MDedge Rheumatology

NEW YORK — Urate, the culprit of gout, affects the vasculature in multiple ways that can raise cardiovascular risk (CV) in an individual with gout, and following guidelines for gout treatment, including the use of colchicine, can be the key to reducing those risks.

“Guideline-concordant gout treatment, which is essentially an anti-inflammatory urate-lowering strategy, at least improves arterial physiology and likely reduces cardiovascular risk,” Michael H. Pillinger, MD, told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference. Dr. Pillinger is professor of medicine and biochemistry and molecular pharmacology at New York University Grossman School of Medicine, New York City, who has published multiple studies on gout.

NYU Grossman School of Medicine

He cited evidence that has shown soluble urate stimulates the production of C-reactive protein (CRP), which is a predictor of cardiovascular disease (CVD). Another study, in which Dr. Pillinger participated, demonstrated that gout patients have impaired vascular endothelial function associated with a chronic, low-level inflammatory state, he said.

“There’s good evidence that urate itself affects the vasculature in multiple ways, and I suspect this may be a model for other metabolic effects on vasculature,” Dr. Pillinger said. “Patients with gout have abnormal endothelium in ways that really convey vascular risk.”
 

Gout, Inflammation, and CVD

However, for rheumatologists to study the association between gout-related inflammation and CVD is “very, very hard,” Dr. Pillinger added. “But I do think that the mechanisms by which gout induces biological changes in the vasculature may provide insights into cardiovascular disease in general.”

One way to evaluate the effects of gout on the endothelium in the clinic is to measure flow-mediated dilation. This technique involves placing an ultrasound probe over the brachial artery and measuring the baseline artery diameter. Then, with the blood pressure cuff over the forearm, inflate it to reduce flow, then release the cuff and measure the brachial artery diameter after the endothelium releases vasodilators.

Dr. Pillinger and colleagues evaluated this technique in 34 patients with gout and 64 controls and found that patients with gout had an almost 50% decrease in flow-mediated dilation, he said. “Interestingly, the higher the urate, the worse the flow; the more the inflammation, the worse the flow, so seemingly corresponding with the severity of the gout,” he said. That raised an obvious question, Dr. Pillinger continued: “If you can treat the gout, can you improve the flow-mediated dilation?”

His group answered that question with a study in 38 previously untreated patients with gout, giving them colchicine 0.6 mg twice daily for a month plus a urate-lowering xanthine oxidase inhibitor (allopurinol or febuxostat) to treat them to a target urate level of < 6 mg/dL. “We saw an increase in endothelial function, and it normalized,” Dr. Pillinger said.

However, some study participants didn’t respond. “They were people with well-established other cardiovascular comorbidities — hypertension, hyperlipidemia,” he said. “I think some people just have vessels that are too damaged to get at them just by fixing their gout problem or their inflammation.”

That means patients with gout need to be treated with colchicine early on to avoid CV problems, Dr. Pillinger added. “We ought to get to them before they have the other problems,” he said.

Managing gout, and the concomitant CV problems, requires vigilance both during and in between flares, Dr. Pillinger said after his presentation.

“We have always taught that patients between flares basically look like people with no gout, but we do know now that patients with gout between flares tend to have what you might call ‘subclinical’ inflammation: CRPs and ESRs [erythrocyte sedimentation rates] that are higher than those of the general population, though not so excessive that they might grab attention,” he said. “We also know that many, if not all, patients between flares have urate deposited in or around their joints, but how these two relate is not fully established.”

Better treatment within 3 months of an acute gout flare may reduce the risk for CV events, he said, but that’s based on speculation more so than clinical data.
 

Potential Benefits of Targeting Inflammation

“More chronically, we know from the cardiologists’ studies that anti-inflammatory therapy should reduce risk in the high-risk general population,” Dr. Pillinger said. “There are no prospective studies confirming that this approach will work among gout patients, but there is no reason why it shouldn’t work — except perhaps that gout patients may have higher inflammation than the general population and also have more comorbidities, so they could perhaps be more resistant.”

Dr. Pillinger said that his group’s studies and another led by Daniel Solomon, MD, at Brigham and Women’s Hospital in Boston, have indicated that anti-inflammatory strategies in gout will lower CV risk.

“And interestingly,” he added, “our data suggest that colchicine use may lower risk not only in high-risk gout patients but also in gout patients who start with no CAD [coronary artery disease] but who seem to have less incident CAD on colchicine. I see this as identifying that gout patients are intrinsically at high risk for CAD, even if they don’t actually have any, so they represent a population for whom lowering chronic inflammation may help prevent incident disease.”

Dr. Pillinger provided more evidence that the understanding of the relationship between gout, gout flares, and CV risk is evolving, said Michael S. Garshick, MD, who attended the conference and is head of the Cardio-Rheumatology Program at NYU Langone, New York City.

NYU Langone

“There’s epidemiologic evidence supporting the association,” Dr. Garshick told this news organization after the conference. “We think that most conditions with immune system activation do tend to have an increased risk of some form of cardiovascular disease, but I think the relationship with gout has been highly underpublicized.”

Many patients with gout tend to have a higher prevalence of traditional cardiometabolic issues, which may compound the relationship, Dr. Garshick added. “However, I would argue that with this patient subset that it doesn’t matter because gout patients have a higher risk of traditional risk factors, and you have to [treat-to-target] those traditional risk factors.”

While the clinical evidence of a link between gout and atherosclerosis may not be conclusive, enough circumstantial evidence exists to believe that treating gout will reduce CV risks, he said. “Some of the imaging techniques do suggest that gouty crystals [are] in the atherosclerotic plaque of gout patients,” Dr. Garshick added. Dr. Pillinger’s work, he said, “is showing us that there are different pathways to develop atherosclerosis.”

Dr. Pillinger disclosed relationships with Federation Bio, Fortress Biotech, Amgen, Scilex, Hikma Pharmaceuticals, LG Chem, and Olatec Therapeutics. Dr. Garshick disclosed relationships with Kiniksa Pharmaceuticals, Agepha Pharma, Bristol Myers Squibb, and Horizon Therapeutics.
 

A version of this article appeared on Medscape.com.

NEW YORK — Urate, the culprit of gout, affects the vasculature in multiple ways that can raise cardiovascular risk (CV) in an individual with gout, and following guidelines for gout treatment, including the use of colchicine, can be the key to reducing those risks.

“Guideline-concordant gout treatment, which is essentially an anti-inflammatory urate-lowering strategy, at least improves arterial physiology and likely reduces cardiovascular risk,” Michael H. Pillinger, MD, told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference. Dr. Pillinger is professor of medicine and biochemistry and molecular pharmacology at New York University Grossman School of Medicine, New York City, who has published multiple studies on gout.

NYU Grossman School of Medicine

He cited evidence that has shown soluble urate stimulates the production of C-reactive protein (CRP), which is a predictor of cardiovascular disease (CVD). Another study, in which Dr. Pillinger participated, demonstrated that gout patients have impaired vascular endothelial function associated with a chronic, low-level inflammatory state, he said.

“There’s good evidence that urate itself affects the vasculature in multiple ways, and I suspect this may be a model for other metabolic effects on vasculature,” Dr. Pillinger said. “Patients with gout have abnormal endothelium in ways that really convey vascular risk.”
 

Gout, Inflammation, and CVD

However, for rheumatologists to study the association between gout-related inflammation and CVD is “very, very hard,” Dr. Pillinger added. “But I do think that the mechanisms by which gout induces biological changes in the vasculature may provide insights into cardiovascular disease in general.”

One way to evaluate the effects of gout on the endothelium in the clinic is to measure flow-mediated dilation. This technique involves placing an ultrasound probe over the brachial artery and measuring the baseline artery diameter. Then, with the blood pressure cuff over the forearm, inflate it to reduce flow, then release the cuff and measure the brachial artery diameter after the endothelium releases vasodilators.

Dr. Pillinger and colleagues evaluated this technique in 34 patients with gout and 64 controls and found that patients with gout had an almost 50% decrease in flow-mediated dilation, he said. “Interestingly, the higher the urate, the worse the flow; the more the inflammation, the worse the flow, so seemingly corresponding with the severity of the gout,” he said. That raised an obvious question, Dr. Pillinger continued: “If you can treat the gout, can you improve the flow-mediated dilation?”

His group answered that question with a study in 38 previously untreated patients with gout, giving them colchicine 0.6 mg twice daily for a month plus a urate-lowering xanthine oxidase inhibitor (allopurinol or febuxostat) to treat them to a target urate level of < 6 mg/dL. “We saw an increase in endothelial function, and it normalized,” Dr. Pillinger said.

However, some study participants didn’t respond. “They were people with well-established other cardiovascular comorbidities — hypertension, hyperlipidemia,” he said. “I think some people just have vessels that are too damaged to get at them just by fixing their gout problem or their inflammation.”

That means patients with gout need to be treated with colchicine early on to avoid CV problems, Dr. Pillinger added. “We ought to get to them before they have the other problems,” he said.

Managing gout, and the concomitant CV problems, requires vigilance both during and in between flares, Dr. Pillinger said after his presentation.

“We have always taught that patients between flares basically look like people with no gout, but we do know now that patients with gout between flares tend to have what you might call ‘subclinical’ inflammation: CRPs and ESRs [erythrocyte sedimentation rates] that are higher than those of the general population, though not so excessive that they might grab attention,” he said. “We also know that many, if not all, patients between flares have urate deposited in or around their joints, but how these two relate is not fully established.”

Better treatment within 3 months of an acute gout flare may reduce the risk for CV events, he said, but that’s based on speculation more so than clinical data.
 

Potential Benefits of Targeting Inflammation

“More chronically, we know from the cardiologists’ studies that anti-inflammatory therapy should reduce risk in the high-risk general population,” Dr. Pillinger said. “There are no prospective studies confirming that this approach will work among gout patients, but there is no reason why it shouldn’t work — except perhaps that gout patients may have higher inflammation than the general population and also have more comorbidities, so they could perhaps be more resistant.”

Dr. Pillinger said that his group’s studies and another led by Daniel Solomon, MD, at Brigham and Women’s Hospital in Boston, have indicated that anti-inflammatory strategies in gout will lower CV risk.

“And interestingly,” he added, “our data suggest that colchicine use may lower risk not only in high-risk gout patients but also in gout patients who start with no CAD [coronary artery disease] but who seem to have less incident CAD on colchicine. I see this as identifying that gout patients are intrinsically at high risk for CAD, even if they don’t actually have any, so they represent a population for whom lowering chronic inflammation may help prevent incident disease.”

Dr. Pillinger provided more evidence that the understanding of the relationship between gout, gout flares, and CV risk is evolving, said Michael S. Garshick, MD, who attended the conference and is head of the Cardio-Rheumatology Program at NYU Langone, New York City.

NYU Langone

“There’s epidemiologic evidence supporting the association,” Dr. Garshick told this news organization after the conference. “We think that most conditions with immune system activation do tend to have an increased risk of some form of cardiovascular disease, but I think the relationship with gout has been highly underpublicized.”

Many patients with gout tend to have a higher prevalence of traditional cardiometabolic issues, which may compound the relationship, Dr. Garshick added. “However, I would argue that with this patient subset that it doesn’t matter because gout patients have a higher risk of traditional risk factors, and you have to [treat-to-target] those traditional risk factors.”

While the clinical evidence of a link between gout and atherosclerosis may not be conclusive, enough circumstantial evidence exists to believe that treating gout will reduce CV risks, he said. “Some of the imaging techniques do suggest that gouty crystals [are] in the atherosclerotic plaque of gout patients,” Dr. Garshick added. Dr. Pillinger’s work, he said, “is showing us that there are different pathways to develop atherosclerosis.”

Dr. Pillinger disclosed relationships with Federation Bio, Fortress Biotech, Amgen, Scilex, Hikma Pharmaceuticals, LG Chem, and Olatec Therapeutics. Dr. Garshick disclosed relationships with Kiniksa Pharmaceuticals, Agepha Pharma, Bristol Myers Squibb, and Horizon Therapeutics.
 

A version of this article appeared on Medscape.com.

NEW YORK — Urate, the culprit of gout, affects the vasculature in multiple ways that can raise cardiovascular risk (CV) in an individual with gout, and following guidelines for gout treatment, including the use of colchicine, can be the key to reducing those risks.

“Guideline-concordant gout treatment, which is essentially an anti-inflammatory urate-lowering strategy, at least improves arterial physiology and likely reduces cardiovascular risk,” Michael H. Pillinger, MD, told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference. Dr. Pillinger is professor of medicine and biochemistry and molecular pharmacology at New York University Grossman School of Medicine, New York City, who has published multiple studies on gout.

NYU Grossman School of Medicine

He cited evidence that has shown soluble urate stimulates the production of C-reactive protein (CRP), which is a predictor of cardiovascular disease (CVD). Another study, in which Dr. Pillinger participated, demonstrated that gout patients have impaired vascular endothelial function associated with a chronic, low-level inflammatory state, he said.

“There’s good evidence that urate itself affects the vasculature in multiple ways, and I suspect this may be a model for other metabolic effects on vasculature,” Dr. Pillinger said. “Patients with gout have abnormal endothelium in ways that really convey vascular risk.”
 

Gout, Inflammation, and CVD

However, for rheumatologists to study the association between gout-related inflammation and CVD is “very, very hard,” Dr. Pillinger added. “But I do think that the mechanisms by which gout induces biological changes in the vasculature may provide insights into cardiovascular disease in general.”

One way to evaluate the effects of gout on the endothelium in the clinic is to measure flow-mediated dilation. This technique involves placing an ultrasound probe over the brachial artery and measuring the baseline artery diameter. Then, with the blood pressure cuff over the forearm, inflate it to reduce flow, then release the cuff and measure the brachial artery diameter after the endothelium releases vasodilators.

Dr. Pillinger and colleagues evaluated this technique in 34 patients with gout and 64 controls and found that patients with gout had an almost 50% decrease in flow-mediated dilation, he said. “Interestingly, the higher the urate, the worse the flow; the more the inflammation, the worse the flow, so seemingly corresponding with the severity of the gout,” he said. That raised an obvious question, Dr. Pillinger continued: “If you can treat the gout, can you improve the flow-mediated dilation?”

His group answered that question with a study in 38 previously untreated patients with gout, giving them colchicine 0.6 mg twice daily for a month plus a urate-lowering xanthine oxidase inhibitor (allopurinol or febuxostat) to treat them to a target urate level of < 6 mg/dL. “We saw an increase in endothelial function, and it normalized,” Dr. Pillinger said.

However, some study participants didn’t respond. “They were people with well-established other cardiovascular comorbidities — hypertension, hyperlipidemia,” he said. “I think some people just have vessels that are too damaged to get at them just by fixing their gout problem or their inflammation.”

That means patients with gout need to be treated with colchicine early on to avoid CV problems, Dr. Pillinger added. “We ought to get to them before they have the other problems,” he said.

Managing gout, and the concomitant CV problems, requires vigilance both during and in between flares, Dr. Pillinger said after his presentation.

“We have always taught that patients between flares basically look like people with no gout, but we do know now that patients with gout between flares tend to have what you might call ‘subclinical’ inflammation: CRPs and ESRs [erythrocyte sedimentation rates] that are higher than those of the general population, though not so excessive that they might grab attention,” he said. “We also know that many, if not all, patients between flares have urate deposited in or around their joints, but how these two relate is not fully established.”

Better treatment within 3 months of an acute gout flare may reduce the risk for CV events, he said, but that’s based on speculation more so than clinical data.
 

Potential Benefits of Targeting Inflammation

“More chronically, we know from the cardiologists’ studies that anti-inflammatory therapy should reduce risk in the high-risk general population,” Dr. Pillinger said. “There are no prospective studies confirming that this approach will work among gout patients, but there is no reason why it shouldn’t work — except perhaps that gout patients may have higher inflammation than the general population and also have more comorbidities, so they could perhaps be more resistant.”

Dr. Pillinger said that his group’s studies and another led by Daniel Solomon, MD, at Brigham and Women’s Hospital in Boston, have indicated that anti-inflammatory strategies in gout will lower CV risk.

“And interestingly,” he added, “our data suggest that colchicine use may lower risk not only in high-risk gout patients but also in gout patients who start with no CAD [coronary artery disease] but who seem to have less incident CAD on colchicine. I see this as identifying that gout patients are intrinsically at high risk for CAD, even if they don’t actually have any, so they represent a population for whom lowering chronic inflammation may help prevent incident disease.”

Dr. Pillinger provided more evidence that the understanding of the relationship between gout, gout flares, and CV risk is evolving, said Michael S. Garshick, MD, who attended the conference and is head of the Cardio-Rheumatology Program at NYU Langone, New York City.

NYU Langone

“There’s epidemiologic evidence supporting the association,” Dr. Garshick told this news organization after the conference. “We think that most conditions with immune system activation do tend to have an increased risk of some form of cardiovascular disease, but I think the relationship with gout has been highly underpublicized.”

Many patients with gout tend to have a higher prevalence of traditional cardiometabolic issues, which may compound the relationship, Dr. Garshick added. “However, I would argue that with this patient subset that it doesn’t matter because gout patients have a higher risk of traditional risk factors, and you have to [treat-to-target] those traditional risk factors.”

While the clinical evidence of a link between gout and atherosclerosis may not be conclusive, enough circumstantial evidence exists to believe that treating gout will reduce CV risks, he said. “Some of the imaging techniques do suggest that gouty crystals [are] in the atherosclerotic plaque of gout patients,” Dr. Garshick added. Dr. Pillinger’s work, he said, “is showing us that there are different pathways to develop atherosclerosis.”

Dr. Pillinger disclosed relationships with Federation Bio, Fortress Biotech, Amgen, Scilex, Hikma Pharmaceuticals, LG Chem, and Olatec Therapeutics. Dr. Garshick disclosed relationships with Kiniksa Pharmaceuticals, Agepha Pharma, Bristol Myers Squibb, and Horizon Therapeutics.
 

A version of this article appeared on Medscape.com.

NEW YORK — Patients with rheumatoid arthritis (RA) carry a high risk for cardiovascular events, but mounting clinical evidence suggests they’re being undertreated to manage that risk. Rheumatologists should consider a patient with RA’s cardiovascular disease (CVD) status before deciding on RA treatments, a researcher of cardiometabolic disorders advised.

“The ORAL Surveillance trial suggests that we need to consider cardiovascular risk factors and maybe do additional screening in these patients before we use RA therapies,” Jon T. Giles, MD, PhD, director of the Cedars-Sinai Inflammatory Arthritis Clinical Center at Cedars-Sinai in Los Angeles, told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.
 

Underuse of Statins

ORAL Surveillance enrolled 4362 patients with RA aged 50 years and older with at least one cardiovascular risk factor. About 23% of all patients were taking statins, as were about half of patients with a history of atherosclerotic CVD (ASCVD).

“A lot of those people should have been on statins,” Dr. Giles said in an interview. “Not because of their RA but because of their risk factors, and then RA brings it up another notch.” In the population with ASCVD, Dr. Giles added, “It should have been more like 70% and 80%. If we’re talking about a disease that has enhanced cardiovascular risk, then the adoption of standard care that you would do for anybody in the general population should be at that standard and maybe above.”

Multiple studies have documented the underlying risk for CVD events, CV mortality, and subclinical atherosclerosis in people with RA, Dr. Giles noted in his presentation. Physiologically, the RA-specific risk factors most linked to CVD risk are systemic inflammation/cytokine excess and specific circulating T-cell and intermediate monocyte subsets, or both, Dr. Giles said.
 

Disease-Modifying Antirheumatic Drugs (DMARDs) and CVD Risk

Likewise, research in the past decade has linked methotrexate and tumor necrosis factor (TNF) inhibitors to reduced ASCVD events in RA. Another study showed that abatacept had an effect similar to that of etanercept in patients with RA, and the ENTRACTE trial, for which Dr. Giles was the lead author, demonstrated that tocilizumab matched etanercept in reducing CV events.

The ORAL Surveillance investigators also reported that patients with RA who were receiving the Janus kinase (JAK) inhibitor tofacitinib had a higher risk for major adverse cardiovascular events and cancers than those on TNF therapy, Dr. Giles noted. While statins in combination with JAK inhibitors may have the potential to provide a balance for controlling CV risk in patients with RA, he said later that the potential of JAK inhibitors in reducing CVD risk in RA “is still unsettled.”

The ongoing TARGET trial is further evaluating the impact of DMARDs on vascular inflammation in RA, said Dr. Giles, who’s also a trial principal investigator. TARGET is randomizing 115 patients with RA who didn’t respond to methotrexate to a TNF inhibitor or the addition of sulfasalazine and hydroxychloroquine to their methotrexate. Patients can be on low-intensity but not high-intensity statin therapy, Dr. Giles said.

TARGET results reported last year demonstrated an 8% decrease in arterial fluorodeoxyglucose (FDG) uptake on PET-CT in both treatment arms. Previous studies, Dr. Giles noted, have shown a potential link between FDG and histologic markers of inflammation. “An 8% decrease in vascular FDG is in line with what you would expect from statin treatment,” he said.

TARGET results published in April showed that a measure of a cluster of 12 cytokines and other inflammatory mediators, known as the multibiomarker disease activity (MBDA) score and marketed under the brand name Vectra DA, may help determine arterial FDG uptake. “Those who had a low MBDA score at week 24 actually had the greatest reduction in the arterial FDG,” he said.

Those results were driven entirely by low serum amyloid A (SAA) levels, Dr. Giles said. Those same results didn’t hold for patients in whom SAA and C-reactive protein were correlated.

“So, there’s more to come here,” Dr. Giles said. “We’re looking at other, much larger biomarker panels.”

Nonetheless, he said, sufficient evidence exists to conclude that treating RA to target reduces CV events. “The idea is that at every visit that you see an RA patient, you measure their disease activity, and if they’re not at the target of low disease activity or remission, then you change their therapy to improve that,” he said in an interview.

But an evidence-based guideline is needed to improve coverage of CVD risks in patients with RA, Dr. Giles said. “There is a movement afoot” for a guideline, he said. “If you just did what is supposed to happen for a general population, you would make some improvements. The risk-benefit [ratio] for statins for people with RA has been looked at, and it’s very favorable.”
 

Unanswered Questions

Dr. Giles noted that the ORAL Surveillance trial has left a number of questions unanswered about the role of JAK inhibitors in managing CVD risk in patients with RA. “The issue that we’re trying to ask is, is it just the TNF inhibitors may be better? Is this a subpopulation issue, or was it just bad luck from the purposes of this one trial? Granted, it was a very large trial, but you can still have luck in terms of getting an effect that’s not accurate.”

Dr. Giles’ “gut feeling” on JAK inhibitors is that they’re not causing harm, but that they’re not as effective as TNF inhibitors in ameliorating CV risks in patients with RA.

Michael S. Garshick, MD, who attended the conference and is head of the cardio-rheumatology program at NYU Langone Health, concurred that a number of unanswered questions persist over the treatment of CVD risk in RA — and autoimmune disease in general.

NYU Langone

“I think we’re still trying to prove that DMARDs reduce cardiovascular risk in autoimmune conditions,” he said. “The epidemiologic data would suggest, yes, that inflammation prevention is beneficial for cardiovascular disease, but the TARGET trial suggested that vascular inflammation improved by treating RA, but that biologic therapy wasn’t better than traditional triple therapy.”

Other questions remain unanswered, Dr. Garshick said.

“Is there a specific immunotherapy that is most beneficial to reduce heart disease in patients with an autoimmune condition, whether it’s rheumatoid arthritis, psoriasis, or lupus?”

Dr. Garshick said he’s specifically interested in the residual risk that exists after treating the autoimmunity. “Do you still have a higher risk for heart disease, and if so, why? Is there something else going on that we can’t see?”

The biggest unanswered question, he said, is “How can we do a better job of recognizing heart disease risk in these patients? That’s the low-hanging fruit that people are studying, but across many of those studies, patients have higher rates of blood pressure, cholesterol issues, obesity, diabetes, and many times, we’re not adequately treating these comorbidities.”

That, Dr. Garshick said, may be a result of physician fatigue. “And so [treatment of these comorbidities is] kicked down the road for a year or years,” he added.

Dr. Giles disclosed financial relationships with Pfizer, AbbVie, Eli Lilly, and Novartis. Dr. Garshick disclosed relationships with Kiniksa Pharmaceuticals, Agepha Pharma, Bristol Myers Squibb, and Horizon Therapeutics.

A version of this article appeared on Medscape.com.

NEW YORK — Patients with rheumatoid arthritis (RA) carry a high risk for cardiovascular events, but mounting clinical evidence suggests they’re being undertreated to manage that risk. Rheumatologists should consider a patient with RA’s cardiovascular disease (CVD) status before deciding on RA treatments, a researcher of cardiometabolic disorders advised.

“The ORAL Surveillance trial suggests that we need to consider cardiovascular risk factors and maybe do additional screening in these patients before we use RA therapies,” Jon T. Giles, MD, PhD, director of the Cedars-Sinai Inflammatory Arthritis Clinical Center at Cedars-Sinai in Los Angeles, told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.
 

Underuse of Statins

ORAL Surveillance enrolled 4362 patients with RA aged 50 years and older with at least one cardiovascular risk factor. About 23% of all patients were taking statins, as were about half of patients with a history of atherosclerotic CVD (ASCVD).

“A lot of those people should have been on statins,” Dr. Giles said in an interview. “Not because of their RA but because of their risk factors, and then RA brings it up another notch.” In the population with ASCVD, Dr. Giles added, “It should have been more like 70% and 80%. If we’re talking about a disease that has enhanced cardiovascular risk, then the adoption of standard care that you would do for anybody in the general population should be at that standard and maybe above.”

Multiple studies have documented the underlying risk for CVD events, CV mortality, and subclinical atherosclerosis in people with RA, Dr. Giles noted in his presentation. Physiologically, the RA-specific risk factors most linked to CVD risk are systemic inflammation/cytokine excess and specific circulating T-cell and intermediate monocyte subsets, or both, Dr. Giles said.
 

Disease-Modifying Antirheumatic Drugs (DMARDs) and CVD Risk

Likewise, research in the past decade has linked methotrexate and tumor necrosis factor (TNF) inhibitors to reduced ASCVD events in RA. Another study showed that abatacept had an effect similar to that of etanercept in patients with RA, and the ENTRACTE trial, for which Dr. Giles was the lead author, demonstrated that tocilizumab matched etanercept in reducing CV events.

The ORAL Surveillance investigators also reported that patients with RA who were receiving the Janus kinase (JAK) inhibitor tofacitinib had a higher risk for major adverse cardiovascular events and cancers than those on TNF therapy, Dr. Giles noted. While statins in combination with JAK inhibitors may have the potential to provide a balance for controlling CV risk in patients with RA, he said later that the potential of JAK inhibitors in reducing CVD risk in RA “is still unsettled.”

The ongoing TARGET trial is further evaluating the impact of DMARDs on vascular inflammation in RA, said Dr. Giles, who’s also a trial principal investigator. TARGET is randomizing 115 patients with RA who didn’t respond to methotrexate to a TNF inhibitor or the addition of sulfasalazine and hydroxychloroquine to their methotrexate. Patients can be on low-intensity but not high-intensity statin therapy, Dr. Giles said.

TARGET results reported last year demonstrated an 8% decrease in arterial fluorodeoxyglucose (FDG) uptake on PET-CT in both treatment arms. Previous studies, Dr. Giles noted, have shown a potential link between FDG and histologic markers of inflammation. “An 8% decrease in vascular FDG is in line with what you would expect from statin treatment,” he said.

TARGET results published in April showed that a measure of a cluster of 12 cytokines and other inflammatory mediators, known as the multibiomarker disease activity (MBDA) score and marketed under the brand name Vectra DA, may help determine arterial FDG uptake. “Those who had a low MBDA score at week 24 actually had the greatest reduction in the arterial FDG,” he said.

Those results were driven entirely by low serum amyloid A (SAA) levels, Dr. Giles said. Those same results didn’t hold for patients in whom SAA and C-reactive protein were correlated.

“So, there’s more to come here,” Dr. Giles said. “We’re looking at other, much larger biomarker panels.”

Nonetheless, he said, sufficient evidence exists to conclude that treating RA to target reduces CV events. “The idea is that at every visit that you see an RA patient, you measure their disease activity, and if they’re not at the target of low disease activity or remission, then you change their therapy to improve that,” he said in an interview.

But an evidence-based guideline is needed to improve coverage of CVD risks in patients with RA, Dr. Giles said. “There is a movement afoot” for a guideline, he said. “If you just did what is supposed to happen for a general population, you would make some improvements. The risk-benefit [ratio] for statins for people with RA has been looked at, and it’s very favorable.”
 

Unanswered Questions

Dr. Giles noted that the ORAL Surveillance trial has left a number of questions unanswered about the role of JAK inhibitors in managing CVD risk in patients with RA. “The issue that we’re trying to ask is, is it just the TNF inhibitors may be better? Is this a subpopulation issue, or was it just bad luck from the purposes of this one trial? Granted, it was a very large trial, but you can still have luck in terms of getting an effect that’s not accurate.”

Dr. Giles’ “gut feeling” on JAK inhibitors is that they’re not causing harm, but that they’re not as effective as TNF inhibitors in ameliorating CV risks in patients with RA.

Michael S. Garshick, MD, who attended the conference and is head of the cardio-rheumatology program at NYU Langone Health, concurred that a number of unanswered questions persist over the treatment of CVD risk in RA — and autoimmune disease in general.

NYU Langone

“I think we’re still trying to prove that DMARDs reduce cardiovascular risk in autoimmune conditions,” he said. “The epidemiologic data would suggest, yes, that inflammation prevention is beneficial for cardiovascular disease, but the TARGET trial suggested that vascular inflammation improved by treating RA, but that biologic therapy wasn’t better than traditional triple therapy.”

Other questions remain unanswered, Dr. Garshick said.

“Is there a specific immunotherapy that is most beneficial to reduce heart disease in patients with an autoimmune condition, whether it’s rheumatoid arthritis, psoriasis, or lupus?”

Dr. Garshick said he’s specifically interested in the residual risk that exists after treating the autoimmunity. “Do you still have a higher risk for heart disease, and if so, why? Is there something else going on that we can’t see?”

The biggest unanswered question, he said, is “How can we do a better job of recognizing heart disease risk in these patients? That’s the low-hanging fruit that people are studying, but across many of those studies, patients have higher rates of blood pressure, cholesterol issues, obesity, diabetes, and many times, we’re not adequately treating these comorbidities.”

That, Dr. Garshick said, may be a result of physician fatigue. “And so [treatment of these comorbidities is] kicked down the road for a year or years,” he added.

Dr. Giles disclosed financial relationships with Pfizer, AbbVie, Eli Lilly, and Novartis. Dr. Garshick disclosed relationships with Kiniksa Pharmaceuticals, Agepha Pharma, Bristol Myers Squibb, and Horizon Therapeutics.

A version of this article appeared on Medscape.com.

NEW YORK — Patients with rheumatoid arthritis (RA) carry a high risk for cardiovascular events, but mounting clinical evidence suggests they’re being undertreated to manage that risk. Rheumatologists should consider a patient with RA’s cardiovascular disease (CVD) status before deciding on RA treatments, a researcher of cardiometabolic disorders advised.

“The ORAL Surveillance trial suggests that we need to consider cardiovascular risk factors and maybe do additional screening in these patients before we use RA therapies,” Jon T. Giles, MD, PhD, director of the Cedars-Sinai Inflammatory Arthritis Clinical Center at Cedars-Sinai in Los Angeles, told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.
 

Underuse of Statins

ORAL Surveillance enrolled 4362 patients with RA aged 50 years and older with at least one cardiovascular risk factor. About 23% of all patients were taking statins, as were about half of patients with a history of atherosclerotic CVD (ASCVD).

“A lot of those people should have been on statins,” Dr. Giles said in an interview. “Not because of their RA but because of their risk factors, and then RA brings it up another notch.” In the population with ASCVD, Dr. Giles added, “It should have been more like 70% and 80%. If we’re talking about a disease that has enhanced cardiovascular risk, then the adoption of standard care that you would do for anybody in the general population should be at that standard and maybe above.”

Multiple studies have documented the underlying risk for CVD events, CV mortality, and subclinical atherosclerosis in people with RA, Dr. Giles noted in his presentation. Physiologically, the RA-specific risk factors most linked to CVD risk are systemic inflammation/cytokine excess and specific circulating T-cell and intermediate monocyte subsets, or both, Dr. Giles said.
 

Disease-Modifying Antirheumatic Drugs (DMARDs) and CVD Risk

Likewise, research in the past decade has linked methotrexate and tumor necrosis factor (TNF) inhibitors to reduced ASCVD events in RA. Another study showed that abatacept had an effect similar to that of etanercept in patients with RA, and the ENTRACTE trial, for which Dr. Giles was the lead author, demonstrated that tocilizumab matched etanercept in reducing CV events.

The ORAL Surveillance investigators also reported that patients with RA who were receiving the Janus kinase (JAK) inhibitor tofacitinib had a higher risk for major adverse cardiovascular events and cancers than those on TNF therapy, Dr. Giles noted. While statins in combination with JAK inhibitors may have the potential to provide a balance for controlling CV risk in patients with RA, he said later that the potential of JAK inhibitors in reducing CVD risk in RA “is still unsettled.”

The ongoing TARGET trial is further evaluating the impact of DMARDs on vascular inflammation in RA, said Dr. Giles, who’s also a trial principal investigator. TARGET is randomizing 115 patients with RA who didn’t respond to methotrexate to a TNF inhibitor or the addition of sulfasalazine and hydroxychloroquine to their methotrexate. Patients can be on low-intensity but not high-intensity statin therapy, Dr. Giles said.

TARGET results reported last year demonstrated an 8% decrease in arterial fluorodeoxyglucose (FDG) uptake on PET-CT in both treatment arms. Previous studies, Dr. Giles noted, have shown a potential link between FDG and histologic markers of inflammation. “An 8% decrease in vascular FDG is in line with what you would expect from statin treatment,” he said.

TARGET results published in April showed that a measure of a cluster of 12 cytokines and other inflammatory mediators, known as the multibiomarker disease activity (MBDA) score and marketed under the brand name Vectra DA, may help determine arterial FDG uptake. “Those who had a low MBDA score at week 24 actually had the greatest reduction in the arterial FDG,” he said.

Those results were driven entirely by low serum amyloid A (SAA) levels, Dr. Giles said. Those same results didn’t hold for patients in whom SAA and C-reactive protein were correlated.

“So, there’s more to come here,” Dr. Giles said. “We’re looking at other, much larger biomarker panels.”

Nonetheless, he said, sufficient evidence exists to conclude that treating RA to target reduces CV events. “The idea is that at every visit that you see an RA patient, you measure their disease activity, and if they’re not at the target of low disease activity or remission, then you change their therapy to improve that,” he said in an interview.

But an evidence-based guideline is needed to improve coverage of CVD risks in patients with RA, Dr. Giles said. “There is a movement afoot” for a guideline, he said. “If you just did what is supposed to happen for a general population, you would make some improvements. The risk-benefit [ratio] for statins for people with RA has been looked at, and it’s very favorable.”
 

Unanswered Questions

Dr. Giles noted that the ORAL Surveillance trial has left a number of questions unanswered about the role of JAK inhibitors in managing CVD risk in patients with RA. “The issue that we’re trying to ask is, is it just the TNF inhibitors may be better? Is this a subpopulation issue, or was it just bad luck from the purposes of this one trial? Granted, it was a very large trial, but you can still have luck in terms of getting an effect that’s not accurate.”

Dr. Giles’ “gut feeling” on JAK inhibitors is that they’re not causing harm, but that they’re not as effective as TNF inhibitors in ameliorating CV risks in patients with RA.

Michael S. Garshick, MD, who attended the conference and is head of the cardio-rheumatology program at NYU Langone Health, concurred that a number of unanswered questions persist over the treatment of CVD risk in RA — and autoimmune disease in general.

NYU Langone

“I think we’re still trying to prove that DMARDs reduce cardiovascular risk in autoimmune conditions,” he said. “The epidemiologic data would suggest, yes, that inflammation prevention is beneficial for cardiovascular disease, but the TARGET trial suggested that vascular inflammation improved by treating RA, but that biologic therapy wasn’t better than traditional triple therapy.”

Other questions remain unanswered, Dr. Garshick said.

“Is there a specific immunotherapy that is most beneficial to reduce heart disease in patients with an autoimmune condition, whether it’s rheumatoid arthritis, psoriasis, or lupus?”

Dr. Garshick said he’s specifically interested in the residual risk that exists after treating the autoimmunity. “Do you still have a higher risk for heart disease, and if so, why? Is there something else going on that we can’t see?”

The biggest unanswered question, he said, is “How can we do a better job of recognizing heart disease risk in these patients? That’s the low-hanging fruit that people are studying, but across many of those studies, patients have higher rates of blood pressure, cholesterol issues, obesity, diabetes, and many times, we’re not adequately treating these comorbidities.”

That, Dr. Garshick said, may be a result of physician fatigue. “And so [treatment of these comorbidities is] kicked down the road for a year or years,” he added.

Dr. Giles disclosed financial relationships with Pfizer, AbbVie, Eli Lilly, and Novartis. Dr. Garshick disclosed relationships with Kiniksa Pharmaceuticals, Agepha Pharma, Bristol Myers Squibb, and Horizon Therapeutics.

A version of this article appeared on Medscape.com.

Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).

According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.

Quantifying the Problem

To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.

However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
 

How Did This Happen?

Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.

For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.

While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
 

What Is Being Done to Correct This?

Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.

This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.

The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
 

A Few Partial Fixes, But Most Complaints Go Ignored

Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.

Ultimate Solution?

This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.

While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.

To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.

Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).

According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.

Quantifying the Problem

To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.

However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
 

How Did This Happen?

Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.

For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.

While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
 

What Is Being Done to Correct This?

Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.

This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.

The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
 

A Few Partial Fixes, But Most Complaints Go Ignored

Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.

Ultimate Solution?

This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.

While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.

To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.

Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).

According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.

Quantifying the Problem

To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.

However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
 

How Did This Happen?

Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.

For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.

While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
 

What Is Being Done to Correct This?

Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.

This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.

The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
 

A Few Partial Fixes, But Most Complaints Go Ignored

Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.

Ultimate Solution?

This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.

While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.

To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.

Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

VIENNA — Nearly one third of anterior cruciate ligament (ACL) injuries appear to heal without surgery, according to an analysis of three-dimensional MRI data taken from the NACOX study, presented as a late-breaking poster at the OARSI 2024 World Congress. 

At 2 years after injury, three-dimensional MRI showed that 13 of 43 (30%) knees had evidence of normal, continuous ACL fibers. Moreover, a further 14 (33%) knees had a continuous ACL fiber structure following rehabilitation alone. ACL fibers were partly (16%) or completely (21%) ruptured in the remainder of cases.

Sara Freeman/Medscape Medical News

“If you think of the ACL like a rope, when there is continuity, it means those fibers have rejoined,” study coauthor Stephanie Filbay, PhD, an associate professor at the University of Melbourne in Australia, told this news organization.

“Within that, there’s a few variations of healing that we’re seeing. Some look like they’ve never been injured, while some have rejoined but appear thinner or longer than a normal ACL,” Dr. Filbay said.

She added: “What all this research is showing is that it’s happening at a much higher rate than we thought possible. And in some of the studies, it looks like ACL healing is associated with very favorable outcomes.”

At OARSI 2024, Dr. Filbay presented additional data from her and others’ research on the relationships between ACL healing and long-term functional outcomes and osteoarthritis (OA) incidence in comparisons between patients’ treatment pathways: Early ACL surgery, rehabilitation followed by delayed surgery, or rehabilitation only.
 

Healing Without Surgery

The idea that the ACL can heal without surgery is relatively recent and perhaps still not widely accepted as a concept, as Dr. Filbay explained during a plenary lecture at the congress.

Dr. Filbay explained that the ideal management of ACL injury depends on the severity of knee injury and whether someone’s knee is stable after trying nonsurgical management. Results of the ACL SNNAP trial, for example, have suggested that surgical reconstruction is superior to a rehabilitation strategy for managing non-acute ACL injuries where there are persistent symptoms of instability.

However, there have been two trials — COMPARE performed in the Netherlands and KANON performed in Sweden — that found that early surgery was no better than a strategy of initial rehabilitation with the option of having a delayed ACL surgery if needed.
 

What Happens Long Term?

Posttraumatic OA is a well-known long-term consequence of ACL injury. According to a recent meta-analysis, there is a sevenfold increased risk for OA comparing people who have and have not had an ACL injury.

ACL injury also results in OA occurring at an earlier age than in people with OA who have not had an ACL injury. This has been shown to progress at a faster rate and be associated with a longer period of disability, Dr. Filbay said at the congress, sponsored by the Osteoarthritis Research Society International.

But does the ACL really heal? Dr. Filbay thinks that it does and has been involved in several studies that have used MRI to look at how the ACL may do so.

In a recently published paper, Dr. Filbay and colleagues reported the findings from a secondary analysis of the KANON trial and found that nearly one in three (30%) of the participants who had been randomized to optional delayed surgery had MRI evidence of healing at 2 years. But when they excluded people who had delayed surgery, 53% of people managed by rehabilitation alone had evidence of healing.

The evaluation also found that those who had a healed vs non-healed ligament had better results using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and that there were better outcomes at 2 years among those with ACL healing vs those who had early or delayed ACL surgery.
 

ACL Continuity and Long-Term Outcomes

At OARSI 2024, Dr. Filbay and colleagues reported an even longer-term secondary analysis of the KANON trial on the relationship between ACL healing at 5 years and outcomes at 11 years. The results were first reported in NEJM Evidence.

Dr. Filbay reported that participants with ACL continuity on MRI at 5 years actually had worse patient-reported outcomes 11 years later than those who were managed with early or delayed ACL reconstruction.

“This does not align with previous findings suggesting better 2-year outcomes compared to the surgically managed groups,” Dr. Filbay said.

However, people with ACL continuity following rehabilitation did seem to show numerically similar or fewer signs of radiographic OA at 11 years vs the surgical groups.

Radiographic OA of the tibiofemoral joint (TFJ) or patellofemoral joint (PFJ) at 11 years was observed in a respective 14% and 21% of people with ACL continuity at 5 years (n = 14) and in 22% and 11% of people with ACL discontinuity at 5 years in the rehabilitation alone group.

By comparison, radiographic OA of the TFJ or PFJ at 11 years was seen in a respective 23% and 35% of people who had rehabilitation with delayed surgery (n = 26) and in 18% and 41% of those who had early surgery (n = 49).

These are descriptive results, Dr. Filbay said, because the numbers were too small to do a statistical analysis. Further, larger, longitudinal studies will be needed.
 

Posttraumatic OA After ACL Surgery

Elsewhere at OARSI 2024, Matthew Harkey, PhD, and colleagues from Michigan State University, East Lansing, Michigan, reported data showing that nearly two thirds of people who undergo surgical reconstruction have symptoms at 6 months that could be indicative of early knee OA.

Knee symptoms indicative of OA declined to 53% at 12 months and 45% at 24 months.

“It’s a bit complex — we can’t outright say arthritis is developing, but there’s a large group of patients whose symptoms linger long after surgery,” Dr. Harkey said in a press release.

“Often, clinicians assume that these postoperative symptoms will naturally improve as patients reengage with their usual activities. However, what we’re seeing suggests these symptoms persist and likely require a targeted approach to manage or improve them,” Dr. Harkey said.

The analysis used data on 3752 individuals aged 14-40 years who were enrolled in the New Zealand ACL Registry and who completed the KOOS at 6, 12, and 24 months after having ACL reconstruction.

Dr. Harkey and team reported that one in three people had persistent early OA symptoms at 2 years, while 23% had no early OA symptoms at any timepoint.

The studies were independently supported. Dr. Filbay and Dr. Harkey had no relevant financial relationships to report.

Dr. Filbay and colleagues have developed a treatment decision aid for individuals who have sustained an ACL injury. This provides information on the different treatment options available and how they compare.

A version of this article appeared on Medscape.com.

VIENNA — Nearly one third of anterior cruciate ligament (ACL) injuries appear to heal without surgery, according to an analysis of three-dimensional MRI data taken from the NACOX study, presented as a late-breaking poster at the OARSI 2024 World Congress. 

At 2 years after injury, three-dimensional MRI showed that 13 of 43 (30%) knees had evidence of normal, continuous ACL fibers. Moreover, a further 14 (33%) knees had a continuous ACL fiber structure following rehabilitation alone. ACL fibers were partly (16%) or completely (21%) ruptured in the remainder of cases.

Sara Freeman/Medscape Medical News

“If you think of the ACL like a rope, when there is continuity, it means those fibers have rejoined,” study coauthor Stephanie Filbay, PhD, an associate professor at the University of Melbourne in Australia, told this news organization.

“Within that, there’s a few variations of healing that we’re seeing. Some look like they’ve never been injured, while some have rejoined but appear thinner or longer than a normal ACL,” Dr. Filbay said.

She added: “What all this research is showing is that it’s happening at a much higher rate than we thought possible. And in some of the studies, it looks like ACL healing is associated with very favorable outcomes.”

At OARSI 2024, Dr. Filbay presented additional data from her and others’ research on the relationships between ACL healing and long-term functional outcomes and osteoarthritis (OA) incidence in comparisons between patients’ treatment pathways: Early ACL surgery, rehabilitation followed by delayed surgery, or rehabilitation only.
 

Healing Without Surgery

The idea that the ACL can heal without surgery is relatively recent and perhaps still not widely accepted as a concept, as Dr. Filbay explained during a plenary lecture at the congress.

Dr. Filbay explained that the ideal management of ACL injury depends on the severity of knee injury and whether someone’s knee is stable after trying nonsurgical management. Results of the ACL SNNAP trial, for example, have suggested that surgical reconstruction is superior to a rehabilitation strategy for managing non-acute ACL injuries where there are persistent symptoms of instability.

However, there have been two trials — COMPARE performed in the Netherlands and KANON performed in Sweden — that found that early surgery was no better than a strategy of initial rehabilitation with the option of having a delayed ACL surgery if needed.
 

What Happens Long Term?

Posttraumatic OA is a well-known long-term consequence of ACL injury. According to a recent meta-analysis, there is a sevenfold increased risk for OA comparing people who have and have not had an ACL injury.

ACL injury also results in OA occurring at an earlier age than in people with OA who have not had an ACL injury. This has been shown to progress at a faster rate and be associated with a longer period of disability, Dr. Filbay said at the congress, sponsored by the Osteoarthritis Research Society International.

But does the ACL really heal? Dr. Filbay thinks that it does and has been involved in several studies that have used MRI to look at how the ACL may do so.

In a recently published paper, Dr. Filbay and colleagues reported the findings from a secondary analysis of the KANON trial and found that nearly one in three (30%) of the participants who had been randomized to optional delayed surgery had MRI evidence of healing at 2 years. But when they excluded people who had delayed surgery, 53% of people managed by rehabilitation alone had evidence of healing.

The evaluation also found that those who had a healed vs non-healed ligament had better results using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and that there were better outcomes at 2 years among those with ACL healing vs those who had early or delayed ACL surgery.
 

ACL Continuity and Long-Term Outcomes

At OARSI 2024, Dr. Filbay and colleagues reported an even longer-term secondary analysis of the KANON trial on the relationship between ACL healing at 5 years and outcomes at 11 years. The results were first reported in NEJM Evidence.

Dr. Filbay reported that participants with ACL continuity on MRI at 5 years actually had worse patient-reported outcomes 11 years later than those who were managed with early or delayed ACL reconstruction.

“This does not align with previous findings suggesting better 2-year outcomes compared to the surgically managed groups,” Dr. Filbay said.

However, people with ACL continuity following rehabilitation did seem to show numerically similar or fewer signs of radiographic OA at 11 years vs the surgical groups.

Radiographic OA of the tibiofemoral joint (TFJ) or patellofemoral joint (PFJ) at 11 years was observed in a respective 14% and 21% of people with ACL continuity at 5 years (n = 14) and in 22% and 11% of people with ACL discontinuity at 5 years in the rehabilitation alone group.

By comparison, radiographic OA of the TFJ or PFJ at 11 years was seen in a respective 23% and 35% of people who had rehabilitation with delayed surgery (n = 26) and in 18% and 41% of those who had early surgery (n = 49).

These are descriptive results, Dr. Filbay said, because the numbers were too small to do a statistical analysis. Further, larger, longitudinal studies will be needed.
 

Posttraumatic OA After ACL Surgery

Elsewhere at OARSI 2024, Matthew Harkey, PhD, and colleagues from Michigan State University, East Lansing, Michigan, reported data showing that nearly two thirds of people who undergo surgical reconstruction have symptoms at 6 months that could be indicative of early knee OA.

Knee symptoms indicative of OA declined to 53% at 12 months and 45% at 24 months.

“It’s a bit complex — we can’t outright say arthritis is developing, but there’s a large group of patients whose symptoms linger long after surgery,” Dr. Harkey said in a press release.

“Often, clinicians assume that these postoperative symptoms will naturally improve as patients reengage with their usual activities. However, what we’re seeing suggests these symptoms persist and likely require a targeted approach to manage or improve them,” Dr. Harkey said.

The analysis used data on 3752 individuals aged 14-40 years who were enrolled in the New Zealand ACL Registry and who completed the KOOS at 6, 12, and 24 months after having ACL reconstruction.

Dr. Harkey and team reported that one in three people had persistent early OA symptoms at 2 years, while 23% had no early OA symptoms at any timepoint.

The studies were independently supported. Dr. Filbay and Dr. Harkey had no relevant financial relationships to report.

Dr. Filbay and colleagues have developed a treatment decision aid for individuals who have sustained an ACL injury. This provides information on the different treatment options available and how they compare.

A version of this article appeared on Medscape.com.

VIENNA — Nearly one third of anterior cruciate ligament (ACL) injuries appear to heal without surgery, according to an analysis of three-dimensional MRI data taken from the NACOX study, presented as a late-breaking poster at the OARSI 2024 World Congress. 

At 2 years after injury, three-dimensional MRI showed that 13 of 43 (30%) knees had evidence of normal, continuous ACL fibers. Moreover, a further 14 (33%) knees had a continuous ACL fiber structure following rehabilitation alone. ACL fibers were partly (16%) or completely (21%) ruptured in the remainder of cases.

Sara Freeman/Medscape Medical News

“If you think of the ACL like a rope, when there is continuity, it means those fibers have rejoined,” study coauthor Stephanie Filbay, PhD, an associate professor at the University of Melbourne in Australia, told this news organization.

“Within that, there’s a few variations of healing that we’re seeing. Some look like they’ve never been injured, while some have rejoined but appear thinner or longer than a normal ACL,” Dr. Filbay said.

She added: “What all this research is showing is that it’s happening at a much higher rate than we thought possible. And in some of the studies, it looks like ACL healing is associated with very favorable outcomes.”

At OARSI 2024, Dr. Filbay presented additional data from her and others’ research on the relationships between ACL healing and long-term functional outcomes and osteoarthritis (OA) incidence in comparisons between patients’ treatment pathways: Early ACL surgery, rehabilitation followed by delayed surgery, or rehabilitation only.
 

Healing Without Surgery

The idea that the ACL can heal without surgery is relatively recent and perhaps still not widely accepted as a concept, as Dr. Filbay explained during a plenary lecture at the congress.

