EULAR/ACR risk stratification criteria for development of rheumatoid arthritis in the risk stage of arthralgia

Hanna W van Steenbergen¹, Frank Doornkamp², Stefano Alivernini³, John Backlund⁴, Catalin Codreanu⁵, Stanley B Cohen⁶, Bernard Combe⁷, Andrew P Cope⁸, Kevin D Deane⁹, Bryant R England¹⁰, Marie Falahee¹¹, Pascal H P de Jong¹², Arnd Kleyer¹³, Diane Lacaille¹⁴, Bertha Maat¹⁵, Kulveer Mankia¹⁶, Elise van Mulligen¹⁷, György Nagy¹⁸, Liam J O'Neil¹⁹, Linda Rodamaker²⁰, Ilfita Sahbudin²¹, Dirkjan van Schaardenburg²², Alexandre Sepriano²³, Jose A P da Silva²⁴, Lukas De Smet¹, Jeffrey A Sparks²⁵, Ewout W Steyerberg², Paul Studenic²⁶, Elisabeth Wethington²⁷, Robert L Landewé²⁸, Karim Raza²⁹, Annette H M van der Helm-van Mil³⁰

Affiliations

¹ Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
² Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands.
³ Division of Rheumatology, Fondazione Policlinico Universitário A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico-Università Cattolica del Sacro Cuore, Rome, Italy.
⁴ At-risk participant.
⁵ Center for Rheumatic Diseases, University of Medicine and Pharmacy, Bucharest, Romania.
⁶ University of Texas Southwestern Medical School, Dallas, TX, USA.
⁷ Montpellier University, Montpellier, France.
⁸ Centre for Rheumatic Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK.
⁹ University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁰ Veterans Affairs Nebraska-Western Iowa Health Care System & University of Nebraska Medical Center, Omaha, NE, USA.
¹¹ Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK.
¹² Department of Rheumatology, Erasmus Medical Centre, Rotterdam, the Netherlands.
¹³ Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Internal Medicine 3, Rheumatology and Immunology University Hospital Erlangen and Friedrich Alexander University (FAU), Erlangen, Germany.
¹⁴ Arthritis Research Canada, Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁵ Patient Research Partner European Alliance of Associations for Rheumatology People with Arthritis and Rheumatism in Europe and National Association ReumaZorg Nederland, the Netherlands.
¹⁶ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and National Institute for Health and Care Research Leeds Biomedical Research Centre, Leeds Teaching Hospitals National Health Services Trust, Leeds, UK.
¹⁷ Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Rheumatology, Erasmus Medical Centre, Rotterdam, the Netherlands.
¹⁸ Department of Rheumatology and Clinical Immunology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary; Heart and Vascular Center, Semmelweis University, Budapest, Hungary; Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary; National Institute of Locomotor Diseases and Disabilities, Budapest, Hungary.
¹⁹ Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
²⁰ Department of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA.
²¹ Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK; National Institute for Health and Care Research Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
²² Amsterdam Rheumatology Center, Reade, Amsterdam, the Netherlands.
²³ Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands; Nova Medical School, Universidade Nova de Lisboa, Lisboa, Portugal.
²⁴ Department of Rheumatology, Centro Hospitalar e Universitário de Coimbra, Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Portugal.
²⁵ Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁶ Department of Internal Medicine 3, Division of Rheumatology, Medical University of Vienna, Vienna, Austria; Department of Medicine (Solna), Division of Rheumatology, Karolinska Institute, Stockholm, Sweden.
²⁷ Patient research partner, Department of Information Services and Technology, National Jewish Health, Denver, CO, USA.
²⁸ Rheumatology & Clinical Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands; Department of Rheumatology, Zuyderland Medical Center, Heerlen, the Netherlands.
²⁹ Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK; Department of Rheumatology, Bronglais Hospital, Hywel Dda University Health Board, Aberystwyth, UK.
³⁰ Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Rheumatology, Erasmus Medical Centre, Rotterdam, the Netherlands. Electronic address: a.h.m.van_der_helm@lumc.nl.

PMID: 40447498
DOI: 10.1016/j.ard.2025.01.021

EULAR/ACR risk stratification criteria for development of rheumatoid arthritis in the risk stage of arthralgia

Hanna W van Steenbergen et al. Ann Rheum Dis. 2025 Sep.

. 2025 Sep;84(9):1445-1457.

doi: 10.1016/j.ard.2025.01.021. Epub 2025 May 8.

Authors

Affiliations

¹ Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
² Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands.
³ Division of Rheumatology, Fondazione Policlinico Universitário A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico-Università Cattolica del Sacro Cuore, Rome, Italy.
⁴ At-risk participant.
⁵ Center for Rheumatic Diseases, University of Medicine and Pharmacy, Bucharest, Romania.
⁶ University of Texas Southwestern Medical School, Dallas, TX, USA.
⁷ Montpellier University, Montpellier, France.
⁸ Centre for Rheumatic Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK.
⁹ University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁰ Veterans Affairs Nebraska-Western Iowa Health Care System & University of Nebraska Medical Center, Omaha, NE, USA.
¹¹ Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK.
¹² Department of Rheumatology, Erasmus Medical Centre, Rotterdam, the Netherlands.
¹³ Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Internal Medicine 3, Rheumatology and Immunology University Hospital Erlangen and Friedrich Alexander University (FAU), Erlangen, Germany.
¹⁴ Arthritis Research Canada, Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁵ Patient Research Partner European Alliance of Associations for Rheumatology People with Arthritis and Rheumatism in Europe and National Association ReumaZorg Nederland, the Netherlands.
¹⁶ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and National Institute for Health and Care Research Leeds Biomedical Research Centre, Leeds Teaching Hospitals National Health Services Trust, Leeds, UK.
¹⁷ Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Rheumatology, Erasmus Medical Centre, Rotterdam, the Netherlands.
¹⁸ Department of Rheumatology and Clinical Immunology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary; Heart and Vascular Center, Semmelweis University, Budapest, Hungary; Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary; National Institute of Locomotor Diseases and Disabilities, Budapest, Hungary.
¹⁹ Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
²⁰ Department of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA.
²¹ Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK; National Institute for Health and Care Research Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
²² Amsterdam Rheumatology Center, Reade, Amsterdam, the Netherlands.
²³ Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands; Nova Medical School, Universidade Nova de Lisboa, Lisboa, Portugal.
²⁴ Department of Rheumatology, Centro Hospitalar e Universitário de Coimbra, Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Portugal.
²⁵ Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁶ Department of Internal Medicine 3, Division of Rheumatology, Medical University of Vienna, Vienna, Austria; Department of Medicine (Solna), Division of Rheumatology, Karolinska Institute, Stockholm, Sweden.
²⁷ Patient research partner, Department of Information Services and Technology, National Jewish Health, Denver, CO, USA.
²⁸ Rheumatology & Clinical Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands; Department of Rheumatology, Zuyderland Medical Center, Heerlen, the Netherlands.
²⁹ Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, UK; Department of Rheumatology, Bronglais Hospital, Hywel Dda University Health Board, Aberystwyth, UK.
³⁰ Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Rheumatology, Erasmus Medical Centre, Rotterdam, the Netherlands. Electronic address: a.h.m.van_der_helm@lumc.nl.

PMID: 40447498
DOI: 10.1016/j.ard.2025.01.021

Abstract

Objectives: The field of rheumatoid arthritis (RA) is moving towards identification of and intervention in people at risk of RA, but a validated risk stratification method is lacking. This work was undertaken to develop a risk stratification method for persons presenting with arthralgia considered to be at risk of RA.

Methods: A joint European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) expert committee was established. Risk factor and outcome data from 10 arthralgia cohorts (including clinically suspect arthralgia and autoantibody-positive arthralgia) were studied. The work focused on differentiating the risk of progression to clinically apparent inflammatory arthritis (IA) within 1 year, using clinical and serologic variables, without and with subclinical joint inflammation detected by ultrasound (US) or magnetic resonance imaging (MRI). Developing RA according to the 2010 EULAR/ACR criteria within 1 year was a secondary outcome. A set of validated risk stratification criteria was developed.

