Experts debate the role of DMARDs in subclinical RA

Subclinical rheumatoid arthritis (RA) is increasingly common in rheumatology practice; however, it is unclear how to manage these patients and whether starting a disease-modifying antirheumatic drug (DMARD) can prevent the development of RA.

During this year’s Great Debate — To Treat or Not? The Role of DMARDS in Subclinical Rheumatoid Arthritis — two sets of experts reviewed the data on subclinical disease and the risk of progression to RA, and presented arguments for and against starting a DMARD in this challenging clinical scenario.

The session is available for on-demand viewing for registered ACR Convergence participants through October 31, 2023, on the virtual meeting website.

Kevin Deane, MD, PhD, Professor of Medicine and the William P. Arend Endowed Chair in Rheumatology Research at the University of Colorado Anschutz Medical Campus, and V. Michael Holers, MD, Professor of Medicine and Immunology and the Scoville Professor of Rheumatology at the University of Colorado, opened the debate by discussing the evolving definition of subclinical RA, or what many believe should be re-characterized as “pre-RA,” and the potential benefits of early intervention.

“We should try to prevent or ameliorate clinical RA by treating in a stage-specific manner pre-RA and those autoimmune processes that actually may have their own signs and symptoms and tissue injury outside of arthritis,” said Dr. Deane, who discussed the potential for RA prevention by treating existing pre-RA autoimmunity.

“This may not necessarily involve what we think of as ‘established’ DMARDs, but I believe there is great rationale to try and move to a prevention stage for RA, as well as other autoimmune diseases,” he said. “Once clinical RA develops, it’s basically forever — when someone gets their first swollen joints, they’re on drugs for the rest of their life. And even if we can’t prevent it, part of the rationale for prevention is if we can modulate disease to a more benign form with earlier intervention, that could really be a benefit.”

Because the definition of what constitutes “pre-RA” is variable, as is the prediction of progression to clinical RA, Dr. Holers, on the other hand, believes that much more study is needed to improve understanding of the pathophysiology in order to ensure interventions are rooted in mechanisms, i.e., non-articular processes and specific endotypes.

“When we’re talking about intervening in this pre-RA stage, we really need to think about not just what we are preventing, but what exactly are we treating in pre-RA that requires an intervention that will keep us from progressing to arthritis and all of its consequences,” Dr. Holers said.

What is referred to as the “causal endotypes hypothesis” that Dr. Holers’ research group and many around the world are increasingly coming to understand operates under the assumption that individuals who are serologically anti-citrullinated protein antibodies (ACPA)-positive are not immunologically well.

“They have abnormalities that are going on, but you just can’t see them, as well as different processes, in the lung and gut for example, that are ongoing and ultimately will lead to systemic disease and targeting of the joints,” he said.

Ultimately, Dr. Holers said, there needs to be established, accurate classification criteria for risk stratification to guide inclusion in trials and regulatory approvals.

Arguing the other side of the question, Janet Pope, MD, MPH, FRCPC, Professor of Medicine at the University of Western Ontario and Division Head of Rheumatology at St. Joseph’s Health Care in London, Ontario, Canada, and Hani El-Gabalawy, MD, FRCPC, Professor of Medicine and Immunology and Endowed Rheumatology Research Chair at the University of Manitoba, Canada, believe the evidence-based data is simply not there. They also discussed the potential challenges in screening for pre-RA and determining if, and for which patients, the benefits outweigh the risks of early “pre-RA-stage” intervention with DMARDs.

“We would argue that not treating subclinical RA is the right thing to do in 2022,” Dr. El-Gabalawy said. “At this point in time, if you look at people who are ACPA-positive, for example, it’s impossible to know who are going to progress to clinical RA and who is not.”

At that stage, in terms of RA prevention, he said it’s too late to treat.

“The immune system is fully primed, the synovium is targeted and engaged, so all we can do is perhaps delay progression. That’s what I believe the clinical trials are showing us right now,” he said.

While emerging and ongoing studies continue to shed more light on the pathophysiology and progression of RA, what is more important, Dr. Pope said, are the things we don’t know yet about the precise application of early intervention at the pre-RA stage.

“Importantly, we don’t know all the predictors of who will eventually progress from pre-RA to clinical RA,” she said. “We know there are triggers — some of which may be modifiable, such as lifestyle issues. And we don’t know why people flare and become drug-resistant. If we’re treating pre-RA, is that going to lead to resistance later? There are many questions that need to be studied before we routinely start treating patients who we believe fall into this “pre-RA” classification.”