis (SJIA) from other diagnoses is difficult. We have recently validated the complex of myeloid-related proteins 8/14 (MRP8/14, also known as S100A8/A9 complex or serum calprotectin) as a helpful biomarker supporting the diagnosis of SJIA. The results were subsequently confirmed with a commercial ELISA. However, further optimization of the analytical technology is important to ensure its feasibility for large-scale use in routine laboratory settings. METHODS To evaluate the accuracy in identifying children with SJIA, the performance of a particle-enhanced immuno-turbidimetric assay for serum calprotectin (sCAL turbo) on an automated laboratory instrument was analyzed. Samples from 615 children were available with the diagnoses SJIA (n = 99), non-systemic JIA (n = 169), infections (n = 51), other inflammatory diseases (n = 126), and acute lymphoblastic leukemia (ALL, n = 147). In addition, samples from 23 healthy controls were included. RESULTS The sCAL turbo assay correlated well with the MRP8/14 ELISA used in previous validation studies (r = 0.99, p < 0.001). It could reliably differentiate SJIA from all other diagnoses with significant accuracy (cutoff at 10,500 ng/ml, sensitivity 84%, specificity 94%, ROC area under curve 0.960, p < 0.001). CONCLUSIONS Serum calprotectin analyses are a helpful tool supporting the diagnosis of SJIA in children with prolonged fever or inflammatory disease. Here, we show that an immuno-turbidimetric assay for detection of serum calprotectin on an automated laboratory instrument can be implemented in clinical laboratory settings to facilitate its use as a diagnostic routine test in clinical practice.
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Affiliation(s)
- Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, D-48149, Germany.
| | - Melanie Saers
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, D-48149, Germany
| | - Carolin Park
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, D-48149, Germany
| | - Ninna Brix
- Department of Pediatric and Adolescent Medicine, Aalborg University Hospital, Aalborg, Denmark
| | - Mia Glerup
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Christoph Kessel
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, D-48149, Germany
| | - Helmut Wittkowski
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, D-48149, Germany
| | - Claas Hinze
- Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, D-48149, Germany
| | - Lillemor Berntson
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Anders Fasth
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Charlotte Myrup
- Department of Pediatrics, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ellen Nordal
- Department of Pediatrics, University Hospital of North Norway, Tromso, Norway
- Department of Clinical Medicine, Arctic University of Norway, Tromso, Norway
| | - Marite Rygg
- Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Henrik Hasle
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Birgitte Klug Albertsen
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Troels Herlin
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Dirk Holzinger
- Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
- Department of Applied Health Sciences, University of Applied Sciences Bochum, Bochum, Germany
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Nijhuis L, Swart JF, Prakken BJ, van Loosdregt J, Vastert SJ. The clinical and experimental treatment of Juvenile Idiopathic Arthritis. Clin Exp Immunol 2023; 213:276-287. [PMID: 37074076 PMCID: PMC10571000 DOI: 10.1093/cei/uxad045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 03/02/2023] [Accepted: 04/18/2023] [Indexed: 04/20/2023] Open
Abstract
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and comprises of multiple subtypes. The most relevant disease subtypes, grouped upon current insight in disease mechanisms, are nonsystemic (oligo- and polyarticular) JIA and systemic JIA (sJIA). In this review, we summarize some of the main proposed mechanisms of disease in both nonsystemic and sJIA and discuss how current therapeutic modalities target some of the pathogenic immune pathways. Chronic inflammation in nonsystemic JIA is the result of a complex interplay between effector and regulatory immune cell subsets, with adaptive immune cells, specifically T-cell subsets and antigen-presenting cells, in a central role. There is, however, also innate immune cell contribution. SJIA is nowadays recognized as an acquired chronic inflammatory disorder with striking autoinflammatory features in the first phase of the disease. Some sJIA patients develop a refractory disease course, with indications for involvement of adaptive immune pathways as well. Currently, therapeutic strategies are directed at suppressing effector mechanisms in both non-systemic and sJIA. These strategies are often not yet optimally tuned nor timed to the known active mechanisms of disease in individual patients in both non-systemic and sJIA. We discuss current treatment strategies in JIA, specifically the 'Step-up' and 'Treat to Target approach' and explore how increased insight into the biology of disease may translate into future more targeted strategies for this chronic inflammatory disease at relevant time points: preclinical disease, active disease, and clinically inactive disease.
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Affiliation(s)
- L Nijhuis
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of pediatric rheumatology & immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - J F Swart
- Department of pediatric rheumatology & immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- University of Utrecht, Utrecht, The Netherlands
| | - B J Prakken
- Department of pediatric rheumatology & immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- University of Utrecht, Utrecht, The Netherlands
| | - J van Loosdregt
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- University of Utrecht, Utrecht, The Netherlands
| | - S J Vastert
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of pediatric rheumatology & immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- University of Utrecht, Utrecht, The Netherlands
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18
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Nieto-González JC, Garulo DC, Boteanu A, Trives-Folguera L, García-Fernández A, Navarro PG, Robledillo JCL, Monteagudo-Saéz I. What to Expect When Systemic Treatment in Juvenile Idiopathic Arthritis Is Withdrawn? J Rheumatol 2023; 50:1326-1332. [PMID: 37527855 DOI: 10.3899/jrheum.2022-1305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2023] [Indexed: 08/03/2023]
Abstract
OBJECTIVE The goal of juvenile idiopathic arthritis (JIA) treatment is to maintain clinical remission. It is also important to reduce drug exposure, whenever possible, in order to avoid or decrease potential side effects. We aimed to analyze remission survival after systemic treatment withdrawal and to determine which factors can influence it. METHODS We conducted a multicenter, observational, longitudinal study. All patients included had a diagnosis of JIA. We analyzed remission survival using Kaplan-Meier curves according to the systemic treatment received (methotrexate [MTX] alone or in combination with biologic disease-modifying antirheumatic drugs [bDMARDs]) and JIA subgroups (oligoarticular and polyarticular course, juvenile spondyloarthritis, and systemic JIA). In addition, risk factors were examined using multivariate analysis. RESULTS We included 404 patients with JIA; 370 of them (92%) had received systemic treatment at some point and half of them (185 patients) had withdrawn on at least 1 occasion. There were 110 patients who flared (59%) with a median time of 2.3 years. There were no differences in remission survival between JIA subcategories. Twenty-nine percent of patients with JIA who received MTX and bDMARDs, in which MTX alone was withdrawn, flared; median time to flare of 6.3 years. However, if only the bDMARD was withdrawn, flares occurred 57% of the time; median time to flare of 1.1 years. CONCLUSION Flares are frequent when systemic treatment is withdrawn, and uveitis or joint injections could be related risk factors. In MTX and biologic-naïve patients, the frequency of flares occurred in more than half of patients, although they were less frequent when clinical remission lasted for > 1 year.
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Affiliation(s)
- Juan Carlos Nieto-González
- J.C. Nieto-González, MD, PhD, L. Trives-Folguera, MD, I. Monteagudo-Saéz, MD, PhD, Department of Rheumatology, Hospital General Universitario Gregorio Marañón;
| | - Daniel Clemente Garulo
- D. Clemente Garulo, MD, PhD, J.C. López Robledillo, MD, Pediatric Rheumatology Unit, Hospital Infantil Universitario Niño Jesús
| | - Alina Boteanu
- A. Boteanu, MD, A. García-Fernández, MD, Department of Rheumatology, Hospital Universitario Ramón y Cajal
| | - Laura Trives-Folguera
- J.C. Nieto-González, MD, PhD, L. Trives-Folguera, MD, I. Monteagudo-Saéz, MD, PhD, Department of Rheumatology, Hospital General Universitario Gregorio Marañón
| | - Antía García-Fernández
- A. Boteanu, MD, A. García-Fernández, MD, Department of Rheumatology, Hospital Universitario Ramón y Cajal
| | - Pablo González Navarro
- P. González Navarro, MSc, Biostatistical Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Juan Carlos López Robledillo
- D. Clemente Garulo, MD, PhD, J.C. López Robledillo, MD, Pediatric Rheumatology Unit, Hospital Infantil Universitario Niño Jesús
| | - Indalecio Monteagudo-Saéz
- J.C. Nieto-González, MD, PhD, L. Trives-Folguera, MD, I. Monteagudo-Saéz, MD, PhD, Department of Rheumatology, Hospital General Universitario Gregorio Marañón
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19
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Maleki A, Patel PD, Foster CS. Juvenile idiopathic arthritis and its associated uveitis. Expert Rev Clin Immunol 2023; 19:1157-1169. [PMID: 37401872 DOI: 10.1080/1744666x.2023.2231154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 06/26/2023] [Indexed: 07/05/2023]
Abstract
INTRODUCTION Juvenile idiopathic arthritis is the most common chronic rheumatologic disease in children. Uveitis is the most common extra-articular manifestation of JIA, and it can be a sight-threatening condition. AREAS COVERED In this review article, we discussed epidemiology, risk factors, clinical presentation, supportive laboratory tests, treatment options, and complications of Juvenile idiopathic arthritis and Juvenile idiopathic arthritis associated uveitis. We covered conventional immunomodulatory therapy and biologic response modifiers agents for different types of Juvenile idiopathic arthritis and their associated uveitis. Finally, we discussed the course of disease, functional outcome, and the quality of life of Juvenile idiopathic arthritis and Juvenile idiopathic arthritis-associated uveitis. EXPERT OPINION Although clinical outcomes of Juvenile idiopathic arthritis and its associated uveitis have been improved over the past three decades by biologic response modifier agents, a significant proportion of patients require active treatment into adult life therefore screening and monitoring of these patients is required during the patient's entire life. The limited number of food and drug administration approved biologic response modifier agents for the treatment of Juvenile idiopathic arthritis associated uveitis justify more randomized clinical trials with new medications in this field.
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Affiliation(s)
- Arash Maleki
- Department of Ophthalmology, University of Florida, Gainesville, FL, USA
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, USA
| | - Priya D Patel
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, USA
| | - C Steven Foster
- Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA
- The Ocular Immunology and Uveitis Foundation, Waltham, MA, USA
- Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
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20
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Brix N, Glerup M, Foell D, Kessel C, Wittkowski H, Berntson L, Fasth A, Nielsen S, Nordal E, Rygg M, Hasle H, Herlin T. Inflammatory Biomarkers Can Differentiate Acute Lymphoblastic Leukemia with Arthropathy from Juvenile Idiopathic Arthritis Better Than Standard Blood Tests. J Pediatr 2023; 258:113406. [PMID: 37023943 DOI: 10.1016/j.jpeds.2023.113406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/21/2023] [Accepted: 03/26/2023] [Indexed: 04/08/2023]
Abstract
OBJECTIVE To evaluate the predictive value of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of inflammatory cytokines in order to differentiate the child with acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA). STUDY DESIGN In this cross-sectional study, we measured S100A9, S100A12, and 14 cytokines in serum from children with ALL (n = 150, including 27 with arthropathy) and JIA (n = 236). We constructed predictive models computing areas under the curve (AUC) as well as predicted probabilities in order to differentiate ALL from JIA. Logistic regression was used for predictions of ALL risk, considering the markers as the respective exposures. We performed internal validation using repeated 10-fold cross-validation and recalibration, adjusted for age. RESULTS In ALL, the levels of S100A9, S100A12, interleukin (IL)-1 beta, IL-4, IL-13, IL-17, matrix metalloproteinase-3, and myeloperoxidase were low compared with JIA (P < .001). IL-13 had an AUC of 100% (95% CI 100%-100%) due to no overlap between the serum levels in the 2 groups. Further, IL-4 and S100A9 had high predictive performance with AUCs of 99% (95% CI 97%-100%) and 98% (95% CI 94%-99%), respectively, exceeding both hemoglobin, platelets, C-reactive protein, and erythrocyte sedimentation rate. CONCLUSIONS The biomarkers S100A9, IL-4, and IL-13 might be valuable markers to differentiate ALL from JIA.
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Affiliation(s)
- Ninna Brix
- Department of Pediatrics and Adolescent Medicine, Aalborg University Hospital, Aalborg, Denmark.
| | - Mia Glerup
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University of Muenster, Muenster, Germany
| | - Christoph Kessel
- Department of Pediatric Rheumatology and Immunology, University of Muenster, Muenster, Germany
| | - Helmut Wittkowski
- Department of Pediatric Rheumatology and Immunology, University of Muenster, Muenster, Germany
| | - Lillemor Berntson
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Anders Fasth
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Susan Nielsen
- Department of Pediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ellen Nordal
- Department of Pediatrics, University Hospital of North Norway, and Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Marite Rygg
- Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway; Department of Pediatrics, St Olavs Hospital, Trondheim, Norway
| | - Henrik Hasle
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Troels Herlin
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
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21
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Wedderburn LR, Ramanan AV, Croft AP, Hyrich KL, Dick AD. Towards molecular-pathology informed clinical trials in childhood arthritis to achieve precision medicine in juvenile idiopathic arthritis. Ann Rheum Dis 2023; 82:449-456. [PMID: 36600186 PMCID: PMC10086280 DOI: 10.1136/ard-2022-222553] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
In childhood arthritis, collectively known as Juvenile idiopathic arthritis (JIA), the rapid rise of available licensed biological and targeted small molecule treatments in recent years has led to improved outcomes. However, real-world data from multiple countries and registries show that despite a large number of available drugs, many children and young people continue to suffer flares and experience significant periods of time with active disease for many years. More than 50% of young people with JIA require ongoing immune suppression well into adult life, and they may have to try multiple different treatments in that time. There are currently no validated tools with which to select specific treatments, nor biomarkers of response to assist in such choices, therefore, current management uses essentially a trial-and-error approach. A further consequence of recent progress is a reducing pool of available children or young people who are eligible for new trials. In this review we consider how progress towards a molecular based approach to defining treatment targets and informing trial design in JIA, combined with novel approaches to clinical trials, could provide strategies to maximise discovery and progress, in order to move towards precision medicine for children with arthritis.
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Affiliation(s)
- Lucy R Wedderburn
- UCL GOS Institute of Child Health, University College London, London, UK
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, UCL, London, UK
- National Institute of Health Research Biomedical Research Centre at GOSH London UK, Great Ormond Street Hospital, London, UK
| | - Athimalaipet V Ramanan
- Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, UK
- Translational Health Sciences, University of Bristol, Bristol, UK
| | - Adam P Croft
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- National Institute of Health Research Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Kimme L Hyrich
- Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
- National Institute of Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK
| | - Andrew D Dick
- Translational Health Sciences, University of Bristol, Bristol, UK
- UCL Institute of Ophthalmology, University College London, London, UK
- National Institute of Health Research Biomedical Research Centre, Moorfields and UCL Institute of Ophthalmology, London, UK
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22
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Chausset A, Lambert C, Belot A, Merlin E, Cannizzaro E, Kone-Paut I, Ballot C, Devauchelle V, Poignant S, Carlomagno R, Lohse A, Barbier C, Despert V, Carbasse A, Sparsa L, Adank E, Vanoni F, Reumaux H, Pillet P, Kaiser D, Hofer M, Freychet C, Schott AM. Individual and environmental determinants associated with longer times to access pediatric rheumatology centers for patients with juvenile idiopathic arthritis, a JIR cohort study. Pediatr Rheumatol Online J 2023; 21:24. [PMID: 36918902 PMCID: PMC10015663 DOI: 10.1186/s12969-023-00809-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 03/07/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Despite guidelines, poor access to appropriate care for juvenile idiopathic arthritis (JIA) patients remains a global issue. Prompt referral to a pediatric rheumatology (PR) center and effective care is known to be critical for changing the natural history of the disease and improving long-term prognosis. This project assesses socio-economic factors of delayed referral to a pediatric rheumatologist (PRst) for JIA patients in France and Switzerland within the Juvenile Inflammatory Rheumatism (JIR) Cohort. METHODS All patients diagnosed with JIA, presenting at one center of the JIRcohort in France or Switzerland with additional data on referral pathway were included. Patient characteristics at first visit to the PR center, dates of visits to healthcare providers during referral, and parent characteristics were extracted from the JIRcohort database. RESULTS Two hundred fifty children were included. The overall median time to first PR assessment was 2.4 months [1.3; 6.9] and ranged widely across the JIA subtypes, from 1.4 months [0.6; 3.8] for children with systemic juvenile idiopathic arthritis (sJIA) to 5.3 months [2.0; 19.1] for children with enthesitis-related arthritis (ERA). A diagnosis of ERA and an appointment with an orthopedist during the referral pathway were significantly associated with a longer time before the first PR visit (hazard ratio HR 0.50 [95% CI: 0.29; 0.84]) and HR 0.68 [95% CI: 0.49; 0.93], respectively) in multivariable analysis. Having a mother with a post-graduate educational attainment level was tendentially associated with a shorter time before the first PR visit, (HR 1.32 [95% CI: 0.99; 1.78]). CONCLUSIONS Time to first PRst visit was most often short compared to other studies and close to the British recommendations. However, this time remained too long for many patients. We observed no social inequities in access to a PRst, but we show the need to improve effective pathway and access to a PR center for JIA patients.
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Affiliation(s)
- Aurélie Chausset
- CRECHE Unit, INSERM CIC 1405, Department of Pediatrics, CHU Clermont-Ferrand, Clermont-Ferrand, France.
- Research on Healthcare Performance (RESHAPE), INSERM U1290, Claude Bernard University Lyon 1, Lyon, France.
- Pédiatrie, CHU Estaing, 1 Place Lucie & Raymond Aubrac, Clermont-Fd cedex1, 63003, France.
| | - Céline Lambert
- Biostatistics Unit, DRCI, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Alexandre Belot
- Pediatric Nephrology, Rheumatology, Dermatology, HFME, Hospices Civils de Lyon, National Referee Centre RAISE & INSERM U1111, Lyon University, Lyon, France
| | - Etienne Merlin
- CRECHE Unit, INSERM CIC 1405, Department of Pediatrics, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Elvira Cannizzaro
- Department of Rheumatology, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Isabelle Kone-Paut
- Department of Pediatrics & Pediatric Rheumatology, Centre de référence maladies auto-inflammatoires rares et amylose inflammatoire (CEREMAIA), Bicêtre University, Paris Sud Hospital, Le Kremlin-Bicêtre, France
| | - Claire Ballot
- Pediatric Hematology, Jean-Minjoz Hospital, Besançon, France
| | - Valérie Devauchelle
- Rheumatology Department, CHU Brest and Brest University, INSERM UMR 1227, Brest, France
| | | | - Raffaella Carlomagno
- Pediatric Immuno-Rheumatology of Western Switzerland, Department Women-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland
- University Hospital, Geneva, Switzerland
| | - Anne Lohse
- Department of Rheumatology, Nord Franche-Comté Hospital, Belfort, France
| | | | | | - Aurélia Carbasse
- Department of Pediatrics, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France
| | | | - Eva Adank
- Department of Pediatrics, Kantonsspital Graubünden, Chur, Switzerland
| | - Federica Vanoni
- Institute of Pediatrics of Southern Switzerland, EOC, Bellinzona, Switzerland
| | - Héloise Reumaux
- Pediatric Rheumatology, Lille University Hospital, Lille, France
| | - Pascal Pillet
- Department of Pediatrics, Hôpital des Enfants, CHRU Bordeaux, Bordeaux, France
| | - Daniela Kaiser
- Department of Pediatrics, Centre Hospitalier Cantonal Luzern, Lucerne, Switzerland
| | - Michael Hofer
- Pediatric Immuno-Rheumatology of Western Switzerland, Department Women-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland
- University Hospital, Geneva, Switzerland
| | - Caroline Freychet
- Research on Healthcare Performance (RESHAPE), INSERM U1290, Claude Bernard University Lyon 1, Lyon, France
- Pediatric Nephrology, Rheumatology, Dermatology, HFME, Hospices Civils de Lyon, National Referee Centre RAISE & INSERM U1111, Lyon University, Lyon, France
- Pediatrics, CHU Saint-Etienne, Saint-Etienne, France
| | - Anne-Marie Schott
- Research on Healthcare Performance (RESHAPE), INSERM U1290, Claude Bernard University Lyon 1, Lyon, France
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23
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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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24
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The Role of Serum Calprotectin in Defining Disease Outcomes in Non-Systemic Juvenile Idiopathic Arthritis: A Pilot Study. Int J Mol Sci 2023; 24:ijms24021671. [PMID: 36675189 PMCID: PMC9866398 DOI: 10.3390/ijms24021671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/04/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Serum calprotectin (MRP8/14) is currently being studied as a promising biomarker of disease activity and outcome in patients with juvenile idiopathic arthritis (JIA) but the data in the literature are conflicting. The aim of our study was to investigate the potential role of serum calprotectin as biomarker of disease activity and flare/remission in a group of nsJIA patients during a follow-up period of 18 months. In this prospective longitudinal study, two groups of patients with ns-JIA (55 active patients and 56 patients in remission according to Wallace's criteria) and a control group (50 children) were recruited at baseline from January 2020 to September 2021. JIA patients were followed for up to 18 months at four timepoints: 3 months (T1), 6 months (T2), 12 months (T3) and 18 months (T4). At each timepoint, the following were recorded: JADAS27, blood counts, ESR, CRP, albumin, ferritin and serum calprotectin. To illustrate the performance of calprotectin, Kaplan-Meier curves were constructed from baseline to relapse/remission, dichotomizing patients at baseline in positive/negative on the basis progressive calprotectin cut-offs. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates. Comparing baseline clinical and laboratory data of the three groups (active vs. inactive JIA vs. controls), only serum calprotectin reached statistical significance (active patients vs. inactive (p = 0.0016) and vs. controls (p = 0.0012)). In the inactive group, during the 18 months of follow up, 31 patients (55.3%) had a relapse. Comparing the baseline data of relapsers vs. non-relapsers, serum calprotectin showed higher levels (p = 0.001) in relapsers. In survival analysis, a log rank test showed significant differences of up to 12 ng/mL (p = 0.045). Multivariate Cox regression confirmed that only baseline calprotectin levels were independently associated with disease recurrence. In the active group, in the 12 months of follow-up, 19 patients (38%) entered remission of the disease. In addition, in this group, the only statistical difference at the baseline was the value of MPR8/14 (p = 0.0001). Log rank test showed significant differences up to 10 ng/mL (p = 0.003). In the multivariate Cox regression, serum calprotectin levels at baseline were independently associated with remission. In conclusion, our study would suggest a dual role for calprotectin in predicting future relapse and treatment response in patients with nsJIA, thus influencing therapeutic decisions and management of these patients during follow up.
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25
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Harsini S, Rezaei N. Autoimmune diseases. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Murias S, Boteanu A, Calvo I, Nuñez E, Bravo B, Bustabad S, Camacho M, Clemente D, Graña J, de Inocencio J, Lacruz L, Mesa-Del-Castillo P, Nieto-González JC, Pinedo MDC, Quesada E, Vargas C, Antón J. What drives the decision to optimise biological treatment in children and youngsters with juvenile idiopathic arthritis? A discrete-choice experiment. REUMATOLOGIA CLINICA 2023; 19:26-33. [PMID: 36603964 DOI: 10.1016/j.reumae.2022.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 12/16/2021] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To analyse factors involved in the decision to optimise biologics in juvenile idiopathic arthritis. METHODS A "discrete-choice" methodology was used. In a nominal group meeting, factors which may influence physicians' decisions to optimise biological dose were identified, together with decision nodes. 1000Minds® was used to create multiple fictitious clinical scenarios based on the factors identified, and to deploy surveys that were sent to a panel of experts. These experts decided for each item which of two clinical scenarios prompted them to optimise the dose of biologic. A conjoint analysis was carried out, and the partial-value functions and the weights of relative importance calculated. RESULTS In the nominal group, three decision nodes were identified: (1) time to decide; (2) to maintain/reduce or prolong interval; (3) what drug to reduce. The factors elicited were different for each node and included patient and drug attributes. The presence of macrophage activation syndrome (MAS), systemic involvement, or subclinical inflammation made the decision easier (highest weights). The presence of joints of difficult control and year of debut influenced the decision in some but not all, and in different directions. Immunogenicity, adherence, and concomitant treatments were also aspects taken into account. CONCLUSIONS The decision to optimise the dose of biological therapy in children and youngster can be divided into several nodes, and the factors, both patient and therapy-related, leading to the decision can be detailed. These decisions taken by experts may be transported to practice, study designs, and guidelines.
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Affiliation(s)
- Sara Murias
- Hospital Universitario La Paz, Madrid, Spain.
| | | | | | | | - Beatriz Bravo
- Hospital Universitario Virgen de las Nieves, Granada, Spain
| | | | | | | | - Jenaro Graña
- Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
| | | | - Lucía Lacruz
- Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | | | | | | | | | - Carmen Vargas
- Hospital Universitario Virgen Macarena, Sevilla, Spain
| | - Jordi Antón
- Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
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Borocco C, Anselmi F, Rossi-Semerano L. Contribution of Ultrasound in Current Practice for Managing Juvenile Idiopathic Arthritis. J Clin Med 2022; 12:91. [PMID: 36614888 PMCID: PMC9821589 DOI: 10.3390/jcm12010091] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/16/2022] [Accepted: 12/21/2022] [Indexed: 12/24/2022] Open
Abstract
The interest and application of musculoskeletal ultrasound (MSUS) in juvenile idiopathic arthritis (JIA) are increasing. Numerous studies have shown that MSUS is more sensitive than clinical examination for detecting subclinical synovitis. MSUS is a well-accepted tool, easily accessible and non-irradiating. Therefore, it is a useful technique throughout JIA management. In the diagnostic work-up, MSUS allows for better characterizing the inflammatory involvement. It helps to define the disease extension, improving the classification of patients into JIA subtypes. Moreover, it is an essential tool for guiding intra-articular and peritendinous procedures. Finally, during the follow-up, in detecting subclinical disease activity, MSUS can be helpful in therapeutic decision-making. Because of several peculiarities related to the growing skeleton, the MSUS standards defined for adults do not apply to children. During the last decade, many teams have made large efforts to define normal and pathological US features in children in different age groups, which should be considered during the US examination. This review describes the specificities of MSUS in children, its applications in clinical practice, and its integration into the new JIA treat-to-target therapeutic approach.
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Affiliation(s)
- Charlotte Borocco
- Department of Paediatric Rheumatology, National Reference Centre for Auto-Inflammatory Diseases and Amyloidosis of Inflammatory Origin (CEREMAIA), Bicêtre Hospital (AP-HP), 94270 Le Kremlin-Bicêtre, France
| | - Federica Anselmi
- Department of Paediatric Rheumatology, National Reference Centre for Auto-Inflammatory Diseases and Amyloidosis of Inflammatory Origin (CEREMAIA), Bicêtre Hospital (AP-HP), 94270 Le Kremlin-Bicêtre, France
- Unit of Paediatric Rheumatology, Department of Translational Medicine, Section of Paediatrics, University of Naples Federico II, 80138 Naples, Italy
| | - Linda Rossi-Semerano
- Department of Paediatric Rheumatology, National Reference Centre for Auto-Inflammatory Diseases and Amyloidosis of Inflammatory Origin (CEREMAIA), Bicêtre Hospital (AP-HP), 94270 Le Kremlin-Bicêtre, France
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Ziegler L, Fuehner S, Kessel C, Hinze C, Klotsche J, Niewerth M, Minden K, Foell D. Soluble interleukin-2 receptor serum levels facilitate prediction of relapses in subgroups of patients with juvenile idiopathic arthritis. Rheumatology (Oxford) 2022; 61:4975-4984. [PMID: 35325053 DOI: 10.1093/rheumatology/keac178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 03/15/2022] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVES JIA is characterised by a chronic disease course. Once patients achieve a state of inactive disease, there are no established biomarkers to predict the further course of inflammation for these patients. Therefore, the purpose of this study was to quantify serum biomarkers during quiescent disease to evaluate their use in identifying JIA patients at risk for future disease flare. METHODS Patients with non-systemic JIA reaching inactive disease status were divided into two groups: 92 patients with future active disease after a median period of 6 months (range 3-9) and 80 patients with persistent inactive disease for the following period (median 11 months, range 7-16) according to the juvenile arthritis DAS (JADAS). Clinical parameters and serum levels of various biomarkers were measured in the state of inactive disease using immunoassays in both groups and were analysed for their potential to predict the further course of disease. RESULTS Soluble interleukin-2 receptor (sIL-2R) serum levels were significantly higher in patients with future active disease (P = 0.021), which especially applied to patients with RF-negative polyarticular and extended oligoarticular JIA (P < 0.001). Higher sIL-2R serum levels during inactive disease were associated with a greater number of active joints at future active disease. CONCLUSION Patients without clinical signs of disease activity already presented with increased sIL-2R serum levels several months before disease relapses, whereas conventional inflammation parameters were not elevated. Determination of sIL-2R serum levels during inactive disease may facilitate identifying patients with subclinical disease activity at risk for future active disease.
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Affiliation(s)
- Linda Ziegler
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster
| | - Sabrina Fuehner
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster
| | - Christoph Kessel
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster
| | - Claas Hinze
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster
| | - Jens Klotsche
- Epidemiology Unit, German Rheumatism Research Center, Berlin, Germany
| | - Martina Niewerth
- Epidemiology Unit, German Rheumatism Research Center, Berlin, Germany
| | - Kirsten Minden
- Epidemiology Unit, German Rheumatism Research Center, Berlin, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster
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Keskitalo PL, Kangas SM, Sard S, Pokka T, Glumoff V, Kulmala P, Vähäsalo P. Myeloid-related protein 8/14 in plasma and serum in patients with new-onset juvenile idiopathic arthritis in real-world setting in a single center. Pediatr Rheumatol Online J 2022; 20:42. [PMID: 35710418 PMCID: PMC9204870 DOI: 10.1186/s12969-022-00701-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 05/30/2022] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE The aim of this study was to analyze the usefulness of myeloid-related protein 8/14 (MRP8/14) in the prediction of disease course in a real-world setting for patients with new-onset juvenile idiopathic arthritis (JIA), to identify the relationship between MRP8/14 and disease activity using the physician's global assessment of disease activity (PGA), and determine whether the MRP8/14 levels measured in serum and plasma are equally useful. METHODS In this prospective follow-up study, 87 new-onset non-systemic JIA patients were studied. Blood and synovial fluid samples were collected prior to any antirheumatic medication use. MRP8/14 was measured from serum (S-MRP8/14), plasma (P-MRP8/14), and synovial fluid samples using ELISA. RESULTS The baseline MRP8/14 blood levels were significantly higher in patients using synthetic antirheumatic drugs than in patients with no systemic medications at 1 year after diagnosis in serum (mean 298 vs. 198 ng/ml, P < 0.001) and in plasma (mean 291 vs. 137 ng/ml, P = 0.001). MRP8/14 levels at the time of JIA diagnosis were higher in patients who started methotrexate during 1.5-year follow-up compared to those who achieved long-lasting inactive disease status without systemic medications (serum: mean 298 vs. 219 ng/ml, P = 0.006 and plasma: 296 vs. 141 ng/ml, P = 0.001). P-MRP8/14 was the most effective predictive variable for disease activity (by PGA) in linear multivariate regression model (combined to ESR, CRP, leukocytes, and neutrophils), whereas S-MRP8/14 was not significant. CONCLUSION Blood MRP8/14 levels at baseline seem to predict disease course in new-onset JIA patients. P-MRP8/14 might be better than S-MRP8/14 when assessing disease activity at the time of JIA diagnosis.
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Affiliation(s)
- Paula L. Keskitalo
- grid.10858.340000 0001 0941 4873PEDEGO Research Unit, University of Oulu, Oulu, Finland ,grid.412326.00000 0004 4685 4917Department of Pediatrics, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland ,grid.412326.00000 0004 4685 4917Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Salla M. Kangas
- grid.10858.340000 0001 0941 4873PEDEGO Research Unit, University of Oulu, Oulu, Finland ,grid.412326.00000 0004 4685 4917Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Sirja Sard
- grid.10858.340000 0001 0941 4873PEDEGO Research Unit, University of Oulu, Oulu, Finland ,grid.412326.00000 0004 4685 4917Department of Pediatrics, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland ,grid.412326.00000 0004 4685 4917Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Tytti Pokka
- grid.10858.340000 0001 0941 4873PEDEGO Research Unit, University of Oulu, Oulu, Finland ,grid.412326.00000 0004 4685 4917Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Virpi Glumoff
- grid.10858.340000 0001 0941 4873Research Unit of Biomedicine, University of Oulu, Oulu, Finland
| | - Petri Kulmala
- grid.10858.340000 0001 0941 4873PEDEGO Research Unit, University of Oulu, Oulu, Finland ,grid.412326.00000 0004 4685 4917Department of Pediatrics, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland ,grid.412326.00000 0004 4685 4917Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Paula Vähäsalo
- PEDEGO Research Unit, University of Oulu, Oulu, Finland. .,Department of Pediatrics, Oulu University Hospital, Kajaanintie 50, 90220, Oulu, Finland. .,Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
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Gerss J, Tedy M, Klein A, Horneff G, Miranda-Garcia M, Kessel C, Holzinger D, Stanevica V, Swart JF, Cabral DA, Brunner HI, Foell D. Prevention of disease flares by risk-adapted stratification of therapy withdrawal in juvenile idiopathic arthritis: results from the PREVENT-JIA trial. Ann Rheum Dis 2022; 81:990-997. [PMID: 35260388 PMCID: PMC9209679 DOI: 10.1136/annrheumdis-2021-222029] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/24/2022] [Indexed: 12/01/2022]
Abstract
Objectives To investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA). Methods This multicentre trial (PREVENT-JIA) enrolled 119 patients with JIA in clinical remission, and 100 patients reached the intervention phase in which the decision whether to continue or stop treatment was based on S100A12 and hsCRP levels. Patients were monitored for 12 months after stopping medication for flares of disease. Results were compared with withdrawal of therapy without biomarker-based stratification in patients from the German Biologika in der Kinderrheumatologie (BiKeR) pharmacovigilance registry. Results In the PREVENT-JIA group, 49 patients had a flare, and 45% of patients stopping medication showed flares within the following 12 months. All patients (n=8) continuing therapy due to permanently elevated S100A12/hsCRP at more than one visit flared during the observation phase. In the BiKeR control group, the total flare rate was 62%, with 60% flaring after stopping medication. The primary outcome, time from therapy withdrawal to first flare (cumulative flare rate after therapy withdrawal), showed a significant difference in favour of the PREVENT-JIA group (p=0.046; HR 0.62, 95% CI 0.38 to 0.99). As additional finding, patients in the PREVENT-JIA trial stopped therapy significantly earlier. Conclusion Biomarker-guided strategies of therapy withdrawal are feasible in clinical practice. This study demonstrates that using predictive markers of subclinical inflammation is a promising tool in the decision-making process of therapy withdrawal, which translates into direct benefit for patients. Trial registration number ISRCTN69963079.
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Affiliation(s)
- Joachim Gerss
- Interdisciplinary Center of Clinical Research, University of Münster, Munster, Germany.,Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany
| | - Monika Tedy
- Department of Pediatric Rheumatology and Immunology, University Hospital Munster, Munster, Germany
| | - Ariane Klein
- Asklepios Children's Hospital, Sankt Augustin, Germany
| | - Gerd Horneff
- Pediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, Germany
| | - Maria Miranda-Garcia
- Department of Pediatric Rheumatology and Immunology, University Hospital Munster, Munster, Germany
| | - Christoph Kessel
- Department of Pediatric Rheumatology and Immunology, University Hospital Munster, Munster, Germany
| | - Dirk Holzinger
- Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
| | - Valda Stanevica
- Department of Pediatrics, Riga Stradins University, Riga, Latvia
| | - Joost F Swart
- Pediatric Immunology, Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | - David A Cabral
- Pediatric Rheumatology, BC Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada
| | - Hermine I Brunner
- Division of Rheumatology, University of Cincinnati, Cincinnati Children's Hospital Medical Center, PRCSG Coordinating Center, Cincinnati, Ohio, USA
| | - Dirk Foell
- Interdisciplinary Center of Clinical Research, University of Münster, Munster, Germany .,Department of Pediatric Rheumatology and Immunology, University Hospital Munster, Munster, Germany
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Abstract
Juvenile idiopathic arthritis (JIA) is an umbrella term for arthritis of unknown origin, lasting for >6 weeks with onset before 16 years of age. JIA is the most common chronic inflammatory rheumatic condition of childhood. According to the International League Against Rheumatism (ILAR) classification, seven mutually exclusive categories of JIA exist based on disease manifestations during the first 6 months of disease. Although the ILAR classification has been useful to foster research, it has been criticized mainly as it does not distinguish those forms of chronic arthritis observed in adults and in children from those that may be unique to childhood. Hence, efforts to provide a new evidence-based classification are ongoing. Similar to arthritis observed in adults, pathogenesis involves autoimmune and autoinflammatory mechanisms. The field has witnessed a remarkable improvement in therapeutic possibilities of JIA owing to the availability of new potent drugs and the possibility to perform controlled trials with support from legislative interventions and large networks availability. The goal of drug therapy in JIA is to rapidly reduce disease activity to inactive disease or clinical remission, minimize drug side effects and achieve a quality of life comparable to that of healthy peers. As JIA can influence all aspects of a child's and their family's life, researchers increasingly recognize improvement of health-related quality of life as a key treatment goal.
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Use of MRP8/14 in clinical practice as a predictor of outcome after methotrexate withdrawal in patients with juvenile idiopathic arthritis. Clin Rheumatol 2022; 41:2825-2830. [PMID: 35486225 PMCID: PMC9474586 DOI: 10.1007/s10067-022-06165-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 11/03/2022]
Abstract
The objective of this study was to determine the effectiveness of MRP8/14 as a predictor of disease flare in patients with juvenile idiopathic arthritis (JIA) following the withdrawal of methotrexate (MTX) in a routine clinical setting. All MRP8/14 tests performed at a single centre in a 27-month period were considered for analysis. Patients were assessed against criteria for inactive disease and subsequent disease flare. Decisions on whether or not to stop treatment were recorded. MRP8/14 results were assessed in conjunction with clinical information. Clinicians were also surveyed to investigate if MRP8/14 influenced their decision to discontinue MTX where this was available at that time point. One hundred four cases met the inclusion criteria during the study period. Although there was no significant difference in flares between patients with an elevated or low MRP8/14 value, in those who stopped MTX (n = 22), no patients with a low MRP8/14 (≤ 4000 ng/ml) result flared (follow-up time 12 months). Clinicians reported that for patients with clinically inactive disease and an elevated MRP8/14 result (> 4000 ng/ml), none would advise withdrawal of MTX. Low MRP8/14 was interpreted favourably when considering stopping MTX treatment in patients with JIA. Implementation of MRP8/14 testing has changed clinical practice at this centre. However, the observation that some patients in our cohort who had an elevated MRP8/14 value did not flare after stopping MTX for non-disease-related reasons highlights the need for further biomarkers to predict the risk of flare off medication in JIA and aid clinicians in treatment decisions. Key Points • First study of serum MRP8/14 measurement in clinical practice to inform treatment decisions in patients with JIA. • No patients with a low MRP8/14 test result went on to suffer a disease flare in 12 months of follow follow-up. • Further biomarkers are needed to predict the risk of flare off medication in JIA and treatment decisions.
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Abstract
Childhood noninfectious uveitis leads to sight-threatening complications. Idiopathic chronic anterior uveitis and juvenile idiopathic arthritis-associated uveitis are most common. Inflammation arises from an immune response against antigens within the eye. Ophthalmic work-up evaluates anatomic involvement, disease activity, ocular complications, and disease course. Local and/or systemic glucocorticoids are initial treatment, but not as long-term sole therapy to avoid glucocorticoids-induced toxicity or persistent ocular inflammation. Children with recurrent, refractory, or severe disease require systemic immunosuppression with methotrexate and/or anti-tumor necrosis factor monoclonal antibody medications (adalimumab, infliximab). Goals of early detection and treatment are to optimize vision in childhood uveitis.
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Affiliation(s)
- Margaret H Chang
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Fegan 6, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Jessica G Shantha
- Department of Ophthalmology, Emory University, Emory Eye Center, 1365 Clifton Road, Clinic Building B, Atlanta, GA 30326, USA
| | - Jacob J Fondriest
- Department of Internal Medicine, Summa Health System, Internal Medicine Center, 55 Arch Street, Suite 1B, Akron, OH 44304, USA; Rush Eye Center, 1725 West Harrison Street, Suite 945, Chicago, IL 60612, USA
| | - Mindy S Lo
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Fegan 6, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Sheila T Angeles-Han
- Division of Rheumatology, Cincinnati Children's Hospital Medical Center, 3333 Burnett Avenue, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA; Division of Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, USA.
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Reiff DD, Stoll ML, Cron RQ. Precision medicine in juvenile idiopathic arthritis-has the time arrived? THE LANCET. RHEUMATOLOGY 2021; 3:e808-e817. [PMID: 38297525 DOI: 10.1016/s2665-9913(21)00252-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/07/2021] [Accepted: 07/28/2021] [Indexed: 12/14/2022]
Abstract
The introduction of disease-modifying anti-rheumatic drug therapies for treating children and adolescents with chronic arthritis (ie, juvenile idiopathic arthritis [JIA]) has revolutionised care and outcomes. The biologic revolution continues to expand, with ever-changing immunological targets coming to market after basic research and clinical trials. The first class of biologics that was beneficial for children with JIA was tumour necrosis factor (TNF) inhibitors. If used early and aggressively, TNF inhibitors are capable of inducing disease remission for most of the seven subtypes of JIA, with the exception of systemic JIA (which more frequently responds to interleukin [IL]-1 or IL-6 inhibition). Nevertheless, there are still subsets of patients with JIA with disease that is difficult to treat or who develop extra-articular features that require a different therapeutic approach. Although finding an effective biological therapy for individual children with JIA can be trial and error, ongoing research and clinical trials are providing insight into a more personalised approach to care. In addition, redefining the JIA classification, in part based on shared similarities with various adult arthritides, could allow for extrapolation of knowledge from studies in adults with chronic arthritis.
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Affiliation(s)
- Daniel D Reiff
- Department of Pediatrics, Division of Rheumatology, University of Alabama, Birmingham, AL, USA
| | - Matthew L Stoll
- Department of Pediatrics, Division of Rheumatology, University of Alabama, Birmingham, AL, USA
| | - Randy Q Cron
- Department of Pediatrics, Division of Rheumatology, University of Alabama, Birmingham, AL, USA.
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Serum Calprotectin a Potential Biomarker in Juvenile Idiopathic Arthritis: A Meta-Analysis. J Clin Med 2021; 10:jcm10214861. [PMID: 34768386 PMCID: PMC8584429 DOI: 10.3390/jcm10214861] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/15/2021] [Accepted: 10/15/2021] [Indexed: 11/17/2022] Open
Abstract
Juvenile idiopathic arthritis (JIA) is the most common inflammatory chronic disease affecting children and adolescents. Today, there are no specific biomarkers of inflammation. Therefore, it is important to identify new markers as predictors of disease activity. Recently, some researchers have directed their interest toward a protein, calprotectin (CLP), as a potential biomarker. The primary objective of our systematic review and meta-analysis was to analyze the possible role of CLP in JIA. Method: A literature search was conducted using PubMed, EMBASE, Scopus, Science Direct on 10 August 2021. The selection of studies was made using the PRISMA 2020 guidelines. Cohen’s d with 95% CI and p-value were used as a measure of effect size. The random effects model was used to account for different sources of variation among studies. Heterogeneity was assessed using Q statistics and I2. The publication bias was analyzed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger’s test. Results: Our results at follow-up showed a statistically significant difference between patients with active disease compared to patients with inactive disease: 0.39 (0.16; 0.62), p = 0.001; without statistical heterogeneity. Another important aspect that emerged were the differences between the systemic disease form and any form of inactive disease showing a different concentration of calprotectin: 0.74 (0.40; 1.08), p < 0.001; without statistical heterogeneity. On the other hand, meta-regression analyses performed on gender, age, duration of disease, percentage of patients with ANA+ or RF+, medium value of ESR or CRP were not statistically significant. A statistically significant difference in serum calprotectin concentration between patients with JIA and healthy controls were observed. In fact, it presented lower values in the control group. Conclusions: The use of serum CLP could represent, in the future, a useful tool in JIA in order to stratify disease activity more accurately and may aid a more tailored approach to drug of choice in children with JIA. Further studies are needed to evaluate CLP as a predictor of flare in combination with other potential biomarkers of subclinical disease activity.
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Selvestrel D, Lucafò M, Pugnetti L, Pagarin S, Moressa V, Pastore S, Taddio A, Stocco G, Decorti G. Responses of patients with juvenile idiopathic arthritis to methotrexate: a genomic outlook. Expert Rev Clin Immunol 2021; 17:1131-1142. [PMID: 34392756 DOI: 10.1080/1744666x.2021.1968833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/12/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Juvenile idiopathic arthritis (JIA) is a chronic disease characterized by persistent joint inflammation. JIA is the most common pediatric chronic rheumatic disease and no curative therapy is currently available. Methotrexate (MTX) is an important treatment for JIA even though a high inter-individual variability in response is observed in patients. Among the factors of this variability, genetics and epigenetics might play an important role. AREAS COVERED This review summarizes the results of pharmacogenetic and pharmacoepigenetic studies regarding MTX response in JIA. Studies considering epigenetic factors in JIA patients are still very limited, therefore this review includes also studies performed in adult patients with rheumatoid arthritis. Moreover, the relevance of biomarkers measured in blood or urine of JIA patients in relation to MTX treatment is discussed. EXPERT OPINION Nowadays, even though many pharmacogenomics studies have been published, a specific genetic marker predictor of MTX efficacy or adverse events has not yet been identified. Encouraging results are available and great expectations rely on the study of epigenetics. Future studies are needed in order to identify genetic and epigenetic biomarkers that can be implemented in the clinical practice.
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Affiliation(s)
| | - Marianna Lucafò
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health Irccs Burlo Garofolo, Trieste, Italy
| | - Letizia Pugnetti
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Sofia Pagarin
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Valentina Moressa
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health Irccs Burlo Garofolo, Trieste, Italy
| | - Serena Pastore
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health Irccs Burlo Garofolo, Trieste, Italy
| | - Andrea Taddio
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health Irccs Burlo Garofolo, Trieste, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Giuliana Decorti
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health Irccs Burlo Garofolo, Trieste, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
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Worm M, Zidane M, Eisert L, Fischer-Betz R, Foeldvari I, Günther C, Iking-Konert C, Kreuter A, Müller-Ladner U, Nast A, Ochsendorf F, Schneider M, Sticherling M, Tenbrock K, Wenzel J, Kuhn A. S2k-Leitlinie zur Diagnostik und Therapie des kutanen Lupus erythematodes - Teil 2: Therapie, Risikofaktoren und spezielle Fragestellungen. J Dtsch Dermatol Ges 2021; 19:1371-1395. [PMID: 34541800 DOI: 10.1111/ddg.14491_g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 02/20/2021] [Indexed: 01/03/2023]
Affiliation(s)
- Margitta Worm
- Allergologie und Immunologie, Klinik für Dermatologie, Venerologie und Allergologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Miriam Zidane
- Division of Evidence-Based Medicine (dEBM), Klinik für Dermatologie, Venerologie und Allergologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Lisa Eisert
- Klinik für Dermatologie und Venerologie, Vivantes Klinikum Neukölln, Berlin
| | - Rebecca Fischer-Betz
- Poliklinik und Funktionsbereich für Rheumatologie, Universitätsklinikum Düsseldorf, Düsseldorf
| | - Ivan Foeldvari
- Hamburger Zentrum für Kinder- und Jugendrheumatologie, Hamburg
| | - Claudia Günther
- Klinik und Poliklinik für Dermatologie, Universitätsklinikum Carl Gustav Carus, Dresden
| | - Christof Iking-Konert
- Zentrum für Innere Medizin der III. Medizinischen Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg
| | - Alexander Kreuter
- Dermatologie, Venerologie und Allergologie, Helios St. Elisabeth Klinik Oberhausen, Oberhausen
| | - Ulf Müller-Ladner
- Abteilung für Rheumatologie und Klinische Immunologie, Kerckhoff-Klinik GmbH, Bad Nauheim
| | - Alexander Nast
- Division of Evidence-Based Medicine (dEBM), Klinik für Dermatologie, Venerologie und Allergologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Falk Ochsendorf
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Frankfurt, Frankfurt am Main
| | - Matthias Schneider
- Poliklinik und Funktionsbereich für Rheumatologie, Universitätsklinikum Düsseldorf, Düsseldorf
| | | | - Klaus Tenbrock
- Klinik für Kinder- und Jugendmedizin, Uniklinik RWTH Aachen, Aachen
| | - Jörg Wenzel
- Dermatologische Klinik, Universitätsklinikum Bonn, Bonn
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La C, Lê PQ, Ferster A, Goffin L, Spruyt D, Lauwerys B, Durez P, Boulanger C, Sokolova T, Rasschaert J, Badot V. Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis. RMD Open 2021; 7:rmdopen-2021-001646. [PMID: 34108235 PMCID: PMC8191626 DOI: 10.1136/rmdopen-2021-001646] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/17/2021] [Indexed: 11/19/2022] Open
Abstract
Introduction In the management of juvenile idiopathic arthritis (JIA), there is a lack of diagnostic and prognostic biomarkers. This study assesses the use of serum calprotectin (sCal) as a marker to monitor disease activity, and as a classification and prognosis tool of response to treatment or risk of flares in patients with JIA. Methods Eighty-one patients with JIA from the CAP48 multicentric cohort were included in this study, as well as 11 non-paediatric healthy controls. An ELISA method was used to quantify sCal with a commercial kit. Results Patients with an active disease compared with healthy controls and with patients with inactive disease showed an eightfold and a twofold increased level of sCal, respectively. sCal was found to be correlated with the C-reactive protein (CRP) and even more strongly with the erythrocyte sedimentation rate. Evolution of DAS28 scores correlated well with evolution of sCal, as opposed to evolution of CRP. With regard to CRP, sCal could differentiate forms with active oligoarthritis from polyarthritis and systemic forms. However, sCal brought an added value compared with the CRP as a prognosis marker. Indeed, patients with active disease and reaching minimal disease activity (according to Juvenile Arthritis Disease Activity Score) at 6 months following the test had higher sCal levels, while patients with inactive disease had higher sCal levels if a flare was observed up to 3–9 months following the test. Conclusions This study confirms the potential uses of sCal as a biomarker in the diagnosis and follow-up of JIA.
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Affiliation(s)
- Céline La
- Department of Rheumatology, CHU Brugmann, Bruxelles, Belgium .,Department of Pediatric Rheumatology, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium.,Department of Rheumatology, Hôpital Erasme, Bruxelles, Belgium
| | - Phu Quoc Lê
- Department of Pediatric Rheumatology, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium
| | - Alina Ferster
- Department of Pediatric Rheumatology, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium
| | - Laurence Goffin
- Department of Pediatric Rheumatology, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium
| | - Delphine Spruyt
- Laboratory of Bone and Metabolic Biochemistry, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Bernard Lauwerys
- Department of Rheumatology, Cliniques universitaires Saint-Luc, Bruxelles, Belgium
| | - Patrick Durez
- Department of Rheumatology, Cliniques universitaires Saint-Luc, Bruxelles, Belgium
| | - Cecile Boulanger
- Department of Rheumatology, Cliniques universitaires Saint-Luc, Bruxelles, Belgium
| | - Tatiana Sokolova
- Institut de Recherche expérimentale et Clinique (IREC), Université catholique de Louvain Secteur des sciences de la santé, Bruxelles, Belgium
| | - Joanne Rasschaert
- Laboratory of Bone and Metabolic Biochemistry, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Valérie Badot
- Department of Rheumatology, CHU Brugmann, Bruxelles, Belgium
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Worm M, Zidane M, Eisert L, Fischer-Betz R, Foeldvari I, Günther C, Iking-Konert C, Kreuter A, Müller-Ladner U, Nast A, Ochsendorf F, Schneider M, Sticherling M, Tenbrock K, Wenzel J, Kuhn A. S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part 2: Therapy, risk factors and other special topics. J Dtsch Dermatol Ges 2021; 19:1371-1395. [PMID: 34338428 DOI: 10.1111/ddg.14491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 02/20/2021] [Indexed: 11/29/2022]
Affiliation(s)
- Margitta Worm
- Allergology and Immunology, Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
| | - Miriam Zidane
- Division of Evidence-Based Medicine (dEBM), Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
| | - Lisa Eisert
- Department of Dermatology and Venereology, Vivantes Klinikum Neukölln, Berlin
| | | | - Ivan Foeldvari
- Hamburg Center for Pediatric and Adolescent Rheumatology, Hamburg
| | - Claudia Günther
- Department and Clinic of Dermatology, University Hospital Carl Gustav Carus, Dresden
| | - Christof Iking-Konert
- Center for Internal Medicine at the IIIrd Medical Department and Clinic, University Hospital Hamburg-Eppendorf
| | - Alexander Kreuter
- Dermatology, Venereology and Allergology, Helios St. Elisabeth Klinik Oberhausen
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Kerckhoff-Klinik GmbH, Bad Nauheim
| | - Alexander Nast
- Division of Evidence-Based Medicine (dEBM), Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
| | - Falk Ochsendorf
- Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt am Main
| | - Matthias Schneider
- Clinic and Functional Division for Rheumatology, University Hospital Düsseldorf
| | | | - Klaus Tenbrock
- Department of Pediatrics and Adolescent Medicine, University Hospital RWTH Aachen
| | - Jörg Wenzel
- Dermatological Department, University Hospital Bonn
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Gohar F, Windschall D. The new role of musculoskeletal ultrasound in the treat-to-target management of juvenile idiopathic arthritis. Rheumatology (Oxford) 2021; 60:2046-2053. [PMID: 33493330 DOI: 10.1093/rheumatology/keab004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/05/2020] [Accepted: 12/16/2020] [Indexed: 11/12/2022] Open
Abstract
This article reviews the role of musculoskeletal ultrasound (MSUS) for the diagnosis, monitoring and treat-to-target management of JIA. Technological advancements in MSUS allow more precise evaluation of arthritis, tenosynovitis and enthesitis versus clinical examination alone, which may assist treatment decisions. In adult studies, serum and synovial biomarkers have correlated with MSUS findings. Within paediatric rheumatology, significant developments in the definition of normal and pathology, a necessity for the future integration of MSUS into treat-to-target management, have already been reached or are underway, which in turn could allow tighter control of disease activity and earlier identification of treatment response and failure, bringing the goal of 'precision medicine' closer. Additionally, the utility of MSUS for the evaluation of subclinical disease remains an unexamined area of interest. 'Ultrasound remission' combined with clinical assessment and immunological markers could therefore potentially improve the treat-to-target management of JIA.
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Affiliation(s)
- Faekah Gohar
- Clinic of Paediatric and Adolescent Rheumatology, St. Josef-Stift Sendenhorst, Northwest German Center for Rheumatology, Sendenhorst, Germany
| | - Daniel Windschall
- Clinic of Paediatric and Adolescent Rheumatology, St. Josef-Stift Sendenhorst, Northwest German Center for Rheumatology, Sendenhorst, Germany
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41
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Taylor ZL, Thompson LE, Bear H, Mizuno T, Vinks AA, Ramsey LB. Toward pharmacogenetic SLCO1B1-guided dosing of methotrexate in arthritis using a murine Slco1b2 knockout model. Clin Transl Sci 2021; 14:2267-2277. [PMID: 34121338 PMCID: PMC8604247 DOI: 10.1111/cts.13086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/14/2021] [Accepted: 05/20/2021] [Indexed: 11/29/2022] Open
Abstract
Low‐dose methotrexate (MTX) is a first‐line therapy for the treatment of arthritis. However, there is considerable interindividual variability in MTX exposure following standard dosing. Polymorphisms in SLCO1B1 significantly effect MTX clearance, altering therapeutic response. One decreased function variant, rs4149056 (c.521T>C, Val174Ala), slows MTX clearance and in vitro uptake of MTX. This phenotype was recapitulated in a mouse model using a knockout (KO) of the murine orthologue, Slco1b2. Our objective was to investigate the impact of this phenotype on the pharmacokinetics and therapeutic outcomes of low‐dose MTX in a murine model of collagen‐induced arthritis (CIA). We evaluated response to MTX in mice with CIA using wildtype (WT), heterozygous, and KO Slco1b2 mice on a DBA1/J background. Arthritis was macroscopically evaluated daily to quantify disease progression. Mice received 2 mg/kg or a pharmacogenetically guided MTX dose subcutaneously 3 times a week for 2 weeks. MTX concentrations were collected at the end of the study and exposure (day*µM) was estimated using a two‐compartment model. Mice displayed a seven‐fold range in MTX exposure and revealed a significant exposure‐response relationship (p = 0.0027). KO mice receiving the 2 mg/kg dosing regimen had 2.3‐fold greater exposure to MTX (p < 0.0001) and a 66% reduction in overall disease progression (p = 0.011) compared to WT mice. However, exposure and response were equivalent when pharmacogenetically guided dosing was used. These studies demonstrate that an exposure‐response relationship exists for MTX and that Slco1b2 genotype affects MTX exposure and therapeutic response. Such evidence supports the use of SLCO1B1‐pharmacogenetic dosing of low‐dose MTX for patients with arthritis.
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Affiliation(s)
- Zachary L Taylor
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio, USA.,Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Lauren E Thompson
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Heather Bear
- Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Alexander A Vinks
- Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Laura B Ramsey
- Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Gunzinger J, Moore P, Athimalaipet R, Dick A. Adalimumab in the treatment of pediatric patients with chronic noninfectious anterior uveitis. EXPERT REVIEW OF OPHTHALMOLOGY 2021. [DOI: 10.1080/17469899.2021.1935240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
| | - Phoebe Moore
- Department of Uveitis, Bristol Eye Hospital, Bristol, UK
| | - Ramanan Athimalaipet
- Bristol Royal Hospital for Children, Upper Maudlin St, Bristol BS2 8BJ, University Hospitals Bristol NHs Foundation Trust & Translational Health Sciences, University of Bristol, Bristol, UK
| | - Andrew Dick
- Bristol Eye Hospital, Institute of Ophthalmology and the National Institute for Health Research Biomedical Research Centre, Moorfields Eye Hospital and University College London, London, UK
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Ganeva M, Fuehner S, Kessel C, Klotsche J, Niewerth M, Minden K, Foell D, Hinze CH, Wittkowski H. Trajectories of disease courses in the inception cohort of newly diagnosed patients with JIA (ICON-JIA): the potential of serum biomarkers at baseline. Pediatr Rheumatol Online J 2021; 19:64. [PMID: 33933108 PMCID: PMC8088653 DOI: 10.1186/s12969-021-00553-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 04/16/2021] [Indexed: 01/03/2023] Open
Abstract
OBJECTIVE Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory joint disorders with a chronic-remitting disease course. Treat-to-target approaches have been proposed but monitoring disease activity and predicting the response to treatment remains challenging. METHODS We analyzed biomarkers and their relationship to outcome within the first year after JIA diagnosis in the German Inception Cohort of Newly diagnosed patients with JIA (ICON-JIA). CRP, CXCL9, CXCL10, CXCL11, erythrocyte sedimentation rate, G-CSF, IL-6, IL-17A, IL-18, MCP-1, MIP-1α, MMP-3, S100A8/A9, S100A12, TNFα, and TWEAK were measured at baseline and 3 months later. RESULTS Two-hundred-sixty-six JIA patients with active disease at baseline were included, with oligoarthritis and rheumatoid factor-negative polyarthritis representing the most frequent categories (72.9%). Most biomarkers were elevated in JIA compared to healthy pediatric controls. Patients with systemic JIA had higher CRP, S100A8/A9 and S100A12 levels compared to other JIA categories. Baseline levels of TWEAK, G-CSF and IL-18 were lower in oligoarthritis patients with disease extension within 1 year. Increased baseline levels of CRP, S100A8/A9, S100A12 and ESR were associated with the subsequent addition of biologic disease-modifying antirheumatic drugs (DMARDs). Higher baseline ESR, G-CSF, IL-6, IL-17A and TNF levels indicated an increased risk for ongoing disease activity after 12 months. CONCLUSION Our data demonstrate that elevated baseline levels of CRP, S100A8/A9 and S100A12 as well as increased ESR are associated with the necessity to escalate therapy during the first 12 month of follow-up. Furthermore, biomarkers related to Th17 activation may inform on future disease course in previously treatment-naïve JIA patients.
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Affiliation(s)
- Margarita Ganeva
- grid.410563.50000 0004 0621 0092Department of Pediatric Rheumatology, Medical University Sofia, Sofia, Bulgaria ,grid.16149.3b0000 0004 0551 4246Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building D3, D-48149 Muenster, Germany
| | - Sabrina Fuehner
- grid.16149.3b0000 0004 0551 4246Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building D3, D-48149 Muenster, Germany
| | - Christoph Kessel
- grid.16149.3b0000 0004 0551 4246Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building D3, D-48149 Muenster, Germany
| | - Jens Klotsche
- grid.418217.90000 0000 9323 8675Epidemiology Unit, German Rheumatism Research Center, Berlin, Germany
| | - Martina Niewerth
- grid.418217.90000 0000 9323 8675Epidemiology Unit, German Rheumatism Research Center, Berlin, Germany
| | - Kirsten Minden
- grid.418217.90000 0000 9323 8675Epidemiology Unit, German Rheumatism Research Center, Berlin, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building D3, D-48149, Muenster, Germany.
| | - Claas H. Hinze
- grid.16149.3b0000 0004 0551 4246Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building D3, D-48149 Muenster, Germany
| | - Helmut Wittkowski
- grid.16149.3b0000 0004 0551 4246Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building D3, D-48149 Muenster, Germany
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44
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Klotsche J, Klein A, Niewerth M, Hoff P, Windschall D, Foeldvari I, Haas JP, Horneff G, Minden K. Re-treatment with etanercept is as effective as the initial firstline treatment in patients with juvenile idiopathic arthritis. Arthritis Res Ther 2021; 23:118. [PMID: 33863349 PMCID: PMC8050932 DOI: 10.1186/s13075-021-02492-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 03/29/2021] [Indexed: 12/21/2022] Open
Abstract
Objectives To determine (i) correlates for etanercept (ETA) discontinuation after achieving an inactive disease and for the subsequent risk of flare and (ii) to analyze the effectiveness of ETA in the re-treatment after a disease flare. Methods Data from two ongoing prospective registries, BiKeR and JuMBO, were used for the analysis. Both registries provide individual trajectories of clinical data and outcomes from childhood to adulthood in juvenile idiopathic arthritis (JIA) patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) and conventional synthetic DMARDs (csDMARDs). Results A total of 1724 patients were treated first with ETA treatment course (338 with second, 54 with third ETA course). Similar rates of discontinuation due to ineffectiveness and adverse events could be observed for the first (19.4%/6.2%), second (18.6%/5.9%), and third (14.8%/5.6%) ETA course. A total of 332 patients (+/−methotrexate, 19.3%) discontinued ETA after achieving remission with the first ETA course. Younger age (hazard ratio (HR) 1.08, p < 0.001), persistent oligoarthritis (HR 1.89, p = 0.004), and shorter duration between JIA onset and ETA start (HR 1.10, p < 0.001), as well as good response to therapy within the first 6 months of treatment (HR 1.11, p < 0.001) significantly correlated to discontinuation with inactive disease. Reoccurrence of active disease was reported for 77% of patients with mean time to flare of 12.1 months. We could not identify any factor correlating to flare risk. The majority of patients were re-treated with ETA (n = 117 of 161; 72.7%) after the flare. One in five patients (n = 23, 19.7%) discontinued ETA again after achieving an inactive disease and about 70% of the patients achieved an inactive disease 12 months after restarting ETA. Conclusion The study confirms the effectiveness of ETA even for re-treatment of patients with JIA. Our data highlight the association of an early bDMARD treatment with a higher rate of inactive disease indicating a window of opportunity.
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Affiliation(s)
- Jens Klotsche
- German Rheumatism Research Centre, Leibniz Institute, 10117, Berlin, Germany.
| | - Ariane Klein
- Centre for Paediatric Rheumatology, Department of Paediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, Germany.,Department of Pediatrics, Medical Faculty, University of Cologne, Cologne, Germany
| | - Martina Niewerth
- German Rheumatism Research Centre, Leibniz Institute, 10117, Berlin, Germany
| | - Paula Hoff
- Endokrinologikum Berlin, 10117, Berlin, Germany
| | - Daniel Windschall
- Department of Paediatric and Adolescent Rheumatology, North-Western German Centre for Rheumatology, St. Josef-Stift Sendenhorst, Sendenhorst, Germany
| | - Ivan Foeldvari
- Hamburg Centre for Pediatric and Adolescent Rheumatology, Hamburg, Germany
| | - Johannes-Peter Haas
- German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany
| | - Gerd Horneff
- Centre for Paediatric Rheumatology, Department of Paediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, Germany
| | - Kirsten Minden
- German Rheumatism Research Centre, Leibniz Institute, 10117, Berlin, Germany.,Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Murray GM, Sen ES, Ramanan AV. Advancing the treatment of juvenile idiopathic arthritis. THE LANCET. RHEUMATOLOGY 2021; 3:e294-e305. [PMID: 38279412 DOI: 10.1016/s2665-9913(20)30426-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/05/2020] [Accepted: 12/02/2020] [Indexed: 01/28/2024]
Abstract
Treatment for juvenile idiopathic arthritis has undergone substantial changes in recent decades. These changes are partly due to the availability of new treatments, mainly biological agents, as well as developments in treatment strategies, including a focus on concepts such as treat-to-target. In addition, the creation of large paediatric research networks has improved patient access to, and design of, clinical trials for rare paediatric diseases. Although these advances have resulted in improvements in care for most patients with juvenile idiopathic arthritis, certain subgroups of patients continue to have a poor prognosis. Further research aims to identify patients in these subgroups early, to personalise their care, improve functional outcomes, and minimise long-term damage and harm. Optimising the duration of therapy for those individuals who require systemic immunosuppression is also of importance. Incorporation of novel biomarkers in combination with validated clinical measures in an effort to predict outcomes and target therapy accordingly is an exciting development.
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Affiliation(s)
- Grainne M Murray
- Department of Paediatric Rheumatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Ethan S Sen
- Department of Paediatric Rheumatology, Great North Children's Hospital, Newcastle upon Tyne, UK; Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Athimalaipet V Ramanan
- Department of Paediatric Rheumatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK; Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
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46
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Wu J, Zhang S, Li J, Zhong X, Feng G, Hu L, He F, Cen H, Chen Y, He Y, Zeng H, Chen X, Mo X. Simultaneous determination of erythrocyte methotrexate polyglutamates by a novel and simple HPLC-MS/MS method with stable isotope-labeled internal standards. J Sep Sci 2021; 44:1852-1865. [PMID: 33646615 DOI: 10.1002/jssc.202001081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 02/21/2021] [Accepted: 02/23/2021] [Indexed: 11/09/2022]
Abstract
Low-dose methotrexate is the first-line therapy for juvenile idiopathic arthritis. In vivo, methotrexate is converted into a series of methotrexate polyglutamates whose intracellular levels contribute significantly to its efficacy and toxicity. In this study, a novel high-performance liquid chromatography-tandem mass spectrometry method was developed and validated to simultaneously determine erythrocyte methotrexate polyglutamates using stable isotope-labeled internal standards. Erythrocyte samples were precipitated by perchloric acid and then determined on an XBridge BEH C18 column with an XP vanguard precolumn in 12 min. The mobile phase consisted of 10 nM ammonium acetate (pH 10) and methanol under gradient elution. The detection was carried out in multiple reaction monitoring mode via an electrospray ionization source in positive ionization mode. The calibration curve for each metabolite was linear from 2.0 to 500.0 nmol/L (r2 > 0.99). The intraday and interday accuracies were between 93.0 and 107.0%, and the corresponding precisions were between 0.8 and 5.2%. The relative recovery ranged from 82.7 to 105.1%, and the relative matrix effect varied from 96.5 to 104.4%. The erythrocyte metabolites were stable for 30 days at -80°C. This simple and accurate method is applicable to routine monitoring of the concentration of erythrocyte methotrexate polyglutamates in patients to achieve individualized treatment.
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Affiliation(s)
- Jingjing Wu
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Song Zhang
- Pediatric Allergy Immunology & Rheumatology Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China
| | - Jiali Li
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, P. R. China
| | - Xiaoli Zhong
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, P. R. China
| | - Guiping Feng
- Pediatric Allergy Immunology & Rheumatology Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China
| | - Liangqing Hu
- Pediatric Allergy Immunology & Rheumatology Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China
| | - Fan He
- Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China
| | - Hanjing Cen
- Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China
| | - Yilu Chen
- Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China
| | - Yanling He
- Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China
| | - Huasong Zeng
- Pediatric Allergy Immunology & Rheumatology Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China
| | - Xiao Chen
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Xiaolan Mo
- Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, P. R. China
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Choida V, Hall-Craggs M, Jebson BR, Fisher C, Leandro M, Wedderburn LR, Ciurtin C. Biomarkers of Response to Biologic Therapy in Juvenile Idiopathic Arthritis. Front Pharmacol 2021; 11:635823. [PMID: 33603671 PMCID: PMC7884612 DOI: 10.3389/fphar.2020.635823] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 12/31/2020] [Indexed: 01/22/2023] Open
Abstract
Background: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthritis of childhood, characterized by various clinical phenotypes associated with variable prognosis. Significant progress has been achieved with the use of biologic treatments, which specifically block pro-inflammatory molecules involved in the disease pathogenesis. The most commonly used biologics in JIA are monoclonal antibodies and recombinant proteins targeting interleukins 1 (IL-1) and 6 (IL-6), and tumor necrosis factor α (TNF-α). Several biomarkers have been investigated in JIA. Aims: To assess the level of evidence available regarding the role of biomarkers in JIA related to guiding clinical and therapeutic decisions, providing disease prognostic information, facilitating disease activity monitoring and assessing biologic treatment response in JIA, as well as propose new strategies for biologic therapy-related biomarker use in JIA. Methods: We searched PubMed for relevant literature using predefined key words corresponding to several categories of biomarkers to assess their role in predicting and assessing biologic treatment response and clinical remission in JIA. Results: We reviewed serological, cellular, genetic, transcriptomic and imaging biomarkers, to identify candidates that are both well-established and widely used, as well as newly investigated in JIA on biologic therapy. We evaluated their role in management of JIA as well as identified the unmet needs for new biomarker discovery and better clinical applications. Conclusion: Although there are no ideal biomarkers in JIA, we identified serological biomarkers with potential clinical utility. We propose strategies of combining biomarkers of response to biologics in JIA, as well as routine implementation of clinically acceptable imaging biomarkers for improved disease assessment performance.
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Affiliation(s)
- Varvara Choida
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, Division of Medicine, University College London, London, United Kingdom
- Department of Adolescent Rheumatology, University College London Hospital, London, United Kingdom
| | | | - Bethany R. Jebson
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, Division of Medicine, University College London, London, United Kingdom
- University College London Great Ormond Street Institute for Child Health, London, United Kingdom
| | - Corinne Fisher
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, Division of Medicine, University College London, London, United Kingdom
- Department of Adolescent Rheumatology, University College London Hospital, London, United Kingdom
| | - Maria Leandro
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, Division of Medicine, University College London, London, United Kingdom
- Department of Adolescent Rheumatology, University College London Hospital, London, United Kingdom
| | - Lucy R. Wedderburn
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, Division of Medicine, University College London, London, United Kingdom
- University College London Great Ormond Street Institute for Child Health, London, United Kingdom
- NIHR Biomedical Research Centre at Great Ormond Street Hospital, London, United Kingdom
| | - Coziana Ciurtin
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, Division of Medicine, University College London, London, United Kingdom
- Department of Adolescent Rheumatology, University College London Hospital, London, United Kingdom
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48
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Chausset A, Pereira B, Echaubard S, Merlin E, Freychet C. Access to paediatric rheumatology care in juvenile idiopathic arthritis: what do we know? A systematic review. Rheumatology (Oxford) 2021; 59:3633-3644. [PMID: 32940701 DOI: 10.1093/rheumatology/keaa438] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/28/2020] [Accepted: 06/21/2020] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVE This review examines time to access appropriate care for JIA patients and analyses the referral pathway before the first paediatric rheumatology (PR) visit. We also describe factors associated with a longer referral. METHODS We performed a systematic literature review, screening electronic databases (PubMed, Web of Science, EMBASE, Cochrane library and Open Grey database) up to February 2020. Articles written before 1994 (i.e. before the introduction of the unifying term JIA) were excluded. RESULTS From 595 nonduplicate citations found, 15 articles were finally included in the review. Most of the studies took place in Europe. The median time to first PR visit ranged from 3 to 10 months, with some disparities between referral pathway and patient characteristics. Patients with systemic-onset JIA had the shortest time to referral. Some clinical and biological factors such as swelling, fever, and elevated CRP and/or ESR were associated with a shorter time to first PR visit. Conversely, enthesitis, older age at symptom onset or pain were associated with a longer time. Whatever the country or world region, and despite disparities in healthcare system organization and healthcare practitioner availabilities, times to access PR were not wide-ranging. CONCLUSION This is the first systematic review to summarize research on access to PR for JIA patients. The pathway of care for JIA patients remains complex, and reasons for delayed referral depend on several factors. Standardized clinical guidelines and fast-track pathways to facilitate prompt referral to specialized teams have to allow for worldwide disparities in healthcare provision.
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Affiliation(s)
- Aurélie Chausset
- Department of Pediatrics, Clermont Ferrand University Hospital, Clermont-Ferrand.,CRECHE Unit, INSERM, CIC 1405, Clermont Auvergne University, Clermont-Ferrand
| | - Bruno Pereira
- Department of Biostatistics, Clermont Ferrand University Hospital, Clermont-Ferrand
| | - Stéphane Echaubard
- Department of Pediatrics, Clermont Ferrand University Hospital, Clermont-Ferrand
| | - Etienne Merlin
- Department of Pediatrics, Clermont Ferrand University Hospital, Clermont-Ferrand.,CRECHE Unit, INSERM, CIC 1405, Clermont Auvergne University, Clermont-Ferrand
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Ruperto N, Brunner HI, Pacheco-Tena C, Louw I, Vega-Cornejo G, Spindler AJ, Kingsbury DJ, Schmeling H, Borzutzky A, Cuttica R, Inman CJ, Malievskiy V, Scott C, Keltsev V, Terreri MT, Viola DO, Xavier RM, Fernandes TAP, Velázquez MDRM, Henrickson M, Clark MB, Bensley KA, Li X, Lo KH, Leu JH, Hsu CH, Hsia EC, Xu Z, Martini A, Lovell DJ. Open-Label Phase 3 Study of Intravenous Golimumab in Patients With Polyarticular Juvenile Idiopathic Arthritis. Rheumatology (Oxford) 2021; 60:4495-4507. [PMID: 33493312 PMCID: PMC8487314 DOI: 10.1093/rheumatology/keab021] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/23/2020] [Indexed: 11/12/2022] Open
Abstract
Objectives To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA). Methods Children aged 2 to <18 years with active pc-JIA despite MTX therapy for ≥2 months received 80 mg/m2 golimumab at weeks 0, 4, then every 8 weeks through week 52 plus MTX weekly through week 28. The primary and major secondary endpoints were PK exposure and model-predicted steady-state area under the curve (AUCss) over an 8-week dosing interval at weeks 28 and 52, respectively. JIA ACR response and safety were also assessed. Results In total, 127 children were treated with i.v. golimumab. JIA ACR 30, 50, 70, and 90 response rates were 84%, 80%, 70% and 47%, respectively, at week 28 and were maintained through week 52. Golimumab serum concentrations and AUCss were 0.40 µg/ml and 399 µg ⋅ day/ml at week 28. PK exposure was maintained at week 52. Steady-state trough golimumab concentrations and AUCss were consistent across age categories and comparable to i.v. golimumab dosed 2 mg/kg in adults with rheumatoid arthritis. Golimumab antibodies and neutralizing antibodies were detected via a highly sensitive drug-tolerant assay in 31% (39/125) and 19% (24/125) of patients, respectively. Median trough golimumab concentration was lower in antibody-positive vs antibody-negative patients. Serious infections were reported in 6% of patients, including one death due to septic shock. Conclusion Body surface area-based dosing of i.v. golimumab was well tolerated and provided adequate PK exposure for clinical efficacy in paediatric patients with active pc-JIA. ClinicalTrials.gov number NCT02277444
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Affiliation(s)
- Nicolino Ruperto
- IRCCS Istituto Giannina Gaslini, Clinica Pediatrica e Reumatologia, PRINTO, Genoa, Italy
| | - Hermine I Brunner
- Cincinnati Children's Hospital Medical Center, Division of Rheumatology, University of Cincinnati, Cincinnati, Ohio, United States of America
| | - César Pacheco-Tena
- Facultad de Medicina, Universidad Autónoma de Chihuahua, Circuito Universitario Campus II, Chihuahua, México
| | - Ingrid Louw
- Panorama Medical Centre, Rheumatology Private Practice, Cape Town, South Africa
| | - Gabriel Vega-Cornejo
- Centro de Reumatología y Autoinmunidad (CREA)/Hospital México Americano, Guadalajara, Jalisco, México
| | - Alberto J Spindler
- Centro Médico Privado de Reumatología, Rheumatology Section, San Miguel de Tucuman, Tucuman, Argentina
| | - Daniel J Kingsbury
- Randall Children's Hospital at Legacy Emanuel, Portland, Oregon, United States of America
| | - Heinrike Schmeling
- Alberta Children's Hospital and Department of Pediatrics, Cumming School of Medicine/University of Calgary, Calgary, Alberta, Canada
| | - Arturo Borzutzky
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rubén Cuttica
- Rheumatology Section, Hospital Pedro de Elizalde, Buenos Aires, Argentina
| | - C J Inman
- Pediatric Rheumatology, University of Utah, Salt Lake City, Utah, United States of America
| | - Victor Malievskiy
- Federal State Budget Educational Institution of Higher Education, Bashkir State Medical University of the Ministry of Healthcare of Russian Federation, Cape Town, South Africa
| | - Christiaan Scott
- Red Cross War Memorial Children's Hospital and Groote Schuur Hospital, Paediatric Rheumatology, University of Cape Town, Cape Town, South Africa
| | - Vladimir Keltsev
- Pediatric Department, Togliatti City Clinical Hospital No. 5, Togliatti, Russian Federation
| | - Maria Teresa Terreri
- Escola Paulista de Medicina/Universidade Federal de São Paulo, Pediatrics, São Paulo, Brazil
| | | | - Ricardo M Xavier
- Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | | | - Michael Henrickson
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Michael B Clark
- Janssen Research & Development, LLC, Spring House, Pennsylvania, United States of America
| | - Karen A Bensley
- Janssen Research & Development, LLC, Spring House, Pennsylvania, United States of America
| | - Xiaoming Li
- Janssen Research & Development, LLC, Spring House, Pennsylvania, United States of America
| | - Kim Hung Lo
- Janssen Research & Development, LLC, Spring House, Pennsylvania, United States of America
| | - Jocelyn H Leu
- Janssen Research & Development, LLC, Spring House, Pennsylvania, United States of America
| | - Chyi-Hung Hsu
- Janssen Research & Development, LLC, Raritan, New Jersey, United States of America
| | - Elizabeth C Hsia
- Janssen Research & Development, LLC, Spring House, Pennsylvania, United States of America
| | - Zhenhua Xu
- Janssen Research & Development, LLC, Spring House, Pennsylvania, United States of America
| | - Alberto Martini
- Università degli Studi di Genova, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DiNOGMI), Genova, Italy
| | - Daniel J Lovell
- Cincinnati Children's Hospital Medical Center, Division of Rheumatology, University of Cincinnati, Cincinnati, Ohio, United States of America
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50
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Barendregt AM, Veldkamp SR, Hissink Muller PCE, van de Geer A, Aarts C, van Gulik EC, Schilham MW, Kessel C, Keizer MP, Hemke R, Nassar-Sheikh Rashid A, Dolman KM, Schonenberg-Meinema D, Ten Cate R, van den Berg JM, Maas M, Kuijpers TW. MRP8/14 and neutrophil elastase for predicting treatment response and occurrence of flare in patients with juvenile idiopathic arthritis. Rheumatology (Oxford) 2021; 59:2392-2401. [PMID: 31904851 PMCID: PMC7449815 DOI: 10.1093/rheumatology/kez590] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 10/22/2019] [Indexed: 11/25/2022] Open
Abstract
Objective To study two neutrophil activation markers, myeloid-related protein (MRP) 8/14 and neutrophil elastase (NE), for their ability to predict treatment response and flare in patients with JIA. Methods Using samples from two cohorts (I and II), we determined MRP8/14 and NE levels of 32 (I) and 81 (II) patients with new-onset, DMARD-naïve arthritis and compared patients who responded to treatment (defined as fulfilling ≥ adjusted ACRpedi50 response and/or inactive disease) with non-responders (defined as fulfilling < adjusted ACRpedi50 response and/or active disease) at 6 and 12 months. Secondly, we compared biomarker levels of 54 (I) and 34 (II) patients with clinically inactive disease who did or did not suffer from a flare of arthritis after 6 or 12 months. Receiver operating characteristic analyses were carried out to study the predictive value of MRP8/14 and NE for treatment response and flare. Results For both cohorts, baseline MRP8/14 and NE levels for patients who did or did not respond to treatment were not different. Also, MRP8/14 and NE levels were not different in patients who did or did not flare. Receiver operating characteristic analysis of MRP8/14 and NE demonstrated areas under the curve <0.7 in both cohorts. Conclusion In our cohorts, MRP8/14 and NE could not predict treatment response. Also, when patients had inactive disease, neither marker could predict flares.
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Affiliation(s)
- Anouk M Barendregt
- Department of Paediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam.,Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam
| | - Saskia R Veldkamp
- Department of Paediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam
| | | | | | - Cathelijn Aarts
- Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands
| | - E Charlotte van Gulik
- Department of Paediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam.,Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam
| | - Marco W Schilham
- Department of Paediatric Rheumatology, Leiden University Medical Center, Leiden
| | - Christoph Kessel
- Department of Paediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, Germany
| | - Mischa P Keizer
- Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands
| | - Robert Hemke
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam
| | - Amara Nassar-Sheikh Rashid
- Department of Paediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam
| | - Koert M Dolman
- Department of Paediatric Rheumatology, Reade, Amsterdam.,Department of Paediatrics, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Dieneke Schonenberg-Meinema
- Department of Paediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam
| | - Rebecca Ten Cate
- Department of Paediatric Rheumatology, Leiden University Medical Center, Leiden
| | - J Merlijn van den Berg
- Department of Paediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam
| | - Mario Maas
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam
| | - Taco W Kuijpers
- Department of Paediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam.,Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands
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