EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis

doi:10.1136/annrheumdis-2021-220884

Guideline

. 2021 Oct;80(10):1286-1298.

doi: 10.1136/annrheumdis-2021-220884. Epub 2021 Aug 6.

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis

Kulveer Mankia^{1

2}, Heidi J Siddle^{3

2}, Andreas Kerschbaumer⁴, Deshire Alpizar Rodriguez⁵, Anca Irinel Catrina⁶, Juan D Cañete⁷, Andrew P Cope⁸, Claire Immediato Daien⁹, Kevin D Deane¹⁰, Hani El Gabalawy¹¹, Axel Finckh¹², V Michael Holers¹³, Marios Koloumas¹⁴, Francesca Ometto¹⁵, Karim Raza^{16

17}, Condruta Zabalan¹⁴, Annette van der Helm-van Mil^{18

19}, Dirkjan van Schaardenburg^{20

21}, Daniel Aletaha²², Paul Emery^{23

24}

Affiliations

¹ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK k.s.mankia@leeds.ac.uk.
² NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, UK.
³ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
⁴ Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria.
⁵ Research Unit, Mexican College of Rheumatology, Coyoacan, Mexico.
⁶ Rheumatology Unit, -, Stockholm, Sweden.
⁷ Department of Rheumatology, Arthritis Unit, Hospital Clinic and IDIBAPS, Barcelona, Spain.
⁸ Faculty of Life Sciences and Medicine, Centre for Rheumatic Diseases, King's College London, London, UK.
⁹ Department of Rheumatology, CHU de Montpellier, University of Montpellier, PhyMedExp, INSERM, CNRS UMR, Montpellier, France.
¹⁰ Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
¹¹ Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
¹² Division of Rheumatology, University of Geneva, Geneva, Switzerland.
¹³ Division of Rheumatology, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
¹⁴ EULAR PARE, Kilchberg, Switzerland.
¹⁵ Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy.
¹⁶ Centre for Musculoskeletal Ageing Research and Research into Inflammatory Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
¹⁷ Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
¹⁸ Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁹ Department of Rheumatology, Erasmus Medical Center, Rotterdam, The Netherlands.
²⁰ Department of Rheumatology, Academic Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.
²¹ Department of Rheumatology, Reade, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands.
²² Department of Rheumatology, Medical University of Vienna, Vienna, Austria.
²³ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK.
²⁴ NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

PMID: 34362746
PMCID: PMC8458095
DOI: 10.1136/annrheumdis-2021-220884

Guideline

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis

Kulveer Mankia et al. Ann Rheum Dis. 2021 Oct.

. 2021 Oct;80(10):1286-1298.

doi: 10.1136/annrheumdis-2021-220884. Epub 2021 Aug 6.

Authors

Affiliations

¹ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK k.s.mankia@leeds.ac.uk.
² NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, UK.
³ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
⁴ Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria.
⁵ Research Unit, Mexican College of Rheumatology, Coyoacan, Mexico.
⁶ Rheumatology Unit, -, Stockholm, Sweden.
⁷ Department of Rheumatology, Arthritis Unit, Hospital Clinic and IDIBAPS, Barcelona, Spain.
⁸ Faculty of Life Sciences and Medicine, Centre for Rheumatic Diseases, King's College London, London, UK.
⁹ Department of Rheumatology, CHU de Montpellier, University of Montpellier, PhyMedExp, INSERM, CNRS UMR, Montpellier, France.
¹⁰ Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
¹¹ Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
¹² Division of Rheumatology, University of Geneva, Geneva, Switzerland.
¹³ Division of Rheumatology, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
¹⁴ EULAR PARE, Kilchberg, Switzerland.
¹⁵ Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy.
¹⁶ Centre for Musculoskeletal Ageing Research and Research into Inflammatory Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
¹⁷ Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
¹⁸ Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁹ Department of Rheumatology, Erasmus Medical Center, Rotterdam, The Netherlands.
²⁰ Department of Rheumatology, Academic Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.
²¹ Department of Rheumatology, Reade, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands.
²² Department of Rheumatology, Medical University of Vienna, Vienna, Austria.
²³ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK.
²⁴ NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

PMID: 34362746
PMCID: PMC8458095
DOI: 10.1136/annrheumdis-2021-220884

Abstract

Background: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA).

Methods: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC.

Results: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach.

Conclusion: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

Keywords: arthritis; autoantibodies; autoimmunity; rheumatoid.

PubMed Disclaimer

Conflict of interest statement

Competing interests: KM: honoraria from Abbvie, Eli Lilly & Co and UCB; grants from Eli Lilly & Co and Gilead. HJS: none declared. AK: speakers bureau, consultancy: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly & Co, Gilead, Merck Sharp and Dohme, Novartis and Pfizer. DAR: scientific advisor for GSK. AIC, JDC and APC: none declared. CID: honoraria from Roche, Chugai, Pfizer, BMS, MSD, Biogen, Abbvie, Sandoz, Janssen, Novartis, Fresenius Kabi and Sanofi; research grants from Pfizer, MSD and Schwa Medico. KR: speaker fees from Abbvie. PE: expert advice to Pfizer, Abbvie, Amgen, MSD, Roche, Sanofi, BMS, Novartis, Eli Lilly & Co, Gilead, Samsung and Celltrion; grants from Abbvie, Eli Lilly & Co, BMS and Samsung.

Figures

**Figure 1**
A summary of assessments and end-points which should be collected in clinical trials and observational studies of individuals at risk of RA, according to the at-risk population. MSK, musculoskeletal; RA, rheumatoid arthritis.

See this image and copyright information in PMC

Cited by

Added value of multiple autoantibody testing for predicting progression to inflammatory arthritis in at-risk individuals.
Ponchel F, Duquenne L, Xie X, Corscadden D, Shuweihdi F, Mankia K, Trouw LA, Emery P. Ponchel F, et al. RMD Open. 2022 Dec;8(2):e002512. doi: 10.1136/rmdopen-2022-002512. RMD Open. 2022. PMID: 36535711 Free PMC article.
Perceptions and experiences of individuals at-risk of rheumatoid arthritis (RA) knowing about their risk of developing RA and being offered preventive treatment: systematic review and thematic synthesis of qualitative studies.
Siddle HJ, Chapman LS, Mankia K, Zăbălan C, Kouloumas M, Raza K, Falahee M, Kerry J, Kerschbaumer A, Aletaha D, Emery P, Richards SH. Siddle HJ, et al. Ann Rheum Dis. 2022 Feb;81(2):159-168. doi: 10.1136/annrheumdis-2021-221160. Epub 2021 Nov 8. Ann Rheum Dis. 2022. PMID: 34750103 Free PMC article.
Acceptable risks of treatments to prevent rheumatoid arthritis among first-degree relatives: demographic and psychological predictors of risk tolerance.
Simons G, Janssen EM, Veldwijk J, DiSantostefano RL, Englbrecht M, Radawski C, Valor-Méndez L, Humphreys JH, Bruce IN, Hauber B, Raza K, Falahee M. Simons G, et al. RMD Open. 2022 Dec;8(2):e002593. doi: 10.1136/rmdopen-2022-002593. RMD Open. 2022. PMID: 36598004 Free PMC article.
The So-Called Pre-Clinical Rheumatoid Arthritis: Doubts, Challenges, and Opportunities.
Sanmartí R, Frade-Sosa B, Ponce A. Sanmartí R, et al. J Clin Med. 2024 Oct 25;13(21):6387. doi: 10.3390/jcm13216387. J Clin Med. 2024. PMID: 39518527 Free PMC article.
Rheumatoid Arthritis: The Continuum of Disease and Strategies for Prediction, Early Intervention, and Prevention.
O'Neil LJ, Alpízar-Rodríguez D, Deane KD. O'Neil LJ, et al. J Rheumatol. 2024 Apr 1;51(4):337-349. doi: 10.3899/jrheum.2023-0334. J Rheumatol. 2024. PMID: 38224993 Free PMC article. Review.

