Drs. El-Gabalawy and O’Neil reply

To the Editor:

We would like to thank Drs. Liu and Hu¹ for their thoughtful comments regarding our recent publication.² In response to the points made in their letter, we would like to make a few comments.

We certainly agree that a practical, biologically based definition of a hypothetical “point of no return” in the preclinical maturation of rheumatoid arthritis (RA) autoimmunity, after which preventing RA onset becomes difficult to achieve, would be quite valuable in assigning at-risk individuals to specific intervention (interception) strategies. To address this key issue, a European Alliance of Associations for Rheumatology/American College of Rheumatology task force was recently established to develop risk stratification approaches across global population-based screening cohorts and arthralgia cohorts for individuals who are deemed to be at elevated risk of developing future RA. A thoughtful review of this topic has recently been published by international experts in the area, many of whom are participating in the task force.³ It is anticipated that within the next 1 to 2 years, the task force will have developed a workable approach to this challenging problem.

As pointed out by Drs. Liu and Hu, the anticitrullinated peptide antibody (ACPA) screening approach is an important consideration.¹ We are validating dried blood spot (DBS) technology for detecting ACPA because of its ease of application and its scalability for screening in remote First Nations communities. Unfortunately, this initial DBS screen for ACPA tells us very little about whether an individual is past a hypothesized point of no return in their RA autoimmunity, keeping in mind that this point is likely to differ between individuals. Because of this, individuals found to be ACPA positive by DBS screening undergo further serum testing, which allows a deeper analysis of the maturation of their ACPA response using autoantigen arrays⁴ and glycosylation assays,⁵ as well as other proteomic biomarkers that we have shown to be associated with progression to RA.⁶ These individuals are then offered the opportunity to participate in a clinical trial using nutritional supplements that are designed to potentially reduce their risk of future RA, this being based on the results from a collagen-induced arthritis model.⁷

It should again be emphasized that assembling at-risk cohorts that are derived from symptomatic individuals presenting to primary care providers with arthralgia, many of whom exhibit imaging evidence of subclinical synovitis, yields a very different study population than assembling such cohorts through population-based screening of family members of patients with RA, or of individuals who attend health fairs, for example. It is reasonable to speculate that most individuals recruited through arthralgia-based screening approaches are more likely to be past the point of no return in the maturation of RA autoimmunity and are indeed quite close to developing clinically classifiable RA. This conclusion is widely supported by the published results of the highly anticipated RA prevention clinical trials using methotrexate, hydroxychloroquine, rituximab, and abatacept, most of which demonstrated delay rather than prevention of RA.⁸

In contrast, population-based ACPA screening approaches are more likely to recruit individuals in whom true prevention may indeed be possible. Unfortunately, many such ACPA-positive individuals will never develop RA, and as we have previously shown in our longitudinal cohort of at-risk family members of First Nations patients with RA, a substantial number will become seronegative after prolonged observation.⁴ Thus, the risk of overtreating such a population is quite real, and careful consideration of the risk-benefit balance of any proposed intervention is needed; a coherent and honest discussion with each participant is also required. We undertook focus groups in our study communities and found that most of the at-risk individuals are quite risk-averse in considering interventions to reduce their risk of developing future RA, regardless of the estimated risk of future RA presented to them. Interventions involving “natural” antiinflammatory (and potentially immunomodulatory) nutritional supplements such as curcumin, omega-3, and vitamin D, would be more readily accepted than oral or injectable RA medicines.

Finally, we particularly wish to thank Drs. Liu and Hu for their insights regarding community engagement practices.¹ These insights are based on their own experience in screening for a potentially fatal cardiomyopathy in remote mountains in China. They encountered significant resistance, particularly in terms of language, communication, religion, and cultural practices. To address this, they recommend that research teams should “undergo cultural sensitivity training beforehand to understand the history, traditions, and contemporary issues of the ethnic community.”¹ Further, they encourage the engagement of healthcare and social workers who are well connected to the community, and who would be “actively involved at every stage of research, from problem identification to implementation and dissemination of results.”¹ We completely agree with this, and indeed we rely extensively on partnerships with health directors in the communities, along with hiring part-time local research assistants. A key principle is regularly traveling to the community and participating in cultural activities that are dear to them. In our opinion, this is arguably the single most important element in a trust-based research partnership with any community.

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