To Treat or Not to Treat? The Great Debate on Treatment of Subclinical Rheumatoid Arthritis

PHILADELPHIA—One of the great advancements in the field of rheumatology in recent years has been the increased understanding of various stages of disease in rheumatoid arthritis (RA), including what is termed subclinical rheumatoid arthritis. However, questions remain regarding whether to treat patients with subclinical disease and whether treatment of these patients has implications in preventing disease progression.

In The Great Debate at ACR Convergence 2022—To Treat or Not? The Role of DMARDs in Subclinical Rheumatoid Arthritis—four outstanding clinicians explored this topic in a lively and engaging discussion.

In Favor of Treating Pre-RA

Representing the side in favor of treatment were Kevin Deane, MD, PhD, associate professor of medicine, William P. Arend Endowed Chair in Rheumatology Research, Division of Rheumatology, University of Colorado School of Medicine, Aurora, and V. Michael Holers, MD, professor of medicine and immunology, Scoville Professor, head, Division of Rheumatology, University of Colorado School of Medicine, Aurora.

Kevin Deane, MD, PhD

Dr. Deane began by describing the natural history of seropositive RA, in which genetic and environmental risk factors likely trigger local and systemic autoimmunity, which progresses to result in seropositivity for antibodies, such as rheumatoid factor and anti-citrullinated protein/peptide antibody (ACPA). Patients then go on to manifest subclinical RA, which can ultimately lead to arthritis that meets criteria for classification as RA. Dr. Deane used the term pre-RA for patients who have objective features of autoimmunity but do not yet have clinical signs of RA (i.e., arthritis that cannot be seen on physical examination).

Dr. Deane noted the goal of rheumatologists should be to try to prevent or ameliorate clinical RA by treating pre-RA in a stage-specific manner that targets the autoimmune processes that may result in symptoms and tissue injury. This may or may not involve the use of established disease-modifying anti-rheumatic drugs (DMARDs), but it should be noted that the non-articular stage of disease (i.e., the stage before the joints are affected) could be the period when treatment can be most effective.

The rationale for pursuing treatment of pre-RA includes: 1) clinical RA is not currently a curable disease for most patients, 2) clinical RA treatments have limited efficacy, 3) the costs associated with clinical RA are high at the individual and societal levels, 4) even if RA is not prevented completely, treating pre-RA may lead to a more benign disease course for patients, and 5) treating a stage of RA that does not include inflammatory arthritis may still reduce pain and fatigue symptoms for patients.

Dr. Deane outlined several key challenges on this subject, namely that definitions of pre-RA remain variable, predictions of which patients will develop clinical RA are still limited in accuracy, clinical trial recruitment of patients at risk for RA but without the disease remains difficult, and effective interventions to prevent RA have not yet been clearly identified or approved.

Dr. Holers helped redefine the important question being asked in the debate, which is not “what are we preventing?” but rather, “what are we treating in pre-RA that requires an intervention that will keep patients from progressing to arthritis and all of its consequences?”

V. Michael Holers, MD

Dr. Holers presented work showing that a subset of patients with pre-RA exhibit ongoing mucosal inflammation in the lung characterized by the presence of autoantibodies, complement elevation and a NETosis phenotype characterized by neutrophils in sputum from these individuals; moreover, in one study, the presence of sputum RA-associated antibodies was more prevalent in subjects who later developed RA compared to subjects without these antibodies.¹ With this in mind, Dr. Holers predicted that RA prevention in the future will focus on correcting mucosa-specific and later checkpoint failures using mechanism-based approaches.

Dr. Deane concluded the presentation by arguing in favor of treating pre-RA with several recommendations. These proposals include how research should seek to better understand the pathogenesis of pre-RA to ensure that interventions are grounded in biologic mechanisms, classification criteria ought to be established for pre-RA to guide trials and regulatory approvals, and ongoing clinical trials should be continued and more efforts made to enhance participation of patients who fit into the pre-RA category.

He ultimately provided a vision for the future in which risk for RA and other autoimmune diseases is evaluated in a similar fashion as to what is done for cardiovascular disease and diabetes, where stage-specific interventions including lifestyle modification in addition to pharmacologic therapy are helpful to patients.

Opposed to Treating Pre-RA

The opposing team in the debate was composed of Janet Pope, MD, MPH, FRCPC, professor of medicine, Division of Rheumatology and Epidemiology and Biostatistics, University of Western Ontario, Schulich School of Medicine, London, Canada, and Hani El-Gabalawy, MD, FRCPC, FCAHS, professor of medicine and immunology, associate department head (internal medicine), Endowed Rheumatology Research Chair, University of Manitoba, Winnipeg, Canada.

Janet Pope, MD, MPH, FRCPC

Dr. El-Gabalawy noted that work from Tanner et al. provides evidence that many patients with positivity for ACPA (especially when it is low titer) often seroconvert to negative testing while being followed longitudinally.² This raises the question of if longitudinal follow-up, rather than treatment, could help protect at least some patients from potential overtreatment.

Indeed, he presented studies demonstrating that ACPA V-domain glycosylation is a more helpful predictor of progression to RA than presence of ACPA alone, and thus an effective and efficient way to screen for such glycosylation, which does not exist now, may be helpful in the future in determining pre-RA patients who are truly at risk for progression.^3,4

Dr. Gabalawy noted that the clinical trials evaluating treatment of pre-RA are thus far only showing the ability to delay, but not prevent, the development of RA. This may mean that treating pre-RA with DMARDs is downstream from the point at which the immune system is already on a course toward the development of RA, and perhaps prevention could only be achieved if the pathway is halted earlier in its course.^5,6

Dr. Pope presented several issues that arise on the subject of treating pre-RA, including how the definition of subclinical RA remains difficult to pin down and make uniform across the country and world. The unknowns with respect to this topic include: which patients will progress from pre-RA to RA? What are the predictors for poor response in patients with pre-RA? What are the tradeoffs between efficacy and potential safety issues in treating a pre-RA population?

She also noted that the concept of ACPA positivity raises both two issues: 1) missing patients who are ACPA negative but may go on to manifest seronegative, and 2) how to deal with ACPA positivity in the general population, where older women who smoke have often been found to have these antibodies.

Dr. Pope explained that risk factors for RA include above normal body mass index, smoking and silica dust exposure. Therefore, for many patients, mitigation of these risk factors may be potentially more helpful and cost effective in preventing RA than would be treating with DMARD therapy.

Already in the VITAL trial, vitamin D and omega 3 fatty acid supplementation were both shown to reduce the incident autoimmune disease rate in the general older adult American population.⁷ Thus, in seeking to avoid overtreatment of patients while still preventing disease, perhaps focusing on risk factors is equally or more beneficial than treating these patients with medication.

In Sum

The debate tackled a complicated, but relevant clinical question that will only increase in importance over time. The audience benefited from the scholarly discussion between the two sides and, though no final resolution was reached on the subject, the discourse helps lay the groundwork for needed research and discussion in the years to come.

Dr. Liebowitz

Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.

References

1. Wilson T, Welch J, Feser M, et al. Sputum RA-associated autoantibodies independently associate with future development of classified RA in an at-risk cohort of individuals with systemic anti-CCP positivity [abstract]. Arthritis Rheumatol. 2022;74 (suppl 9).
2. Tanner S, Dufault B, Smolik I, et al. A prospective study of the development of inflammatory arthritis in the family members of Indigenous North American people with rheumatoid arthritis. Arthritis Rheumatol. 2019 Sep;71(9):1494–1503.
3. Hafkenscheid L, de Moel E, Smolik I, et al. N-linked glycans in the variable domain of IgG anti-citrullinated protein antibodies predict the development of rheumatoid arthritis. Arthritis Rheumatol. 2019 Oct;71(10):1626–1633.
4. Kissel T, Hafkenscheid L, Wesemael TJ, et al. IgG anti-citrullinated protein antibody variable domain glycosylation increases before the onset of rheumatoid arthritis and stabilizes thereafter: A cross-sectional study encompassing ~1,500 samples. Arthritis Rheumatol. 2022Jul;74(7):1147–1158.
5. Gerlag DM, Safy M, Maijer KI, et al. Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: The PRAIRI study. Ann Rheum Dis. 2019 Feb;78(2):179–185.
6. Rech J, Ostergaard M, Tascilar K, et al. Abatacept reverses subclinical arthritis in patients with high-risk to develop rheumatoid arthritis—Results from the randomized, placebo-controlled ARIAA study in RA-at risk patients [abstract]. Arthritis Rheumatol. 2021;73(suppl 9).
7. Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022 Jan 26;376:e066452.