See all "Cited by" articles

References

1. Mankia K, Emery P. Preclinical rheumatoid arthritis: progress toward prevention. Arthritis Rheumatol 2016;68:779–88. 10.1002/art.39603 - DOI - PubMed
1. Gerlag DM, Raza K, van Baarsen LGM, et al. . EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the study Group for risk factors for rheumatoid arthritis. Ann Rheum Dis 2012;71:638–41. 10.1136/annrheumdis-2011-200990 - DOI - PMC - PubMed
1. van Steenbergen HW, Huizinga TWJ, van der Helm-van Mil AHM. The preclinical phase of rheumatoid arthritis: what is acknowledged and what needs to be assessed? Arthritis Rheum 2013;65:2219–32. 10.1002/art.38013 - DOI - PubMed
1. Deane KD, Striebich CC, Holers VM. Editorial: prevention of rheumatoid arthritis: now is the time, but how to proceed? Arthritis Rheumatol 2017;69:873–7. 10.1002/art.40061 - DOI - PMC - PubMed
1. Mankia K, Emery P. A new window of opportunity in rheumatoid arthritis: targeting at-risk individuals. Curr Opin Rheumatol 2016;28:260–6. 10.1097/BOR.0000000000000268 - DOI - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

[1] Mankia K, Emery P. Preclinical rheumatoid arthritis: progress toward prevention. Arthritis Rheumatol 2016;68:779–88. 10.1002/art.39603 - DOI - PubMed

[2] Mankia K, Emery P. Preclinical rheumatoid arthritis: progress toward prevention. Arthritis Rheumatol 2016;68:779–88. 10.1002/art.39603 - DOI - PubMed

[3] Gerlag DM, Raza K, van Baarsen LGM, et al. . EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the study Group for risk factors for rheumatoid arthritis. Ann Rheum Dis 2012;71:638–41. 10.1136/annrheumdis-2011-200990 - DOI - PMC - PubMed

[4] Gerlag DM, Raza K, van Baarsen LGM, et al. . EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the study Group for risk factors for rheumatoid arthritis. Ann Rheum Dis 2012;71:638–41. 10.1136/annrheumdis-2011-200990 - DOI - PMC - PubMed

[5] van Steenbergen HW, Huizinga TWJ, van der Helm-van Mil AHM. The preclinical phase of rheumatoid arthritis: what is acknowledged and what needs to be assessed? Arthritis Rheum 2013;65:2219–32. 10.1002/art.38013 - DOI - PubMed

[6] van Steenbergen HW, Huizinga TWJ, van der Helm-van Mil AHM. The preclinical phase of rheumatoid arthritis: what is acknowledged and what needs to be assessed? Arthritis Rheum 2013;65:2219–32. 10.1002/art.38013 - DOI - PubMed

[7] Deane KD, Striebich CC, Holers VM. Editorial: prevention of rheumatoid arthritis: now is the time, but how to proceed? Arthritis Rheumatol 2017;69:873–7. 10.1002/art.40061 - DOI - PMC - PubMed

[8] Deane KD, Striebich CC, Holers VM. Editorial: prevention of rheumatoid arthritis: now is the time, but how to proceed? Arthritis Rheumatol 2017;69:873–7. 10.1002/art.40061 - DOI - PMC - PubMed

[9] Mankia K, Emery P. A new window of opportunity in rheumatoid arthritis: targeting at-risk individuals. Curr Opin Rheumatol 2016;28:260–6. 10.1097/BOR.0000000000000268 - DOI - PubMed

[10] Mankia K, Emery P. A new window of opportunity in rheumatoid arthritis: targeting at-risk individuals. Curr Opin Rheumatol 2016;28:260–6. 10.1097/BOR.0000000000000268 - DOI - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis

Affiliations

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical