RA studies lag in examining comorbid populations
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A slew of recent clinical trials and the continued development of new treatments have ensured that the state of rheumatoid arthritis treatment is more advanced than ever before.
But patients with RA are notoriously at a very high risk of developing comorbidities — upwards of 80% of patients with RA have at least one comorbidity, according to studies. And in attempting to understand and treat comorbid RA, there’s still work to be done.
Bryant England, MD, an associate professor in the division of rheumatology and immunology at the University of Nebraska Medical Center, told Healio that the progression of recent clinical trials suggests the need for a fundamental shift in methodology to better study the wider population of patients with RA.
“We know that the majority of RA patients are multimorbid,” England said. “The patients in these clinical trials, that’s not the kind of patient I’m seeing regularly in my clinic. If we look at large registries, we’ll see that over half of RA patients are multi-morbid. I think it’s time we finally match up the populations we’re studying with the populations we’re seeing in clinic.”
ORAL Surveillance trial sheds light
England pointed specifically to the recent ORAL Surveillance trial, which studied treatment of RA with tofacitinib (Xeljanz, Pfizer) in a population of patients with RA aged 50 years and older with increased cardiovascular risk factors, compared with treatment with a TNF inhibitor.
The study, which was published in January, showed that treatment with tofacitinib in this population showed higher risk of cancers and major cardiovascular events. These adverse effects did not previously manifest in studies of populations that were not at higher risk of comorbidities.
“This demonstrates to us the population that we’re testing our drugs in is critically important to assessing the balance of risks and benefits,” England said. “Most of our RA clinical trials are in a pretty healthy population that’s free of comorbidities. We’ve looked at many of those trials of tofacitinib and other JAK inhibitors and we saw some signals: diverticulitis, lipid changes, herpes zoster infections. We originally didn’t see these signals, but now we test them in a higher risk population and we start to see some of these signals.”
To England, it illustrated the increased, often unmet need for studies specifically targeting populations that are comorbid or are at risk of becoming comorbid.
“To me this screams that we have do these types of trials,” England said. “They may have to be pragmatic trials, as we may not necessarily be able to do this exact same type of study with all of our therapies, but we need to evaluate the efficacy and safety of these therapies in real-world populations.”
Determining disease processes
England also pointed to the GLORIA trial, a Dutch study published in May that examined the use of low-dose prednisone in RA treatment, specifically targeting an elderly population with a mean of 2.1 comorbidities. Once again, adverse reactions were found.
“The GLORIA trial is another recent trial done in an elderly population looking at glucocorticoids,” England said. “Infections were the adverse event that popped out more in those treated with glucocorticoids. Herpes zoster, shingles ... Those kinds of conditions may not be directly related to rheumatoid arthritis, but are going to complicate some of the therapies we choose.”
The results from these studies can have a very meaningful impact on a rheumatologist’s day-to-day interaction with their patients, most of whom are likely to be comorbid or at risk of comorbidity. England says that makes the need for increased scholarship into comorbid populations even more dire — the totality of a patient’s health situation, beyond just RA, will determine the direction of their treatment plan.
“What we really need to do is figure out what is the disease process that’s driving their symptoms and how can we improve the management of that,” England said. “For us as rheumatologists it’s pretty straightforward most of the time to separate what’s a joint symptom and what is not, but for the patient they just know they don’t feel well.”
Safety first
England works at a multidisciplinary clinic that specifically treats patients who have developed autoimmune lung diseases, meaning that coordinating with other specialists to put together a treatment plan that addresses comorbidities is a part of his daily life.
This approach helps streamline the process in what can be a fragmented health care environment, but no process is perfect. And until further research into comorbid RA sheds more light on how certain diseases intersect, patient safety and risk management is even more of a paramount concern.
“Our therapy decisions are usually a balance of risks and benefits,” England said. “The risk side of the equation is what we tend to get more worried about. The elderly or those with more chronic conditions, those people tend to have more adverse effects. They’re more likely to get infections, have cardiac events, those other complications of treatment. It makes us give pause at the decisions we’re making, and ask whether we’re more concerned about safety to the point where that risk to benefit ratio changes.”
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