Dr. Filbay explained that the ideal management of ACL injury depends on the severity of knee injury and whether someone’s knee is stable after trying nonsurgical management. Results of the ACL SNNAP trial, for example, have suggested that surgical reconstruction is superior to a rehabilitation strategy for managing non-acute ACL injuries where there are persistent symptoms of instability.

However, there have been two trials — COMPARE performed in the Netherlands and KANON performed in Sweden — that found that early surgery was no better than a strategy of initial rehabilitation with the option of having a delayed ACL surgery if needed.
 

What Happens Long Term?

Posttraumatic OA is a well-known long-term consequence of ACL injury. According to a recent meta-analysis, there is a sevenfold increased risk for OA comparing people who have and have not had an ACL injury.

ACL injury also results in OA occurring at an earlier age than in people with OA who have not had an ACL injury. This has been shown to progress at a faster rate and be associated with a longer period of disability, Dr. Filbay said at the congress, sponsored by the Osteoarthritis Research Society International.

But does the ACL really heal? Dr. Filbay thinks that it does and has been involved in several studies that have used MRI to look at how the ACL may do so.

In a recently published paper, Dr. Filbay and colleagues reported the findings from a secondary analysis of the KANON trial and found that nearly one in three (30%) of the participants who had been randomized to optional delayed surgery had MRI evidence of healing at 2 years. But when they excluded people who had delayed surgery, 53% of people managed by rehabilitation alone had evidence of healing.

The evaluation also found that those who had a healed vs non-healed ligament had better results using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and that there were better outcomes at 2 years among those with ACL healing vs those who had early or delayed ACL surgery.
 

ACL Continuity and Long-Term Outcomes

At OARSI 2024, Dr. Filbay and colleagues reported an even longer-term secondary analysis of the KANON trial on the relationship between ACL healing at 5 years and outcomes at 11 years. The results were first reported in NEJM Evidence.

Dr. Filbay reported that participants with ACL continuity on MRI at 5 years actually had worse patient-reported outcomes 11 years later than those who were managed with early or delayed ACL reconstruction.

“This does not align with previous findings suggesting better 2-year outcomes compared to the surgically managed groups,” Dr. Filbay said.

However, people with ACL continuity following rehabilitation did seem to show numerically similar or fewer signs of radiographic OA at 11 years vs the surgical groups.

Radiographic OA of the tibiofemoral joint (TFJ) or patellofemoral joint (PFJ) at 11 years was observed in a respective 14% and 21% of people with ACL continuity at 5 years (n = 14) and in 22% and 11% of people with ACL discontinuity at 5 years in the rehabilitation alone group.

By comparison, radiographic OA of the TFJ or PFJ at 11 years was seen in a respective 23% and 35% of people who had rehabilitation with delayed surgery (n = 26) and in 18% and 41% of those who had early surgery (n = 49).

These are descriptive results, Dr. Filbay said, because the numbers were too small to do a statistical analysis. Further, larger, longitudinal studies will be needed.
 

Posttraumatic OA After ACL Surgery

Elsewhere at OARSI 2024, Matthew Harkey, PhD, and colleagues from Michigan State University, East Lansing, Michigan, reported data showing that nearly two thirds of people who undergo surgical reconstruction have symptoms at 6 months that could be indicative of early knee OA.

Knee symptoms indicative of OA declined to 53% at 12 months and 45% at 24 months.

“It’s a bit complex — we can’t outright say arthritis is developing, but there’s a large group of patients whose symptoms linger long after surgery,” Dr. Harkey said in a press release.

“Often, clinicians assume that these postoperative symptoms will naturally improve as patients reengage with their usual activities. However, what we’re seeing suggests these symptoms persist and likely require a targeted approach to manage or improve them,” Dr. Harkey said.

The analysis used data on 3752 individuals aged 14-40 years who were enrolled in the New Zealand ACL Registry and who completed the KOOS at 6, 12, and 24 months after having ACL reconstruction.

Dr. Harkey and team reported that one in three people had persistent early OA symptoms at 2 years, while 23% had no early OA symptoms at any timepoint.

The studies were independently supported. Dr. Filbay and Dr. Harkey had no relevant financial relationships to report.

Dr. Filbay and colleagues have developed a treatment decision aid for individuals who have sustained an ACL injury. This provides information on the different treatment options available and how they compare.

A version of this article appeared on Medscape.com.

Meningitis has been highlighted as a novel risk factor for trigeminal neuralgia in a nationwide, propensity-matched study of hospital admissions.

In multivariate analysis, the odds of meningitis were threefold higher in patients admitted with trigeminal neuralgia than in matched controls without trigeminal neuralgia.

This is the first nationwide population-based study of the rare, chronic pain disorder to identify the prevalence of trigeminal neuralgia admissions in the United States and risk factors contributing to trigeminal neuralgia development.

“Our results affirm known associations between trigeminal neuralgia and comorbidities like multiple sclerosis, and they also identify meningitis as a novel risk factor for trigeminal neuralgia,” said investigator Megan Tang, BS, a medical student at the Icahn School of Medicine at Mount Sinai, New York City.

The findings were presented at the American Association of Neurological Surgeons (AANS) 2024 annual meeting.
 

Strong Clinical Risk Factors

Trigeminal neuralgia is a rare pain disorder involving neurovascular compression of the trigeminal nerve. Its etiology and risk factors are poorly understood. Current literature is based on limited datasets and reports inconsistent risk factors across studies.

To better understand the disorder, researchers used International Classification of Diseases (ICD)-9 codes to identify trigeminal neuralgia admissions in the National Inpatient Sample from 2016 to 2019, and then propensity matched them 1:1 to non-trigeminal neuralgia admissions based on demographics, socioeconomic status, and Charlson comorbidity index scores.

Univariate analysis identified 136,345 trigeminal neuralgia admissions or an overall prevalence of 0.096%.

Trigeminal neuralgia admissions had lower morbidity than non-trigeminal neuralgia admissions and a higher prevalence of non-White patients, private insurance, and prolonged length of stay, Ms. Tang said.

Patients admitted for trigeminal neuralgia also had a higher prevalence of several chronic conditions, including hypertension, hyperlipidemia, and osteoarthritis; inflammatory conditions like lupus, meningitis, rheumatoid arthritis, and inflammatory bowel disease; and neurologic conditions including multiple sclerosis, epilepsy, stroke, and neurovascular compression disorders.

In multivariate analysis, investigators identified meningitis as a previously unknown risk factor for trigeminal neuralgia (odds ratio [OR], 3.1; P < .001).

Other strong risk factors were neurovascular compression disorders (OR, 39.82; P < .001) and multiple sclerosis (OR, 12.41; P < .001). Non-White race (Black; OR, 1.09; Hispanic; OR, 1.23; Other; OR, 1.24) and use of Medicaid (OR, 1.07) and other insurance (OR, 1.17) were demographic risk factors for trigeminal neuralgia.

“This finding points us toward future work exploring the potential mechanisms of predictors, most notably inflammatory conditions in trigeminal neuralgia development,” Ms. Tang concluded.

She declined to comment further on the findings, noting the investigators are still finalizing the results and interpretation.
 

Ask About Meningitis, Fever

Commenting on the findings, Michael D. Staudt, MD, MSc, University Hospitals Cleveland Medical Center, said that many patients who present with classical trigeminal neuralgia will have a blood vessel on MRI that is pressing on the trigeminal nerve.

“Obviously, the nerve is bathed in cerebrospinal fluid. So, if there’s an inflammatory marker, inflammation, or infection that could be injuring the nerve in a way that we don’t yet understand, that could be something that could cause trigeminal neuralgia without having to see a blood vessel,” said Dr. Staudt, who was not involved in the study. “It makes sense, theoretically. Something that’s inflammatory, something that’s irritating, that’s novel.”

Currently, predictive markers include clinical history, response to classical medications such as carbamazepine, and MRI findings, Dr. Staudt noted.

“Someone shows up with symptoms and MRI, and it’s basically do they have a blood vessel or not,” he said. “Treatments are generally within the same categories, but we don’t think it’s the same sort of success rate as seeing a blood vessel.”

Further research is needed, but, in the meantime, Dr. Staudt said, “We can ask patients who show up with facial pain if they’ve ever had meningitis or some sort of fever that preceded their onset of pain.”

The study had no specific funding. Ms. Tang and coauthor Jack Y. Zhang, MS, reported no relevant financial disclosures. Dr. Staudt reported serving as a consultant for Abbott and as a scientific adviser and consultant for Boston Scientific.

A version of this article appeared on Medscape.com.

Meningitis has been highlighted as a novel risk factor for trigeminal neuralgia in a nationwide, propensity-matched study of hospital admissions.

In multivariate analysis, the odds of meningitis were threefold higher in patients admitted with trigeminal neuralgia than in matched controls without trigeminal neuralgia.

This is the first nationwide population-based study of the rare, chronic pain disorder to identify the prevalence of trigeminal neuralgia admissions in the United States and risk factors contributing to trigeminal neuralgia development.

“Our results affirm known associations between trigeminal neuralgia and comorbidities like multiple sclerosis, and they also identify meningitis as a novel risk factor for trigeminal neuralgia,” said investigator Megan Tang, BS, a medical student at the Icahn School of Medicine at Mount Sinai, New York City.

The findings were presented at the American Association of Neurological Surgeons (AANS) 2024 annual meeting.
 

Strong Clinical Risk Factors

Trigeminal neuralgia is a rare pain disorder involving neurovascular compression of the trigeminal nerve. Its etiology and risk factors are poorly understood. Current literature is based on limited datasets and reports inconsistent risk factors across studies.

To better understand the disorder, researchers used International Classification of Diseases (ICD)-9 codes to identify trigeminal neuralgia admissions in the National Inpatient Sample from 2016 to 2019, and then propensity matched them 1:1 to non-trigeminal neuralgia admissions based on demographics, socioeconomic status, and Charlson comorbidity index scores.

Univariate analysis identified 136,345 trigeminal neuralgia admissions or an overall prevalence of 0.096%.

Trigeminal neuralgia admissions had lower morbidity than non-trigeminal neuralgia admissions and a higher prevalence of non-White patients, private insurance, and prolonged length of stay, Ms. Tang said.

Patients admitted for trigeminal neuralgia also had a higher prevalence of several chronic conditions, including hypertension, hyperlipidemia, and osteoarthritis; inflammatory conditions like lupus, meningitis, rheumatoid arthritis, and inflammatory bowel disease; and neurologic conditions including multiple sclerosis, epilepsy, stroke, and neurovascular compression disorders.

In multivariate analysis, investigators identified meningitis as a previously unknown risk factor for trigeminal neuralgia (odds ratio [OR], 3.1; P < .001).

Other strong risk factors were neurovascular compression disorders (OR, 39.82; P < .001) and multiple sclerosis (OR, 12.41; P < .001). Non-White race (Black; OR, 1.09; Hispanic; OR, 1.23; Other; OR, 1.24) and use of Medicaid (OR, 1.07) and other insurance (OR, 1.17) were demographic risk factors for trigeminal neuralgia.

“This finding points us toward future work exploring the potential mechanisms of predictors, most notably inflammatory conditions in trigeminal neuralgia development,” Ms. Tang concluded.

She declined to comment further on the findings, noting the investigators are still finalizing the results and interpretation.
 

Ask About Meningitis, Fever

Commenting on the findings, Michael D. Staudt, MD, MSc, University Hospitals Cleveland Medical Center, said that many patients who present with classical trigeminal neuralgia will have a blood vessel on MRI that is pressing on the trigeminal nerve.

“Obviously, the nerve is bathed in cerebrospinal fluid. So, if there’s an inflammatory marker, inflammation, or infection that could be injuring the nerve in a way that we don’t yet understand, that could be something that could cause trigeminal neuralgia without having to see a blood vessel,” said Dr. Staudt, who was not involved in the study. “It makes sense, theoretically. Something that’s inflammatory, something that’s irritating, that’s novel.”

Currently, predictive markers include clinical history, response to classical medications such as carbamazepine, and MRI findings, Dr. Staudt noted.

“Someone shows up with symptoms and MRI, and it’s basically do they have a blood vessel or not,” he said. “Treatments are generally within the same categories, but we don’t think it’s the same sort of success rate as seeing a blood vessel.”

Further research is needed, but, in the meantime, Dr. Staudt said, “We can ask patients who show up with facial pain if they’ve ever had meningitis or some sort of fever that preceded their onset of pain.”

The study had no specific funding. Ms. Tang and coauthor Jack Y. Zhang, MS, reported no relevant financial disclosures. Dr. Staudt reported serving as a consultant for Abbott and as a scientific adviser and consultant for Boston Scientific.

A version of this article appeared on Medscape.com.

Meningitis has been highlighted as a novel risk factor for trigeminal neuralgia in a nationwide, propensity-matched study of hospital admissions.

In multivariate analysis, the odds of meningitis were threefold higher in patients admitted with trigeminal neuralgia than in matched controls without trigeminal neuralgia.

This is the first nationwide population-based study of the rare, chronic pain disorder to identify the prevalence of trigeminal neuralgia admissions in the United States and risk factors contributing to trigeminal neuralgia development.

“Our results affirm known associations between trigeminal neuralgia and comorbidities like multiple sclerosis, and they also identify meningitis as a novel risk factor for trigeminal neuralgia,” said investigator Megan Tang, BS, a medical student at the Icahn School of Medicine at Mount Sinai, New York City.

The findings were presented at the American Association of Neurological Surgeons (AANS) 2024 annual meeting.
 

Strong Clinical Risk Factors

Trigeminal neuralgia is a rare pain disorder involving neurovascular compression of the trigeminal nerve. Its etiology and risk factors are poorly understood. Current literature is based on limited datasets and reports inconsistent risk factors across studies.

To better understand the disorder, researchers used International Classification of Diseases (ICD)-9 codes to identify trigeminal neuralgia admissions in the National Inpatient Sample from 2016 to 2019, and then propensity matched them 1:1 to non-trigeminal neuralgia admissions based on demographics, socioeconomic status, and Charlson comorbidity index scores.

Univariate analysis identified 136,345 trigeminal neuralgia admissions or an overall prevalence of 0.096%.

Trigeminal neuralgia admissions had lower morbidity than non-trigeminal neuralgia admissions and a higher prevalence of non-White patients, private insurance, and prolonged length of stay, Ms. Tang said.

Patients admitted for trigeminal neuralgia also had a higher prevalence of several chronic conditions, including hypertension, hyperlipidemia, and osteoarthritis; inflammatory conditions like lupus, meningitis, rheumatoid arthritis, and inflammatory bowel disease; and neurologic conditions including multiple sclerosis, epilepsy, stroke, and neurovascular compression disorders.

In multivariate analysis, investigators identified meningitis as a previously unknown risk factor for trigeminal neuralgia (odds ratio [OR], 3.1; P < .001).

Other strong risk factors were neurovascular compression disorders (OR, 39.82; P < .001) and multiple sclerosis (OR, 12.41; P < .001). Non-White race (Black; OR, 1.09; Hispanic; OR, 1.23; Other; OR, 1.24) and use of Medicaid (OR, 1.07) and other insurance (OR, 1.17) were demographic risk factors for trigeminal neuralgia.

“This finding points us toward future work exploring the potential mechanisms of predictors, most notably inflammatory conditions in trigeminal neuralgia development,” Ms. Tang concluded.

She declined to comment further on the findings, noting the investigators are still finalizing the results and interpretation.
 

Ask About Meningitis, Fever

Commenting on the findings, Michael D. Staudt, MD, MSc, University Hospitals Cleveland Medical Center, said that many patients who present with classical trigeminal neuralgia will have a blood vessel on MRI that is pressing on the trigeminal nerve.

“Obviously, the nerve is bathed in cerebrospinal fluid. So, if there’s an inflammatory marker, inflammation, or infection that could be injuring the nerve in a way that we don’t yet understand, that could be something that could cause trigeminal neuralgia without having to see a blood vessel,” said Dr. Staudt, who was not involved in the study. “It makes sense, theoretically. Something that’s inflammatory, something that’s irritating, that’s novel.”

Currently, predictive markers include clinical history, response to classical medications such as carbamazepine, and MRI findings, Dr. Staudt noted.

“Someone shows up with symptoms and MRI, and it’s basically do they have a blood vessel or not,” he said. “Treatments are generally within the same categories, but we don’t think it’s the same sort of success rate as seeing a blood vessel.”

Further research is needed, but, in the meantime, Dr. Staudt said, “We can ask patients who show up with facial pain if they’ve ever had meningitis or some sort of fever that preceded their onset of pain.”

The study had no specific funding. Ms. Tang and coauthor Jack Y. Zhang, MS, reported no relevant financial disclosures. Dr. Staudt reported serving as a consultant for Abbott and as a scientific adviser and consultant for Boston Scientific.

A version of this article appeared on Medscape.com.

VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?

“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.

Sara Freeman/Medscape Medical News

Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.

“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
 

Weight Loss Benefits

Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.

In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.

It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.

“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
 

Weight Rebound

Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.

“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.

Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.

“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
 

Weight Loss Affects Bone

Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.

Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.

Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.

Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
 

GLP-1 and Bone Effects

Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.

Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”

The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.

These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
 

New Role for Dipeptidyl Transferase Inhibitors?

Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.

Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.

“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”

For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.

Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).

DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.

Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
 

Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?

So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.

“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.

Sara Freeman/Medscape Medical News

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com .

VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?

“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.

Sara Freeman/Medscape Medical News

Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.

“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
 

Weight Loss Benefits

Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.

In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.

It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.

“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
 

Weight Rebound

Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.

“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.

Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.

“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
 

Weight Loss Affects Bone

Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.

Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.

Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.

Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
 

GLP-1 and Bone Effects

Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.

Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”

The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.

These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
 

New Role for Dipeptidyl Transferase Inhibitors?

Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.

Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.

“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”

For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.

Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).

DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.

Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
 

Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?

So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.

“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.

Sara Freeman/Medscape Medical News

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com .

VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?

“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.

Sara Freeman/Medscape Medical News

Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.

“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
 

Weight Loss Benefits

Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.

In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.

It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.

“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
 

Weight Rebound

Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.

“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.

Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.

“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
 

Weight Loss Affects Bone

Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.

Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.

Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.

Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
 

GLP-1 and Bone Effects

Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.

Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”

The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.

These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
 

New Role for Dipeptidyl Transferase Inhibitors?

Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.

Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.

“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”

For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.

Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).

DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.

Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
 

Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?

So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.

“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.

Sara Freeman/Medscape Medical News

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com .

NEW YORK — Systemic autoimmune disease is well-recognized as a major risk factor for cardiovascular disease (CVD), but less recognized as a cardiovascular risk factor is a history of pregnancy complications, including preeclampsia, and cardiologists and rheumatologists need to include an obstetric history when managing patients with autoimmune diseases, a specialist in reproductive health in rheumatology told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.

“Autoimmune diseases, lupus in particular, increase the risk for both cardiovascular disease and maternal placental syndromes,” Lisa R. Sammaritano, MD, a professor at Hospital for Special Surgery in New York City and a specialist in reproductive health issues in rheumatology patients, told attendees. “For those patients who have complications during pregnancy, it further increases their already increased risk for later cardiovascular disease.”
 

CVD Risk Double Whammy

A history of systemic lupus erythematosus (SLE) and problematic pregnancy can be a double whammy for CVD risk. Dr. Sammaritano cited a 2022 meta-analysis that showed patients with SLE had a 2.5 times greater risk for stroke and almost three times greater risk for myocardial infarction than people without SLE.

Maternal placental syndromes include pregnancy loss, restricted fetal growth, preeclampsia, premature membrane rupture, placental abruption, and intrauterine fetal demise, Dr. Sammaritano said. Hypertensive disorders of pregnancy, formerly called adverse pregnancy outcomes, she noted, include gestational hypertension, preeclampsia, and eclampsia.

Pregnancy complications can have an adverse effect on the mother’s postpartum cardiovascular health, Dr. Sammaritano noted, a fact borne out by the cardiovascular health after maternal placental syndromes population-based retrospective cohort study and a 2007 meta-analysis that found a history of preeclampsia doubles the risk for venous thromboembolism, stroke, and ischemic heart disease up to 15 years after pregnancy.

“It is always important to obtain a reproductive health history from patients with autoimmune diseases,” Dr. Sammaritano told this news organization in an interview. “This is an integral part of any medical history. In the usual setting, this includes not only pregnancy history but also use of contraception in reproductive-aged women. Unplanned pregnancy can lead to adverse outcomes in the setting of active or severe autoimmune disease or when teratogenic medications are used.”

Pregnancy history can be a factor in a woman’s cardiovascular health more than 15 years postpartum, even if a woman is no longer planning a pregnancy or is menopausal. “As such, this history is important in assessing every woman’s risk profile for CVD in addition to usual traditional risk factors,” Dr. Sammaritano said.

“It is even more important for women with autoimmune disorders, who have been shown to have an already increased risk for CVD independent of their pregnancy history, likely related to a chronic inflammatory state and other autoimmune-related factors such as presence of antiphospholipid antibodies [aPL] or use of corticosteroids.”

Timing of disease onset is also an issue, she said. “In patients with SLE, for example, onset of CVD is much earlier than in the general population,” Dr. Sammaritano said. “As a result, these patients should likely be assessed for risk — both traditional and other risk factors — earlier than the general population, especially if an adverse obstetric history is present.”

At the younger end of the age continuum, women with autoimmune disease, including SLE and antiphospholipid syndrome, who are pregnant should be put on guideline-directed low-dose aspirin preeclampsia prophylaxis, Dr. Sammaritano said. “Whether every patient with SLE needs this is still uncertain, but certainly, those with a history of renal disease, hypertension, or aPL antibody clearly do,” she added.

The evidence supporting hydroxychloroquine (HCQ) in these patients is controversial, but Dr. Sammaritano noted two meta-analyses, one in 2022 and the other in 2023, that showed that HCQ lowered the risk for preeclampsia in women.

“The clear benefit of HCQ in preventing maternal disease complications, including flare, means we recommend it regardless for all patients with SLE at baseline and during pregnancy [if tolerated],” Dr. Sammaritano said. “The benefit or optimal use of these medications in other autoimmune diseases is less studied and less certain.”

Dr. Sammaritano added in her presentation, “We really need better therapies and, hopefully, those will be on the way, but I think the takeaway message, particularly for practicing rheumatologists and cardiologists, is to ask the question about obstetric history. Many of us don’t. It doesn’t seem relevant in the moment, but it really is in terms of the patient’s long-term risk for cardiovascular disease.”
 

The Case for Treatment During Pregnancy

Prophylaxis against pregnancy complications in patients with autoimmune disease may be achievable, Taryn Youngstein, MBBS, consultant rheumatologist and codirector of the Centre of Excellence in Vasculitis Research, Imperial College London, London, England, told this news organization after Dr. Sammaritano’s presentation. At the 2023 American College of Rheumatology Annual Meeting, her group reported the safety and effectiveness of continuing tocilizumab in pregnant women with Takayasu arteritis, a large-vessel vasculitis predominantly affecting women of reproductive age.

“What traditionally happens is you would stop the biologic particularly before the third trimester because of safety and concerns that the monoclonal antibody is actively transported across the placenta, which means the baby gets much more concentration of the drug than the mum,” Dr. Youngstein said.

It’s a situation physicians must monitor closely, she said. “The mum is donating their immune system to the baby, but they’re also donating drug.”

“In high-risk patients, we would share decision-making with the patient,” Dr. Youngstein continued. “We have decided it’s too high of a risk for us to stop the drug, so we have been continuing the interleukin-6 [IL-6] inhibitor throughout the entire pregnancy.”

The data from Dr. Youngstein’s group showed that pregnant women with Takayasu arteritis who continued IL-6 inhibition therapy all carried to term with healthy births.

“We’ve shown that it’s relatively safe to do that, but you have to be very careful in monitoring the baby,” she said. This includes not giving the infant any live vaccines at birth because it will have the high levels of IL-6 inhibition, she said.

Dr. Sammaritano and Dr. Youngstein had no relevant financial relationships to disclose.

A version of this article appeared on Medscape.com.

NEW YORK — Systemic autoimmune disease is well-recognized as a major risk factor for cardiovascular disease (CVD), but less recognized as a cardiovascular risk factor is a history of pregnancy complications, including preeclampsia, and cardiologists and rheumatologists need to include an obstetric history when managing patients with autoimmune diseases, a specialist in reproductive health in rheumatology told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.

“Autoimmune diseases, lupus in particular, increase the risk for both cardiovascular disease and maternal placental syndromes,” Lisa R. Sammaritano, MD, a professor at Hospital for Special Surgery in New York City and a specialist in reproductive health issues in rheumatology patients, told attendees. “For those patients who have complications during pregnancy, it further increases their already increased risk for later cardiovascular disease.”
 

CVD Risk Double Whammy

A history of systemic lupus erythematosus (SLE) and problematic pregnancy can be a double whammy for CVD risk. Dr. Sammaritano cited a 2022 meta-analysis that showed patients with SLE had a 2.5 times greater risk for stroke and almost three times greater risk for myocardial infarction than people without SLE.

Maternal placental syndromes include pregnancy loss, restricted fetal growth, preeclampsia, premature membrane rupture, placental abruption, and intrauterine fetal demise, Dr. Sammaritano said. Hypertensive disorders of pregnancy, formerly called adverse pregnancy outcomes, she noted, include gestational hypertension, preeclampsia, and eclampsia.

Pregnancy complications can have an adverse effect on the mother’s postpartum cardiovascular health, Dr. Sammaritano noted, a fact borne out by the cardiovascular health after maternal placental syndromes population-based retrospective cohort study and a 2007 meta-analysis that found a history of preeclampsia doubles the risk for venous thromboembolism, stroke, and ischemic heart disease up to 15 years after pregnancy.

“It is always important to obtain a reproductive health history from patients with autoimmune diseases,” Dr. Sammaritano told this news organization in an interview. “This is an integral part of any medical history. In the usual setting, this includes not only pregnancy history but also use of contraception in reproductive-aged women. Unplanned pregnancy can lead to adverse outcomes in the setting of active or severe autoimmune disease or when teratogenic medications are used.”

Pregnancy history can be a factor in a woman’s cardiovascular health more than 15 years postpartum, even if a woman is no longer planning a pregnancy or is menopausal. “As such, this history is important in assessing every woman’s risk profile for CVD in addition to usual traditional risk factors,” Dr. Sammaritano said.

“It is even more important for women with autoimmune disorders, who have been shown to have an already increased risk for CVD independent of their pregnancy history, likely related to a chronic inflammatory state and other autoimmune-related factors such as presence of antiphospholipid antibodies [aPL] or use of corticosteroids.”

Timing of disease onset is also an issue, she said. “In patients with SLE, for example, onset of CVD is much earlier than in the general population,” Dr. Sammaritano said. “As a result, these patients should likely be assessed for risk — both traditional and other risk factors — earlier than the general population, especially if an adverse obstetric history is present.”

At the younger end of the age continuum, women with autoimmune disease, including SLE and antiphospholipid syndrome, who are pregnant should be put on guideline-directed low-dose aspirin preeclampsia prophylaxis, Dr. Sammaritano said. “Whether every patient with SLE needs this is still uncertain, but certainly, those with a history of renal disease, hypertension, or aPL antibody clearly do,” she added.

The evidence supporting hydroxychloroquine (HCQ) in these patients is controversial, but Dr. Sammaritano noted two meta-analyses, one in 2022 and the other in 2023, that showed that HCQ lowered the risk for preeclampsia in women.

“The clear benefit of HCQ in preventing maternal disease complications, including flare, means we recommend it regardless for all patients with SLE at baseline and during pregnancy [if tolerated],” Dr. Sammaritano said. “The benefit or optimal use of these medications in other autoimmune diseases is less studied and less certain.”

Dr. Sammaritano added in her presentation, “We really need better therapies and, hopefully, those will be on the way, but I think the takeaway message, particularly for practicing rheumatologists and cardiologists, is to ask the question about obstetric history. Many of us don’t. It doesn’t seem relevant in the moment, but it really is in terms of the patient’s long-term risk for cardiovascular disease.”
 

The Case for Treatment During Pregnancy

Prophylaxis against pregnancy complications in patients with autoimmune disease may be achievable, Taryn Youngstein, MBBS, consultant rheumatologist and codirector of the Centre of Excellence in Vasculitis Research, Imperial College London, London, England, told this news organization after Dr. Sammaritano’s presentation. At the 2023 American College of Rheumatology Annual Meeting, her group reported the safety and effectiveness of continuing tocilizumab in pregnant women with Takayasu arteritis, a large-vessel vasculitis predominantly affecting women of reproductive age.

“What traditionally happens is you would stop the biologic particularly before the third trimester because of safety and concerns that the monoclonal antibody is actively transported across the placenta, which means the baby gets much more concentration of the drug than the mum,” Dr. Youngstein said.

It’s a situation physicians must monitor closely, she said. “The mum is donating their immune system to the baby, but they’re also donating drug.”

“In high-risk patients, we would share decision-making with the patient,” Dr. Youngstein continued. “We have decided it’s too high of a risk for us to stop the drug, so we have been continuing the interleukin-6 [IL-6] inhibitor throughout the entire pregnancy.”

The data from Dr. Youngstein’s group showed that pregnant women with Takayasu arteritis who continued IL-6 inhibition therapy all carried to term with healthy births.

“We’ve shown that it’s relatively safe to do that, but you have to be very careful in monitoring the baby,” she said. This includes not giving the infant any live vaccines at birth because it will have the high levels of IL-6 inhibition, she said.

Dr. Sammaritano and Dr. Youngstein had no relevant financial relationships to disclose.

A version of this article appeared on Medscape.com.

NEW YORK — Systemic autoimmune disease is well-recognized as a major risk factor for cardiovascular disease (CVD), but less recognized as a cardiovascular risk factor is a history of pregnancy complications, including preeclampsia, and cardiologists and rheumatologists need to include an obstetric history when managing patients with autoimmune diseases, a specialist in reproductive health in rheumatology told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.

“Autoimmune diseases, lupus in particular, increase the risk for both cardiovascular disease and maternal placental syndromes,” Lisa R. Sammaritano, MD, a professor at Hospital for Special Surgery in New York City and a specialist in reproductive health issues in rheumatology patients, told attendees. “For those patients who have complications during pregnancy, it further increases their already increased risk for later cardiovascular disease.”
 

CVD Risk Double Whammy

A history of systemic lupus erythematosus (SLE) and problematic pregnancy can be a double whammy for CVD risk. Dr. Sammaritano cited a 2022 meta-analysis that showed patients with SLE had a 2.5 times greater risk for stroke and almost three times greater risk for myocardial infarction than people without SLE.

Maternal placental syndromes include pregnancy loss, restricted fetal growth, preeclampsia, premature membrane rupture, placental abruption, and intrauterine fetal demise, Dr. Sammaritano said. Hypertensive disorders of pregnancy, formerly called adverse pregnancy outcomes, she noted, include gestational hypertension, preeclampsia, and eclampsia.

Pregnancy complications can have an adverse effect on the mother’s postpartum cardiovascular health, Dr. Sammaritano noted, a fact borne out by the cardiovascular health after maternal placental syndromes population-based retrospective cohort study and a 2007 meta-analysis that found a history of preeclampsia doubles the risk for venous thromboembolism, stroke, and ischemic heart disease up to 15 years after pregnancy.

“It is always important to obtain a reproductive health history from patients with autoimmune diseases,” Dr. Sammaritano told this news organization in an interview. “This is an integral part of any medical history. In the usual setting, this includes not only pregnancy history but also use of contraception in reproductive-aged women. Unplanned pregnancy can lead to adverse outcomes in the setting of active or severe autoimmune disease or when teratogenic medications are used.”

Pregnancy history can be a factor in a woman’s cardiovascular health more than 15 years postpartum, even if a woman is no longer planning a pregnancy or is menopausal. “As such, this history is important in assessing every woman’s risk profile for CVD in addition to usual traditional risk factors,” Dr. Sammaritano said.

“It is even more important for women with autoimmune disorders, who have been shown to have an already increased risk for CVD independent of their pregnancy history, likely related to a chronic inflammatory state and other autoimmune-related factors such as presence of antiphospholipid antibodies [aPL] or use of corticosteroids.”

Timing of disease onset is also an issue, she said. “In patients with SLE, for example, onset of CVD is much earlier than in the general population,” Dr. Sammaritano said. “As a result, these patients should likely be assessed for risk — both traditional and other risk factors — earlier than the general population, especially if an adverse obstetric history is present.”

At the younger end of the age continuum, women with autoimmune disease, including SLE and antiphospholipid syndrome, who are pregnant should be put on guideline-directed low-dose aspirin preeclampsia prophylaxis, Dr. Sammaritano said. “Whether every patient with SLE needs this is still uncertain, but certainly, those with a history of renal disease, hypertension, or aPL antibody clearly do,” she added.

The evidence supporting hydroxychloroquine (HCQ) in these patients is controversial, but Dr. Sammaritano noted two meta-analyses, one in 2022 and the other in 2023, that showed that HCQ lowered the risk for preeclampsia in women.

“The clear benefit of HCQ in preventing maternal disease complications, including flare, means we recommend it regardless for all patients with SLE at baseline and during pregnancy [if tolerated],” Dr. Sammaritano said. “The benefit or optimal use of these medications in other autoimmune diseases is less studied and less certain.”

Dr. Sammaritano added in her presentation, “We really need better therapies and, hopefully, those will be on the way, but I think the takeaway message, particularly for practicing rheumatologists and cardiologists, is to ask the question about obstetric history. Many of us don’t. It doesn’t seem relevant in the moment, but it really is in terms of the patient’s long-term risk for cardiovascular disease.”
 

The Case for Treatment During Pregnancy

Prophylaxis against pregnancy complications in patients with autoimmune disease may be achievable, Taryn Youngstein, MBBS, consultant rheumatologist and codirector of the Centre of Excellence in Vasculitis Research, Imperial College London, London, England, told this news organization after Dr. Sammaritano’s presentation. At the 2023 American College of Rheumatology Annual Meeting, her group reported the safety and effectiveness of continuing tocilizumab in pregnant women with Takayasu arteritis, a large-vessel vasculitis predominantly affecting women of reproductive age.

“What traditionally happens is you would stop the biologic particularly before the third trimester because of safety and concerns that the monoclonal antibody is actively transported across the placenta, which means the baby gets much more concentration of the drug than the mum,” Dr. Youngstein said.

It’s a situation physicians must monitor closely, she said. “The mum is donating their immune system to the baby, but they’re also donating drug.”

“In high-risk patients, we would share decision-making with the patient,” Dr. Youngstein continued. “We have decided it’s too high of a risk for us to stop the drug, so we have been continuing the interleukin-6 [IL-6] inhibitor throughout the entire pregnancy.”

The data from Dr. Youngstein’s group showed that pregnant women with Takayasu arteritis who continued IL-6 inhibition therapy all carried to term with healthy births.

“We’ve shown that it’s relatively safe to do that, but you have to be very careful in monitoring the baby,” she said. This includes not giving the infant any live vaccines at birth because it will have the high levels of IL-6 inhibition, she said.

Dr. Sammaritano and Dr. Youngstein had no relevant financial relationships to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for cardiovascular diseases (CVDs) such as ischemic heart disease, stroke, and congestive heart failure in patients with ankylosing spondylitis (AS) compared with lower doses.

METHODOLOGY:

• NSAIDs can suppress inflammation and relieve pain in patients with AS, but long-term treatment with NSAIDs poses concerns regarding gastrointestinal and renal toxicities and increased CVD risk.
• This nationwide cohort study used data from the Korean National Health Insurance database to investigate the risk for CVD associated with an increasing NSAID dosage in a real-world AS cohort.
• Investigators recruited 19,775 patients (mean age, 36.1 years; 75% men) with newly diagnosed AS and without any prior CVD between January 2010 and December 2018, among whom 99.7% received NSAID treatment and 30.2% received tumor necrosis factor inhibitor treatment.
• A time-varying approach was used to assess the NSAID exposure, wherein periods of NSAID use were defined as “NSAID-exposed” and periods longer than 1 month without NSAID use were defined as “NSAID-unexposed.”
• The primary outcome was the composite outcome of ischemic heart disease, stroke, or congestive heart failure.

TAKEAWAY:

• During the follow-up period of 98,290 person-years, 1663 cases of CVD were identified, which included 1157 cases of ischemic heart disease, 301 cases of stroke, and 613 cases of congestive heart failure.
• After adjusting for confounders, each defined daily dose increase in NSAIDs raised the risk for incident CVD by 10% (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.08-1.13).
• Similarly, increasing the dose of NSAIDs was associated with an increased risk for ischemic heart disease (aHR, 1.08; 95% CI, 1.05-1.11), stroke (aHR, 1.09; 95% CI, 1.04-1.15), and congestive heart failure (aHR, 1.12; 95% CI, 1.08-1.16).
• The association between increasing NSAID dose and increased CVD risk was consistent across various subgroups, with NSAIDs posing a greater threat to cardiovascular health in women than in men.

IN PRACTICE:

The authors wrote, “Taken together, these results suggest that increasing the dose of NSAIDs is associated with a higher cardiovascular risk in AS, but that the increased risk might be lower than that in the general population.”

SOURCE:

First author Ji-Won Kim, MD, PhD, of the Division of Rheumatology, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, the Republic of Korea, and colleagues had their work published online on April 9 in Annals of the Rheumatic Diseases.

LIMITATIONS:

The study was of retrospective nature. The levels of acute phase reactants and AS disease activity could not be determined owing to a lack of data in the National Health Insurance database. The accuracy of the diagnosis of cardiovascular outcomes on the basis of the International Classification of Disease codes was also questionable.

DISCLOSURES:

The study was supported by the National Research Foundation of Korea. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for cardiovascular diseases (CVDs) such as ischemic heart disease, stroke, and congestive heart failure in patients with ankylosing spondylitis (AS) compared with lower doses.

METHODOLOGY:

• NSAIDs can suppress inflammation and relieve pain in patients with AS, but long-term treatment with NSAIDs poses concerns regarding gastrointestinal and renal toxicities and increased CVD risk.
• This nationwide cohort study used data from the Korean National Health Insurance database to investigate the risk for CVD associated with an increasing NSAID dosage in a real-world AS cohort.
• Investigators recruited 19,775 patients (mean age, 36.1 years; 75% men) with newly diagnosed AS and without any prior CVD between January 2010 and December 2018, among whom 99.7% received NSAID treatment and 30.2% received tumor necrosis factor inhibitor treatment.
• A time-varying approach was used to assess the NSAID exposure, wherein periods of NSAID use were defined as “NSAID-exposed” and periods longer than 1 month without NSAID use were defined as “NSAID-unexposed.”
• The primary outcome was the composite outcome of ischemic heart disease, stroke, or congestive heart failure.

TAKEAWAY:

• During the follow-up period of 98,290 person-years, 1663 cases of CVD were identified, which included 1157 cases of ischemic heart disease, 301 cases of stroke, and 613 cases of congestive heart failure.
• After adjusting for confounders, each defined daily dose increase in NSAIDs raised the risk for incident CVD by 10% (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.08-1.13).
• Similarly, increasing the dose of NSAIDs was associated with an increased risk for ischemic heart disease (aHR, 1.08; 95% CI, 1.05-1.11), stroke (aHR, 1.09; 95% CI, 1.04-1.15), and congestive heart failure (aHR, 1.12; 95% CI, 1.08-1.16).
• The association between increasing NSAID dose and increased CVD risk was consistent across various subgroups, with NSAIDs posing a greater threat to cardiovascular health in women than in men.

IN PRACTICE:

The authors wrote, “Taken together, these results suggest that increasing the dose of NSAIDs is associated with a higher cardiovascular risk in AS, but that the increased risk might be lower than that in the general population.”

SOURCE:

First author Ji-Won Kim, MD, PhD, of the Division of Rheumatology, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, the Republic of Korea, and colleagues had their work published online on April 9 in Annals of the Rheumatic Diseases.

LIMITATIONS:

The study was of retrospective nature. The levels of acute phase reactants and AS disease activity could not be determined owing to a lack of data in the National Health Insurance database. The accuracy of the diagnosis of cardiovascular outcomes on the basis of the International Classification of Disease codes was also questionable.

DISCLOSURES:

The study was supported by the National Research Foundation of Korea. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for cardiovascular diseases (CVDs) such as ischemic heart disease, stroke, and congestive heart failure in patients with ankylosing spondylitis (AS) compared with lower doses.

METHODOLOGY:

• NSAIDs can suppress inflammation and relieve pain in patients with AS, but long-term treatment with NSAIDs poses concerns regarding gastrointestinal and renal toxicities and increased CVD risk.
• This nationwide cohort study used data from the Korean National Health Insurance database to investigate the risk for CVD associated with an increasing NSAID dosage in a real-world AS cohort.
• Investigators recruited 19,775 patients (mean age, 36.1 years; 75% men) with newly diagnosed AS and without any prior CVD between January 2010 and December 2018, among whom 99.7% received NSAID treatment and 30.2% received tumor necrosis factor inhibitor treatment.
• A time-varying approach was used to assess the NSAID exposure, wherein periods of NSAID use were defined as “NSAID-exposed” and periods longer than 1 month without NSAID use were defined as “NSAID-unexposed.”
• The primary outcome was the composite outcome of ischemic heart disease, stroke, or congestive heart failure.

TAKEAWAY:

• During the follow-up period of 98,290 person-years, 1663 cases of CVD were identified, which included 1157 cases of ischemic heart disease, 301 cases of stroke, and 613 cases of congestive heart failure.
• After adjusting for confounders, each defined daily dose increase in NSAIDs raised the risk for incident CVD by 10% (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.08-1.13).
• Similarly, increasing the dose of NSAIDs was associated with an increased risk for ischemic heart disease (aHR, 1.08; 95% CI, 1.05-1.11), stroke (aHR, 1.09; 95% CI, 1.04-1.15), and congestive heart failure (aHR, 1.12; 95% CI, 1.08-1.16).
• The association between increasing NSAID dose and increased CVD risk was consistent across various subgroups, with NSAIDs posing a greater threat to cardiovascular health in women than in men.

IN PRACTICE:

The authors wrote, “Taken together, these results suggest that increasing the dose of NSAIDs is associated with a higher cardiovascular risk in AS, but that the increased risk might be lower than that in the general population.”

SOURCE:

First author Ji-Won Kim, MD, PhD, of the Division of Rheumatology, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, the Republic of Korea, and colleagues had their work published online on April 9 in Annals of the Rheumatic Diseases.

LIMITATIONS:

The study was of retrospective nature. The levels of acute phase reactants and AS disease activity could not be determined owing to a lack of data in the National Health Insurance database. The accuracy of the diagnosis of cardiovascular outcomes on the basis of the International Classification of Disease codes was also questionable.

DISCLOSURES:

The study was supported by the National Research Foundation of Korea. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A diagnostic model based on the concentrations of four metabolites and one lipid ratio can reliably predict cancer in patients with rheumatic and musculoskeletal diseases (RMDs) or paraneoplasia, providing high sensitivity and specificity.

METHODOLOGY:

• The metabolome profile can differentiate between nonspecific inflammatory symptoms such as those associated with paraneoplastic conditions or RMDs, which can help accelerate cancer diagnosis and treatment.
• To assess if changes in the serum metabolome profile could indicate cancer in patients with RMD, researchers performed nuclear magnetic resonance analysis of the sera of patients with rheumatoid arthritis (RA) with a history of invasive cancer (n = 56; age, 69.9 years; 76.8% women) or without such history (n = 52; age, 56.1 years; 57.7% women).
• Blinded validation was conducted in a cohort of patients with RA or spondyloarthritis with or without a history of invasive cancer.
• Additionally, the model performance was tested in a cohort of patients having RA or spondyloarthritis with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, and facultative solid noninvasive precancerous lesions and nonmelanoma skin cancer; in samples prior to the development of malignancy; and in a cohort of patients with systemic lupus erythematosus (SLE).
• The final model comprised five variables. The goodness of fit of the model was described using the area under the receiver operating characteristic curve (AUC).

TAKEAWAY:

• Based on the concentrations of acetate, creatine, glycine, and formate and the L1/L6 lipid ratio, the diagnostic model yielded an excellent AUC (0.987) and high sensitivity (0.932) and specificity (0.946) for cancer diagnosis in patients with RA.
• The diagnostic model yielded an AUC of 0.937 in the blinded validation cohort of patients with RA and an AUC of 0.927 in the merged RA and spondyloarthritis cohort.
• Although the diagnostic model accurately diagnosed cancer in all the patients with paraneoplasia, it could do so accurately in only 50% of patients with noninvasive or in situ precancerous lesions and nonmelanoma skin cancers.
• The performance of the model was poor in the SLE cohort (AUC, 0.656), and it could not identify patients at risk for later invasive cancer development.

IN PRACTICE:

“This limited-invasive assay has considerable potential of high clinical value to facilitate timely diagnosis of cancer in paraneoplastic rheumatic syndromes as well as become a valuable active surveillance tool in RA and SpA [spondyloarthritis] patients with a high risk of developing cancer,” the authors wrote.

SOURCE:

The study, led by Karolina Gente, MHBA, Heidelberg University Hospital, Heidelberg, Germany, was published online on April 1, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The limited invasiveness during sampling might account for the model’s inability to identify three early-stage, low-grade tumors and its nonreliability in identifying noninvasive facultative precancerous lesions and nonmelanoma skin cancers. Given its poor performance in the SLE cohort, the model may not be suitable for universal application in more systemic rheumatic diseases.

DISCLOSURES:

This study was supported by an unrestricted investigator-initiated grant from the Foundation Commission of the Medical Faculty, University of Heidelberg, Germany. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A diagnostic model based on the concentrations of four metabolites and one lipid ratio can reliably predict cancer in patients with rheumatic and musculoskeletal diseases (RMDs) or paraneoplasia, providing high sensitivity and specificity.

METHODOLOGY:

• The metabolome profile can differentiate between nonspecific inflammatory symptoms such as those associated with paraneoplastic conditions or RMDs, which can help accelerate cancer diagnosis and treatment.
• To assess if changes in the serum metabolome profile could indicate cancer in patients with RMD, researchers performed nuclear magnetic resonance analysis of the sera of patients with rheumatoid arthritis (RA) with a history of invasive cancer (n = 56; age, 69.9 years; 76.8% women) or without such history (n = 52; age, 56.1 years; 57.7% women).
• Blinded validation was conducted in a cohort of patients with RA or spondyloarthritis with or without a history of invasive cancer.
• Additionally, the model performance was tested in a cohort of patients having RA or spondyloarthritis with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, and facultative solid noninvasive precancerous lesions and nonmelanoma skin cancer; in samples prior to the development of malignancy; and in a cohort of patients with systemic lupus erythematosus (SLE).
• The final model comprised five variables. The goodness of fit of the model was described using the area under the receiver operating characteristic curve (AUC).

TAKEAWAY:

• Based on the concentrations of acetate, creatine, glycine, and formate and the L1/L6 lipid ratio, the diagnostic model yielded an excellent AUC (0.987) and high sensitivity (0.932) and specificity (0.946) for cancer diagnosis in patients with RA.
• The diagnostic model yielded an AUC of 0.937 in the blinded validation cohort of patients with RA and an AUC of 0.927 in the merged RA and spondyloarthritis cohort.
• Although the diagnostic model accurately diagnosed cancer in all the patients with paraneoplasia, it could do so accurately in only 50% of patients with noninvasive or in situ precancerous lesions and nonmelanoma skin cancers.
• The performance of the model was poor in the SLE cohort (AUC, 0.656), and it could not identify patients at risk for later invasive cancer development.

IN PRACTICE:

“This limited-invasive assay has considerable potential of high clinical value to facilitate timely diagnosis of cancer in paraneoplastic rheumatic syndromes as well as become a valuable active surveillance tool in RA and SpA [spondyloarthritis] patients with a high risk of developing cancer,” the authors wrote.

SOURCE:

The study, led by Karolina Gente, MHBA, Heidelberg University Hospital, Heidelberg, Germany, was published online on April 1, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The limited invasiveness during sampling might account for the model’s inability to identify three early-stage, low-grade tumors and its nonreliability in identifying noninvasive facultative precancerous lesions and nonmelanoma skin cancers. Given its poor performance in the SLE cohort, the model may not be suitable for universal application in more systemic rheumatic diseases.

DISCLOSURES:

This study was supported by an unrestricted investigator-initiated grant from the Foundation Commission of the Medical Faculty, University of Heidelberg, Germany. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A diagnostic model based on the concentrations of four metabolites and one lipid ratio can reliably predict cancer in patients with rheumatic and musculoskeletal diseases (RMDs) or paraneoplasia, providing high sensitivity and specificity.

METHODOLOGY:

• The metabolome profile can differentiate between nonspecific inflammatory symptoms such as those associated with paraneoplastic conditions or RMDs, which can help accelerate cancer diagnosis and treatment.
• To assess if changes in the serum metabolome profile could indicate cancer in patients with RMD, researchers performed nuclear magnetic resonance analysis of the sera of patients with rheumatoid arthritis (RA) with a history of invasive cancer (n = 56; age, 69.9 years; 76.8% women) or without such history (n = 52; age, 56.1 years; 57.7% women).
• Blinded validation was conducted in a cohort of patients with RA or spondyloarthritis with or without a history of invasive cancer.
• Additionally, the model performance was tested in a cohort of patients having RA or spondyloarthritis with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, and facultative solid noninvasive precancerous lesions and nonmelanoma skin cancer; in samples prior to the development of malignancy; and in a cohort of patients with systemic lupus erythematosus (SLE).
• The final model comprised five variables. The goodness of fit of the model was described using the area under the receiver operating characteristic curve (AUC).

TAKEAWAY:

• Based on the concentrations of acetate, creatine, glycine, and formate and the L1/L6 lipid ratio, the diagnostic model yielded an excellent AUC (0.987) and high sensitivity (0.932) and specificity (0.946) for cancer diagnosis in patients with RA.
• The diagnostic model yielded an AUC of 0.937 in the blinded validation cohort of patients with RA and an AUC of 0.927 in the merged RA and spondyloarthritis cohort.
• Although the diagnostic model accurately diagnosed cancer in all the patients with paraneoplasia, it could do so accurately in only 50% of patients with noninvasive or in situ precancerous lesions and nonmelanoma skin cancers.
• The performance of the model was poor in the SLE cohort (AUC, 0.656), and it could not identify patients at risk for later invasive cancer development.

IN PRACTICE:

“This limited-invasive assay has considerable potential of high clinical value to facilitate timely diagnosis of cancer in paraneoplastic rheumatic syndromes as well as become a valuable active surveillance tool in RA and SpA [spondyloarthritis] patients with a high risk of developing cancer,” the authors wrote.

SOURCE:

The study, led by Karolina Gente, MHBA, Heidelberg University Hospital, Heidelberg, Germany, was published online on April 1, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The limited invasiveness during sampling might account for the model’s inability to identify three early-stage, low-grade tumors and its nonreliability in identifying noninvasive facultative precancerous lesions and nonmelanoma skin cancers. Given its poor performance in the SLE cohort, the model may not be suitable for universal application in more systemic rheumatic diseases.

DISCLOSURES:

This study was supported by an unrestricted investigator-initiated grant from the Foundation Commission of the Medical Faculty, University of Heidelberg, Germany. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.