<p>There is a growing number of targeted therapies with efficacy for rheumatoid arthritis (RA), but they can be associated with toxicities, limiting their use in certain patients. Therefore, research on and clinical development of new agents are ongoing. Our 3 experts consider the challenges of balancing efficacy and safety when developing RA therapeutics.</p>

JAK inhibitors are the latest “kids on the block” in terms of therapies for RA, and they are likely to remain the latest kids on the block for a while. They are very effective, and they also work fast. In clinical trials, several JAK inhibitors were shown to be better than standard therapies, either as monotherapy or in a combination.

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No one is debating the efficacy of the JAK inhibitors, but the ORAL Surveillance study of tofacitinib pointed to the potential for adverse events such as heart disease, clots, and cancer in at-risk populations. I do not think that we are ever going to resolve this issue, as there have been no cardiac outcomes studies for other JAK inhibitors, and phase 3 trials of JAK inhibitors have typically excluded at-risk populations. This is unfortunate because JAK inhibitors are used not only for RA but also for a variety of other diseases.

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When I am starting other biologic therapies for my patients with RA, I do not think about the same safety issues because infection is the main signal that is seen with immunosuppressives in older patients. However, I am very careful about using any of the JAK inhibitors in patients with a prior cardiovascular event, a prior clot, or an underlying malignancy, since I do not know what the risk is.

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There was a lot of excitement about and interest in the potential for PD-1 agonist use in RA, but studies in peresolimab have been discontinued. In addition, a late-breaking poster on vagal nerve stimulation was presented at American College of Rheumatology (ACR) Convergence 2024 that I think will generate interest and add to the research that is being done in this area. Finally, there is also a lot of hype around CAR T-cell therapy for patients with RA. I have never seen anything generate so much enthusiasm with such a limited number of patients.

I do not want to dismiss the results of the ORAL Surveillance study, but I think it is unfortunate that it led to many people wanting to stay away from using JAK inhibitors. That trial was studying a specific patient population with a high risk, and the issues really showed up among those in that group with the highest risk. Also, the study was assessing tofacitinib, so it is not clear if there is truly a class effect.

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I am very curious about whether people will feel differently in another year or so, after tofacitinib goes generic and becomes one of the cheaper ways of managing RA. But, at the moment, I see that our fellows and junior faculty are slightly more frightened by JAK inhibitors, despite the fact that they are incredibly effective and do have a role in treatment, in my mind.

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I wonder whether the lupus trials of upadacitinib may have some value because that is a higher-risk population, both for cardiovascular disease and for thrombotic events. If a signal does not show up in those fairly large trials, will that give people any sort of comfort in using JAK inhibitors? Or is that something we will continue to struggle with?

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Look at the way dermatologists have dealt with psoriasis. They have gone through each generation of biologic treatments to find very specific therapies that target inflammatory processes rather than immune processes to control disease without a high infection risk. It would be fabulous if we could find that target in RA, but I do not see anything on the near horizon for sure.

In practice, rheumatologists remain uncertain about when to use JAK inhibitors, and that uncertainty is an issue and a challenge. Part of the problem is that there is a slightly increased risk of heart disease, infection, and malignancy just from having RA. So, it is going to be extremely difficult to sort out the effects of a drug because, if the drug treats the underlying disease, you have a bidirectional effect (ie, you reduce the risk from RA, but you add the risk from the drug). One would have to study a population in whom the risk is greater, such as patients over the age of 65, to potentially find a signal.

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In the past, there have also been safety concerns regarding anti-TNF drugs. The patients enrolled in the clinical trials of anti-TNF therapies were very low risk. So, we did a postmarketing study of etanercept in a high-risk population, where enrolled patients had RA and at least 1 comorbid disease, such as diabetes. This study was stopped early because there were hardly any adverse events reported. In fact, the number of adverse events was so small that it would have taken too many patients to show a difference.

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GLP-1 receptor agonists are certainly something to think about for patients with RA, and there will be research studies evaluating their use. Is there an anti-inflammatory effect specifically with the use of those drugs, independent of the weight loss? There will likely be multiple uses of GLP-1 agents, but, in RA, I think that we are fairly far away from using them at the moment.