Results: Using data from 2293 symptomatic at-risk individuals, a stratification method was derived consisting of 6 clinical and serologic variables (morning stiffness, patient-reported joint swelling, difficulty making a fist, C-reactive protein, rheumatoid factor, and anti-citrullinated peptide antibody) yielding an area under the curve (AUC) of 0.80 (95% CI, 0.77-0.83) for IA development. The inclusion of US variables did not increase the discriminative ability. When MRI-detected subclinical inflammation variables were included, the AUC was 0.87 (95% CI, 0.82-0.90). In the presence of clinical, serologic, and MRI variables, a sensitivity and specificity of >75% was achieved. For RA development, the AUC of the criteria with MRI was 0.93 (95% CI, 0.90-0.97).

Conclusions: EULAR/ACR risk stratification criteria have been developed for people with arthralgia in secondary care who are considered at risk for RA. They can be applied in the absence or presence of imaging data and have been developed to define homogeneous risk groups for future prevention trials.

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Conflict of interest statement

Competing interests The authors reported the following competing interests, outside the submitted work. SA–grants or contracts: Novartis, AbbVie; payment for lectures: AbbVie, Eli Lilly, Sandoz. CC–payment or honoraria for lectures: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis, Pfizer, Sobi; leadership or fiduciary role in other board: President-elect of Romanian Society of Rheumatology, President of Romanian Registry of Rheumatic Diseases. SBC–grants or contracts: investigator and consultant Amgen, AbbVie, BMS, Pfizer; consulting fees: Amgen, AbbVie, BMS, Pfizer; payment or honoraria for lectures: Pfizer; participation on a data safety monitoring board (DSMB): Gilead. APC–grants or contracts: BMS, UCB; consulting fees: BMS, Galvani, Janssen, UCB, Lilly; payment or honoraria for lectures: BMS, Galapagos; leadership or fiduciary role in other board: chair EULAR Research Centre Clinical Research subcommittee. KD–payment or honoraria for lectures: Werfen, ThermoFisher; receipt of equipment, materials: Werfen. BE–grants or contracts: Boehringer Ingelheim; consulting fees: Boehringer Ingelheim. AK–consulting fees: Novartis Deutschland GmbH, Eli Lilly Deutschland GmbH, Gilead Sciences, Medac GmbH. KM–grants or contracts: Gilead, Lilly, Serac Healthcare, Astra Zeneca; consulting fees: Galapagos, Lilly, Serac Healthcare, Deepcure, Zura Bio; payment or honoraria for lectures: AbbVie, Galapagos; support for attending meetings and/or travel: Lilly; participation on a DSMB: Galapagos. LJON–consulting fees: Fresenius Kabi, UCB; payment or honoraria for lectures: AbbVie. AS–grants or contracts: FOREUM; consulting fees: AbbVie, UCB, Novartis; payment of honoraria for lectures: Lilly, AbbVie; support for attending meetings and/or travel: Janssen, Lilly; leadership of fiduciary role in other board: editor in chief ARP Rheumatology, associate editor RMD Open. JAPdS–consulting fees: Amgen, Fresenius Kabi; payment or honoraria for lectures: UCB, Amgen; participation on a DSMB: Fresenius Kabi. JAS–grants or contracts: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Rheumatology Research Foundation, R. Bruce and Joan M. Mickey Research Scholar Fund, Gordon and Llura Gund Foundation, BMS, Boehringer Ingelheim, Sonoma Biotherapeutics; consulting fees: AbbVie, Amgen, Boehringer Ingelheim, BMS, Gilead, Inova Diagnostics, Johnson & Johnson, MustangBio, Optum, Pfizer, ReCor, Sana, Sobi, UCB. PS–grants or contracts: FOREUM, Horizon/HADEA, AAL, EUREKA, Jubiläumsfond der Stadt Wien; consulting fees: AbbVie; payment or honoraria for lectures: AstraZeneca; support for attending meetings and/or travel: Janssen, Galapagos. RL–payment or honoraria for lectures: AbbVie, UCB, Pfizer, Galapagos, Janssen Pharma, Novartis, Lilly; participation on a DSMB: UCB SLE trial; leadership or fiduciary role in other board: ASA board; other financial or nonfinancial interests: director of Rheumatology Consultancy BV, director of Joint Imaging BV. KR–grants or contracts: BMS.

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EULAR/ACR risk stratification criteria for development of rheumatoid arthritis in the risk stage of arthralgia

Affiliations

EULAR/ACR risk stratification criteria for development of rheumatoid arthritis in the risk stage of arthralgia

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials