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Vagus nerve stimulation for rheumatology? Maybe
The work is being led by SetPoint Medical, a small company in Valencia, Calif., just north of Los Angeles. Its vagus nerve stimulation (VNS) device, dubbed the microregulator, has been implanted in 14 patients with refractory rheumatoid arthritis (RA) in the company’s initial safety study.
The microregulator is a small lithium ion battery encased in an inert silastic pod; it’s surgically implanted to sit atop the vagus nerve in the left side of the neck, and delivers an electrical pulse at set intervals. Data from the 12-week, sham-controlled safety study is set to be unblinded in coming weeks. A pivotal trial also is in the works, perhaps to start in late 2019, according to rheumatologist and SetPoint’s Chief Medical Officer David Chernoff, MD.
Although SetPoint is ahead of the pack, it’s not alone. ElectroCore, a biotech company in Basking Ridge, N.J., has expressed interest in pursuing rheumatoid arthritis and Sjögren’s syndrome indications for its gammaCore device, a vagus nerve stimulator patients apply to the neck. It’s already on the market for migraines and cluster headaches.
Researchers recently reported a small decrease in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) results after 16 RA patients with flares used the device for 4 days (Ann Rheum Dis. 2018;77:1401. Abstract AB0481). In another recent open-label study, 15 women with Sjögren’s reported less fatigue while using the device for a month (Arthritis Rheumatol. 2017;69[suppl 10]: Abstract 563).
Meanwhile, The Feinstein Institute for Medical Research, based in Manhasset, N.Y., on Long Island, recently reported positive outcomes in 18 patients with systemic lupus erythematosus, using its own novel device, which stimulates the vagus nerve through the ear lobe. VNS was delivered for 5 minutes per day for 4 days (Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2652).
On day 5, patients who received VNS, versus sham patients in whom the device was not turned on, had a significant decrease in pain, fatigue, and joint scores. The investigators concluded that “additional studies evaluating this promising intervention and its potential mechanisms are warranted.”
“We are clearly ahead of everybody because we’ve already implanted people, but I think it’s good for the field if more people are chasing this. The more resources that are put into it, the more we can show that this approach actually works,” said SetPoint’s Dr. Chernoff.
The hope
In general, interest in VNS for rheumatology is being driven by the possibility that it may reduce proinflammatory cytokines, which opens the door for VNS as an alternative to biologics. The hope is that instead of going after tumor necrosis factor and other cytokines one at a time, VNS could be used to target a range of cytokines all at once, without the cost and side effects of biologics.
“It seems so dramatically different” from what rheumatologists have done in the past, “that our first instinct is to say ‘oh, that’s ridiculous,’ but the science behind it is actually not bad. There may indeed be something to this,” said rheumatologist Joel Kremer, MD, Pfaff Family Professor of Medicine at Albany (N.Y.) Medical College.
Dr. Kremer reviewed SetPoint’s early scientific data after being asked by the company to participate in the safety study; he declined for logistical reasons.
He noted that “there are some strange interactions between the CNS and inflammatory disease.” When RA patients have a stroke, for instance, RA goes into remission on the side of their body affected by the stroke. “That’s been known for decades, but we really don’t understand what’s going on there,” Dr. Kremer said.
The evidence
Perhaps the strongest evidence to date for VNS as a cytokine blocker in rheumatology comes from an open-label, 12-week study, also conducted by SetPoint, in 17 patients with active RA despite methotrexate treatment; some had failed biologics (Proc Natl Acad Sci U S A. 2016 Jul 19;113[29]:8284-9. doi: 10.1073/pnas.160563511).
The microregulator wasn’t ready yet, so investigators implanted a VNS system commercially available for epilepsy and reprogrammed it to deliver a 60-second pulse once a day to the left cervical vagus nerve, which was increased after a month to four 60-second stimulations a day in nonresponders.
The investigators “observed that TNF production in cultured peripheral blood obtained ... on day 42 was significantly reduced from” 21 days before the study was started (TNF 2,900 pg/mL on day –21, versus 1,776 pg/mL on day 42; P less than .05).
When VNS was shut off, TNF production increased; when it was turned back on, it dropped. Interleukin 6 also fell significantly among responders. Overall, DAS28-CRP scores fell about 1.5 points on the 10-point scale from baseline to week 12.
Two-year outcomes were recently reported (Ann Rheum Dis. 2018;77:981-2. Abstract SAT0240). All 17 patients elected to continue treatment after the initial 12 weeks. Biologics were added in nine subjects (53%), because of no or limited response to VNS. Investigators were free to change the VNS dosing regimen, which varied during the study extension up to eight 60-second bursts a day. The roughly 1.5-point improvement in DAS28-CRP was maintained at 2 years.
“These long-term data suggest that bioelectronic therapy may be used as an alternative to, or in combination with, biological[s],” concluded Dr. Chernoff and other study team members.
Awaiting more data
When asked for comment, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, said “there certainly are neurotropic factors” at play in rheumatology, “so there’s sort of a potential reason why” VNS might work, “but we need to understand far more about its mechanism, and [remember] that open-label studies are not to be believed until” large, randomized, blinded, placebo-controlled studies are done.
Dr. Furst also is an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). He is in part-time practice in Los Angeles and Seattle.
If everything works out, however, “the vagus nerve may give us a much wider opportunity to block a host of cytokines; it may change the whole paradigm of how we manage rheumatoid arthritis. I think this is possibly a groundbreaking new therapeutic area, much in the way the biologics were” 20 years ago, said rheumatologist Norman B. Gaylis, MD.
Several of the 14 patients in SetPoint’s safety study were enrolled at Dr. Gaylis’s practice in Aventura, Fla., just north of Miami; he said he is eagerly awaiting for the results to be unblinded. If clinical response in that study and others correlates with a cytokine response, “that’s going to be big, and very significant” in the rheumatology community, he said.
SetPoint’s microregulator is charged wirelessly through a collar patients wear for a few minutes once a week. Dosing can also be adjusted through the collar with the help of a computer application.
The device wasn’t turned on in 4 of the 14 patients in the safety study, as a sham control, but shamming was problematic because patients can potentially feel VNS as a buzz or a change in their voice. To get around that potential confounder, both sham and treated patients were told they might or might not feel something during the study.
Implantation takes about an hour, and is much less complex than implanting currently available epilepsy VNS systems, which require implantation of both a power source on the chest wall and wire coils on the vagus nerve.
Cardiac concerns are the main safety issue with VNS, beyond the surgery itself. Cardiac monitoring was done in the safety study to “ensure that we did not cause things like bradycardia, heart block, syncope, etc.” Dr. Chernoff said. So far, they haven’t turned out to be a problem.
Dr. Furst and Dr. Kremer had no relevant disclosures. Dr. Gaylis was compensated by SetPoint for participating in the safety study; he is a consultant and investigator for Electrocore. Dr. Furst and Dr. Gaylis are members of the editorial advisory board for MDedge Rheumatology/Rheumatology News.
The work is being led by SetPoint Medical, a small company in Valencia, Calif., just north of Los Angeles. Its vagus nerve stimulation (VNS) device, dubbed the microregulator, has been implanted in 14 patients with refractory rheumatoid arthritis (RA) in the company’s initial safety study.
The microregulator is a small lithium ion battery encased in an inert silastic pod; it’s surgically implanted to sit atop the vagus nerve in the left side of the neck, and delivers an electrical pulse at set intervals. Data from the 12-week, sham-controlled safety study is set to be unblinded in coming weeks. A pivotal trial also is in the works, perhaps to start in late 2019, according to rheumatologist and SetPoint’s Chief Medical Officer David Chernoff, MD.
Although SetPoint is ahead of the pack, it’s not alone. ElectroCore, a biotech company in Basking Ridge, N.J., has expressed interest in pursuing rheumatoid arthritis and Sjögren’s syndrome indications for its gammaCore device, a vagus nerve stimulator patients apply to the neck. It’s already on the market for migraines and cluster headaches.
Researchers recently reported a small decrease in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) results after 16 RA patients with flares used the device for 4 days (Ann Rheum Dis. 2018;77:1401. Abstract AB0481). In another recent open-label study, 15 women with Sjögren’s reported less fatigue while using the device for a month (Arthritis Rheumatol. 2017;69[suppl 10]: Abstract 563).
Meanwhile, The Feinstein Institute for Medical Research, based in Manhasset, N.Y., on Long Island, recently reported positive outcomes in 18 patients with systemic lupus erythematosus, using its own novel device, which stimulates the vagus nerve through the ear lobe. VNS was delivered for 5 minutes per day for 4 days (Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2652).
On day 5, patients who received VNS, versus sham patients in whom the device was not turned on, had a significant decrease in pain, fatigue, and joint scores. The investigators concluded that “additional studies evaluating this promising intervention and its potential mechanisms are warranted.”
“We are clearly ahead of everybody because we’ve already implanted people, but I think it’s good for the field if more people are chasing this. The more resources that are put into it, the more we can show that this approach actually works,” said SetPoint’s Dr. Chernoff.
The hope
In general, interest in VNS for rheumatology is being driven by the possibility that it may reduce proinflammatory cytokines, which opens the door for VNS as an alternative to biologics. The hope is that instead of going after tumor necrosis factor and other cytokines one at a time, VNS could be used to target a range of cytokines all at once, without the cost and side effects of biologics.
“It seems so dramatically different” from what rheumatologists have done in the past, “that our first instinct is to say ‘oh, that’s ridiculous,’ but the science behind it is actually not bad. There may indeed be something to this,” said rheumatologist Joel Kremer, MD, Pfaff Family Professor of Medicine at Albany (N.Y.) Medical College.
Dr. Kremer reviewed SetPoint’s early scientific data after being asked by the company to participate in the safety study; he declined for logistical reasons.
He noted that “there are some strange interactions between the CNS and inflammatory disease.” When RA patients have a stroke, for instance, RA goes into remission on the side of their body affected by the stroke. “That’s been known for decades, but we really don’t understand what’s going on there,” Dr. Kremer said.
The evidence
Perhaps the strongest evidence to date for VNS as a cytokine blocker in rheumatology comes from an open-label, 12-week study, also conducted by SetPoint, in 17 patients with active RA despite methotrexate treatment; some had failed biologics (Proc Natl Acad Sci U S A. 2016 Jul 19;113[29]:8284-9. doi: 10.1073/pnas.160563511).
The microregulator wasn’t ready yet, so investigators implanted a VNS system commercially available for epilepsy and reprogrammed it to deliver a 60-second pulse once a day to the left cervical vagus nerve, which was increased after a month to four 60-second stimulations a day in nonresponders.
The investigators “observed that TNF production in cultured peripheral blood obtained ... on day 42 was significantly reduced from” 21 days before the study was started (TNF 2,900 pg/mL on day –21, versus 1,776 pg/mL on day 42; P less than .05).
When VNS was shut off, TNF production increased; when it was turned back on, it dropped. Interleukin 6 also fell significantly among responders. Overall, DAS28-CRP scores fell about 1.5 points on the 10-point scale from baseline to week 12.
Two-year outcomes were recently reported (Ann Rheum Dis. 2018;77:981-2. Abstract SAT0240). All 17 patients elected to continue treatment after the initial 12 weeks. Biologics were added in nine subjects (53%), because of no or limited response to VNS. Investigators were free to change the VNS dosing regimen, which varied during the study extension up to eight 60-second bursts a day. The roughly 1.5-point improvement in DAS28-CRP was maintained at 2 years.
“These long-term data suggest that bioelectronic therapy may be used as an alternative to, or in combination with, biological[s],” concluded Dr. Chernoff and other study team members.
Awaiting more data
When asked for comment, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, said “there certainly are neurotropic factors” at play in rheumatology, “so there’s sort of a potential reason why” VNS might work, “but we need to understand far more about its mechanism, and [remember] that open-label studies are not to be believed until” large, randomized, blinded, placebo-controlled studies are done.
Dr. Furst also is an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). He is in part-time practice in Los Angeles and Seattle.
If everything works out, however, “the vagus nerve may give us a much wider opportunity to block a host of cytokines; it may change the whole paradigm of how we manage rheumatoid arthritis. I think this is possibly a groundbreaking new therapeutic area, much in the way the biologics were” 20 years ago, said rheumatologist Norman B. Gaylis, MD.
Several of the 14 patients in SetPoint’s safety study were enrolled at Dr. Gaylis’s practice in Aventura, Fla., just north of Miami; he said he is eagerly awaiting for the results to be unblinded. If clinical response in that study and others correlates with a cytokine response, “that’s going to be big, and very significant” in the rheumatology community, he said.
SetPoint’s microregulator is charged wirelessly through a collar patients wear for a few minutes once a week. Dosing can also be adjusted through the collar with the help of a computer application.
The device wasn’t turned on in 4 of the 14 patients in the safety study, as a sham control, but shamming was problematic because patients can potentially feel VNS as a buzz or a change in their voice. To get around that potential confounder, both sham and treated patients were told they might or might not feel something during the study.
Implantation takes about an hour, and is much less complex than implanting currently available epilepsy VNS systems, which require implantation of both a power source on the chest wall and wire coils on the vagus nerve.
Cardiac concerns are the main safety issue with VNS, beyond the surgery itself. Cardiac monitoring was done in the safety study to “ensure that we did not cause things like bradycardia, heart block, syncope, etc.” Dr. Chernoff said. So far, they haven’t turned out to be a problem.
Dr. Furst and Dr. Kremer had no relevant disclosures. Dr. Gaylis was compensated by SetPoint for participating in the safety study; he is a consultant and investigator for Electrocore. Dr. Furst and Dr. Gaylis are members of the editorial advisory board for MDedge Rheumatology/Rheumatology News.
The work is being led by SetPoint Medical, a small company in Valencia, Calif., just north of Los Angeles. Its vagus nerve stimulation (VNS) device, dubbed the microregulator, has been implanted in 14 patients with refractory rheumatoid arthritis (RA) in the company’s initial safety study.
The microregulator is a small lithium ion battery encased in an inert silastic pod; it’s surgically implanted to sit atop the vagus nerve in the left side of the neck, and delivers an electrical pulse at set intervals. Data from the 12-week, sham-controlled safety study is set to be unblinded in coming weeks. A pivotal trial also is in the works, perhaps to start in late 2019, according to rheumatologist and SetPoint’s Chief Medical Officer David Chernoff, MD.
Although SetPoint is ahead of the pack, it’s not alone. ElectroCore, a biotech company in Basking Ridge, N.J., has expressed interest in pursuing rheumatoid arthritis and Sjögren’s syndrome indications for its gammaCore device, a vagus nerve stimulator patients apply to the neck. It’s already on the market for migraines and cluster headaches.
Researchers recently reported a small decrease in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) results after 16 RA patients with flares used the device for 4 days (Ann Rheum Dis. 2018;77:1401. Abstract AB0481). In another recent open-label study, 15 women with Sjögren’s reported less fatigue while using the device for a month (Arthritis Rheumatol. 2017;69[suppl 10]: Abstract 563).
Meanwhile, The Feinstein Institute for Medical Research, based in Manhasset, N.Y., on Long Island, recently reported positive outcomes in 18 patients with systemic lupus erythematosus, using its own novel device, which stimulates the vagus nerve through the ear lobe. VNS was delivered for 5 minutes per day for 4 days (Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2652).
On day 5, patients who received VNS, versus sham patients in whom the device was not turned on, had a significant decrease in pain, fatigue, and joint scores. The investigators concluded that “additional studies evaluating this promising intervention and its potential mechanisms are warranted.”
“We are clearly ahead of everybody because we’ve already implanted people, but I think it’s good for the field if more people are chasing this. The more resources that are put into it, the more we can show that this approach actually works,” said SetPoint’s Dr. Chernoff.
The hope
In general, interest in VNS for rheumatology is being driven by the possibility that it may reduce proinflammatory cytokines, which opens the door for VNS as an alternative to biologics. The hope is that instead of going after tumor necrosis factor and other cytokines one at a time, VNS could be used to target a range of cytokines all at once, without the cost and side effects of biologics.
“It seems so dramatically different” from what rheumatologists have done in the past, “that our first instinct is to say ‘oh, that’s ridiculous,’ but the science behind it is actually not bad. There may indeed be something to this,” said rheumatologist Joel Kremer, MD, Pfaff Family Professor of Medicine at Albany (N.Y.) Medical College.
Dr. Kremer reviewed SetPoint’s early scientific data after being asked by the company to participate in the safety study; he declined for logistical reasons.
He noted that “there are some strange interactions between the CNS and inflammatory disease.” When RA patients have a stroke, for instance, RA goes into remission on the side of their body affected by the stroke. “That’s been known for decades, but we really don’t understand what’s going on there,” Dr. Kremer said.
The evidence
Perhaps the strongest evidence to date for VNS as a cytokine blocker in rheumatology comes from an open-label, 12-week study, also conducted by SetPoint, in 17 patients with active RA despite methotrexate treatment; some had failed biologics (Proc Natl Acad Sci U S A. 2016 Jul 19;113[29]:8284-9. doi: 10.1073/pnas.160563511).
