EULAR Releases Points-to-Consider for Conducting Clinical Research Among Individuals at Risk for RA

RA in hand
Rheumatoid arthritis. General practitioner examining a patient’s hand for signs of rheumatoid arthritis. This condition is caused by the immune system attacking the body’s own tissues, causing progressive joint and cartilage destruction. As the cartilage is worn away, new bone grows as part of the repair process. This causes stiffness and deformity of the fingers. Treatment is with anti-inflammatory drugs and physiotherapy.
The European Alliance of Associations for Rheumatology (EULAR) has issued points-to-consider for conducting clinical trials and observational studies among individuals at risk for rheumatoid arthritis.

The European Alliance of Associations for Rheumatology (EULAR) has issued points-to-consider for clinical trials and observational studies conducted among individuals at risk of rheumatoid arthritis (RA). The full guidance was published in Annals of the Rheumatic Diseases.

In RA, there is a preclinical phase characterized by an increase in several types of autoantibodies. Researchers are actively studying data from at-risk individuals to better understand RA pathobiology, predict the onset and timing of RA, and develop interventions to prevent RA. In light of the limited number of at-risk individuals available for inclusion in clinical research and due to the heterogeneity of current clinical trials, the EULAR convened a multidisciplinary taskforce to develop guidance to inform future research efforts.

The EULAR taskforce developed 4 key questions related to the design of clinical trials including individuals at risk for RA. After the meeting, members of the taskforce conducted systematic literature reviews to address the key questions and developed draft points-to-consider and a research agenda. At the next meeting and through subsequent discussions, the taskforce reviewed these results and draft guidance and agreed on 1 overarching principle, 10 points to consider, and a research agenda. The level of agreement for the overarching principle and points to consider was assessed anonymously using a score of 0 (absolutely disagree) to 10 (absolutely agree).

Overarching Principle

All clinical trials and observational studies conducted among at-risk individuals should measure key epidemiologic and demographic characteristics including age, sex, body mass index (BMI), ethnicity, smoking status, and family history of RA.

Recording these features may allow for direct comparison and integration of datasets from multiple cohorts.

Points to Consider

1.At-risk individuals should be classified according to their clinical presentation during trials and observational studies. Categories, based on the presence of specific risk factors, may include those without symptoms, those with musculoskeletal symptoms but without arthritis, and those with early arthritis. 

Asymptomatic individuals are defined as those without arthralgia or other musculoskeletal symptoms or those whose symptoms (eg, fatigue) are not exclusively musculoskeletal in nature; subclinical inflammation is defined as the presence of joint inflammation on imaging but the absence of arthritis; and clinical arthritis is the presence of inflammatory joint swelling
2.The development of clinical arthritis or progression to RA (using the 2010 American College of Rheumatology [ACR]/EULAR RA criteria) should be considered as study endpoints in longitudinal studies.
3.Among at-risk populations without clinical or subclinical disease, development of subclinical inflammation on ultrasound or magnetic resonance imaging (MRI) should be considered as a study endpoint.

Among individuals at risk for RA with musculoskeletal symptoms, subclinical synovitis on ultrasound may have an effect on clinical decision-making.
4.Among at-risk populations with clinical arthritis (palindromic rheumatism or undifferentiated arthritis), study endpoints should include disease remission (on/off therapy).
5.Core and emerging risk factors, based on current clinical evidence, should be assessed in a population-specific manner.

Core risk factors for asymptomatic at-risk RA include genetic risk factors and serum anticitrullinated protein antibodies (ACPA); for musculoskeletal symptoms without arthritis and early clinical arthritis they include genetic markers, ACPA/rheumatoid factor, subclinical inflammation on imaging, and clinical symptoms (eg, joint tenderness and early morning stiffness).
6.In future clinical trials and longitudinal studies, risk factors should be assessed at baseline and repeated based on the intervention and population being studied.
7.Clinical trials have primarily focused on the prevention of clinical arthritis or RA. Future trials should also assess the ability of the intervention to modify specific risk factors and the risk for progression to RA.
8.In patients with early clinical arthritis, such as synovitis, drug intervention may alter progression to RA and improve the outcome of RA therapy.

However, there is no evidence regarding the association between drug interventions and delayed disease progression among at-risk individuals without clinical arthritis.
9.Individuals participating in clinical trials and observational studies should be informed about their risk of developing RA using an individually tailored approach. This may be useful in promoting participation and engagement in future studies.
10.An individual’s knowledge about their risk of developing RA may inform their decision to participate in clinical trials and observational studies.

The research agenda developed by the taskforce identifies key questions that should be addressed by future clinical trials and observational studies. These questions center around identifying clinical trial participants, defining study endpoints, assessing risk factors for RA, developing standard methodologies, and discussing risk with potential trial participants.

“The overarching principle and 10 points to consider set out a broad framework, which covers the key areas for conducting clinical trials and studies in at-risk individuals,” the authors concluded, “These statements should help [harmonize] the datasets produced by future studies and facilitate collaboration in this important area. They should also improve the validity of individual trials and studies, [optimizing] outputs from hard to recruit populations, which often require unique patient cohorts and infrastructure. It is hoped that this guidance will help [galvanize] future collaborative efforts in studies of at-risk individuals and RA prevention.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Mankia, K, Siddle HJ, Kerschbaumer A, et al. EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis. Ann Rheum Dis. Published online August 6, 2021. doi:10.1136/annrheumdis-2021-220884