The microregulator wasn’t ready yet, so investigators implanted a VNS system commercially available for epilepsy and reprogrammed it to deliver a 60-second pulse once a day to the left cervical vagus nerve, which was increased after a month to four 60-second stimulations a day in nonresponders.
The investigators “observed that TNF production in cultured peripheral blood obtained ... on day 42 was significantly reduced from” 21 days before the study was started (TNF 2,900 pg/mL on day –21, versus 1,776 pg/mL on day 42; P less than .05).
When VNS was shut off, TNF production increased; when it was turned back on, it dropped. Interleukin 6 also fell significantly among responders. Overall, DAS28-CRP scores fell about 1.5 points on the 10-point scale from baseline to week 12.
Two-year outcomes were recently reported (Ann Rheum Dis. 2018;77:981-2. Abstract SAT0240). All 17 patients elected to continue treatment after the initial 12 weeks. Biologics were added in nine subjects (53%), because of no or limited response to VNS. Investigators were free to change the VNS dosing regimen, which varied during the study extension up to eight 60-second bursts a day. The roughly 1.5-point improvement in DAS28-CRP was maintained at 2 years.
“These long-term data suggest that bioelectronic therapy may be used as an alternative to, or in combination with, biological[s],” concluded Dr. Chernoff and other study team members.
Awaiting more data
When asked for comment, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, said “there certainly are neurotropic factors” at play in rheumatology, “so there’s sort of a potential reason why” VNS might work, “but we need to understand far more about its mechanism, and [remember] that open-label studies are not to be believed until” large, randomized, blinded, placebo-controlled studies are done.
Dr. Furst also is an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). He is in part-time practice in Los Angeles and Seattle.
If everything works out, however, “the vagus nerve may give us a much wider opportunity to block a host of cytokines; it may change the whole paradigm of how we manage rheumatoid arthritis. I think this is possibly a groundbreaking new therapeutic area, much in the way the biologics were” 20 years ago, said rheumatologist Norman B. Gaylis, MD.
Several of the 14 patients in SetPoint’s safety study were enrolled at Dr. Gaylis’s practice in Aventura, Fla., just north of Miami; he said he is eagerly awaiting for the results to be unblinded. If clinical response in that study and others correlates with a cytokine response, “that’s going to be big, and very significant” in the rheumatology community, he said.
SetPoint’s microregulator is charged wirelessly through a collar patients wear for a few minutes once a week. Dosing can also be adjusted through the collar with the help of a computer application.
The device wasn’t turned on in 4 of the 14 patients in the safety study, as a sham control, but shamming was problematic because patients can potentially feel VNS as a buzz or a change in their voice. To get around that potential confounder, both sham and treated patients were told they might or might not feel something during the study.
Implantation takes about an hour, and is much less complex than implanting currently available epilepsy VNS systems, which require implantation of both a power source on the chest wall and wire coils on the vagus nerve.
Cardiac concerns are the main safety issue with VNS, beyond the surgery itself. Cardiac monitoring was done in the safety study to “ensure that we did not cause things like bradycardia, heart block, syncope, etc.” Dr. Chernoff said. So far, they haven’t turned out to be a problem.
Dr. Furst and Dr. Kremer had no relevant disclosures. Dr. Gaylis was compensated by SetPoint for participating in the safety study; he is a consultant and investigator for Electrocore. Dr. Furst and Dr. Gaylis are members of the editorial advisory board for MDedge Rheumatology/Rheumatology News.
Much still unknown about inflammation’s role in RA patients’ CVD risk
A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
Hints of inflammation’s effects in non-RA patients
The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.
A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).
The trial was remarkable in that it was stopped early for efficacy, he noted.
“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”
The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).
Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.
Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
Effect of RA treatments on CVD risk
The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.
“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.
One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).
All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.
With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.
“I think we’ll know more about this in the near future,” he said.
As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.
The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.
Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
The TARGET trial
In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.
“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.
However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.
The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.
“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.
A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”
“The answer is partially yes and partially no,” he said.
The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.
RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).
“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.
“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.
The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.
“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
Hints of inflammation’s effects in non-RA patients
The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.
A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).
The trial was remarkable in that it was stopped early for efficacy, he noted.
“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”
The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).
Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.
Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
Effect of RA treatments on CVD risk
The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.
“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.
One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).
All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.
With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.
“I think we’ll know more about this in the near future,” he said.
As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.
The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.
Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
The TARGET trial
In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.
“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.
However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.
The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.
“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.
A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”
“The answer is partially yes and partially no,” he said.
The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.
RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).
“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.
“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.
The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.
“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
A variety of trials, some recent and some a decade old, have highlighted the role of inflammation on cardiovascular disease risk in both patients with and without rheumatoid arthritis, spurring greater interest in alleviating inflammation across a wide range of patients, Jon T. Giles, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
However, questions remain about the unique contributions of inflammation to CVD risk in RA patients and the effect of RA treatments on that risk, which future studies hope to answer.
Hints of inflammation’s effects in non-RA patients
The JUPITER trial published more than a decade ago, for example, tested the effects of statins in nearly 18,000 older adults without rheumatoid arthritis (RA) who had elevated levels of inflammation, defined as a C-reactive protein (CRP) level of greater than 2 mg/L and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. Such patients would otherwise be considered low risk and not eligible for statin therapy, said Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York.
A marked decrease in the incidence of cardiovascular disease (CVD) events was seen in those treated with statins, compared with those who received placebo, and all patient subgroups benefited; the number needed to treat to prevent one event was 32 at 5 years (N Engl J Med. 2008;359:2195-207).
The trial was remarkable in that it was stopped early for efficacy, he noted.
“So the question is: Should we be thinking about systemic inflammation as the real target here? And should RA patients who have elevated persistent levels of CRP really be the people that we’re thinking about?” he asked. “Obviously this needs to be tested; we don’t know.”
The more recent CANTOS trial looking at secondary CVD prevention in more than 10,000 non-RA patients with a prior myocardial infarction also highlighted the role of inflammation and provided “some support that decreasing inflammatory cytokines may be important for reducing [CVD] events,” he said (N Engl J Med. 2017;377:1119-31).
Participants were treated with the interleukin-1 inhibitor canakinumab (Ilaris) or placebo, and canakinumab was associated with about a 15% reduction in CVD events, providing “more proof of concept to look at the inflammatory innate immune contribution to CVD risk,” Dr. Giles said.
Treated patients had more infections, but they also had less gout, less arthritis, and less cancer than did those who received placebo, he noted.
Effect of RA treatments on CVD risk
The effects of existing treatments for RA also highlight the importance of inflammation in CVD risk in RA patients, he said, noting that data support a role for immunomodulators for risk reduction.
“There’s a lot of observational epidemiology in this space – mostly for methotrexate and [tumor necrosis factor (TNF)] inhibitors,” he said.
One analysis showed that across 8 cohort studies involving methotrexate, the disease-modifying antirheumatic agent reduced the risk of CVD events by 28%, and that across 16 cohort studies, TNF inhibitors reduced the risk by 30% (Ann Rheum Dis. 2015 Mar;74[3]:480-9).
All of the methotrexate studies showed a reduction, and almost all of the TNF inhibitor trials showed a reduction, Dr. Giles noted.
With respect to other non-TNF biologics, claims data suggest that abatacept (Orencia) is similar to the TNF inhibitor etanercept (Enbrel) with respect to CVD risk, and in a head-to-head, randomized clinical trial of more than 3,000 RA patients presented as a late-breaking abstract at the ACR annual meeting in 2016, Dr. Giles and his colleagues found similar cardiovascular safety between the anti-IL-6 receptor blocker tocilizumab (Actemra) and etanercept.
“I think we’ll know more about this in the near future,” he said.
As for the mechanisms of these agents, early data and animal models suggest that abatacept may play “a special role” in atherosclerosis reduction related to its effects on T cell CTLA-4 over-expression, and methotrexate also seems to have a number of “potential mechanistic benefits” that render it atheroprotective, he said.
The disappointing findings from the recently reported CIRT trial, which showed no benefit of methotrexate for secondary CVD prevention in non-RA patients (N Engl J Med. 2019;380:752-62), has dampened enthusiasm regarding methotrexate’s role here, but it is important to note that patients enrolled in CIRT, unlike those in JUPITER and CANTOS, were not enrolled based on elevated levels of CRP, Dr. Giles said.
Various studies of TNF inhibitors have shown atheroprotective effects through reductions in macrophage-derived inflammatory cytokines, downregulation of adhesion molecules on endothelial cells, improving the function of high-density lipoprotein, stabilizing atherosclerotic plaque remodeling, and reducing procoagulant states.
The TARGET trial
In a recent study of 17 patients with RA, Dr. Giles and his colleagues showed that TNF inhibitor therapy with either adalimumab (Humira) or etanercept significantly reduced aortic inflammation as measured by baseline and 8-week fluorodeoxyglucose (FDG) PET-CT.
“Is this proof that this helps? It’s not proof; there’s no control group, we don’t know that this is not the natural progression of vascular inflammation in these patients,” he said.
However, the findings were suggestive enough to prompt the launch of the TARGET trial, which is now enrolling patients at centers in the United States and Canada, Dr. Giles said.
The TARGET trial is a project involving his team at Columbia University along with researchers from Brigham and Women’s Hospital, Boston. They plan to enroll 200 RA patients without CVD who have an inadequate response to methotrexate. Participants will be randomized to receive an added TNF inhibitor or added triple therapy, and the primary outcome will be changes in inflammation in the aortic and carotid arteries on FDG PET-CT at 6 months versus baseline.
“So stay tuned and hopefully we’ll have some good information about the effect of two different types of treatments for rheumatoid arthritis on vascular inflammation,” Dr. Giles said.
A final question he addressed is whether the RA-CVD risk link is really a problem that has already been solved – one that “we’re just learning about after the fact.”
“The answer is partially yes and partially no,” he said.
The most up-to-date estimate of whether RA patients have a problem with CVD comes from a Swedish population-based study of more than 15,700 RA patients and nearly 70,900 comparators, which was published in 2018 and showed across-the-board declines in CVD rates over time.
RA and non-RA patients experienced an overall 40% reduction in acute coronary syndromes between 1997 and 2014, but the relative difference in event rates between the groups persisted (Ann Rheum Dis. 2017;76:1642-7).
“There is still a gap ... so we haven’t answered this question yet,” he said, adding that “the rates have been reduced, but we want those rates to be equal or maybe even less.
“Why can’t RA patients have less cardiovascular disease if we’re using drugs that are so effective for treating the inflammatory component of atherogenesis?” he asked.
The authors of the study noted that most RA patients in Sweden are in low disease activity by 3-6 months, so they were “a little confounded by why there is no equalization of these rates as of yet,” he said.
“I think we still have more to learn about this problem, and it is still a problem in our patients,” Dr. Giles said.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
FDA: Safety signal emerged with higher dose of tofacitinib in RA study
the Food and Drug Administration reported.
The trial’s Data Safety and Monitoring Board identified the signal in patients taking a 10-mg dose of tofacitinib twice daily, the FDA said in a safety announcement.
Pfizer, the trial’s sponsor, took “immediate action” to transition patients in the ongoing trial from the 10-mg, twice-daily dose to 5 mg twice daily, which is the approved dose for adult patients with moderate to severe rheumatoid arthritis, the agency said. The 10-mg, twice-daily dose is approved only in the dosing regimen for patients with ulcerative colitis. Xeljanz is also approved to treat psoriatic arthritis. The 11-mg, once-daily dose of Xeljanz XR that is approved to treat rheumatoid arthritis and psoriatic arthritis was not tested in the trial.
The ongoing study was designed to assess risks of cardiovascular events, cancer, and opportunistic infections with tofacitinib 10 mg twice daily or 5 mg twice daily versus the risks in a control group treated with a tumor necrosis factor (TNF) inhibitor, according to the statement.
Patients had to be 50 years of age or older and have at least one cardiovascular risk factor to be eligible for the study, which was required by the agency in 2012 when it approved tofacitinib, the statement says.
The FDA is reviewing trial data and working with Pfizer to better understand the safety signal, its effect on patients, and how tofacitinib should be used, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a news release. The trial will continue and is expected to be completed by the end of 2019.
“The agency will take appropriate action, as warranted, to ensure patients enrolled in this and other trials are protected and that health care professionals and clinical trial researchers understand the risks associated with this use,” she added.
Health care professionals should follow tofacitinib prescribing information, monitor patients for the signs and symptoms of pulmonary embolism, and advise patients to seek medical attention immediately if they experience those signs and symptoms, according to the statement.
“We are communicating now, given the serious nature of the safety issue, to ensure that patients taking tofacitinib are aware that the FDA still believes the benefits of taking tofacitinib for its approved uses continue to outweigh the risks,” Dr. Woodcock said in the release.
While not approved in rheumatoid arthritis, the 10-mg, twice-daily dose of tofacitinib is approved in the dosing regimen for patients with ulcerative colitis, the release says.
the Food and Drug Administration reported.
The trial’s Data Safety and Monitoring Board identified the signal in patients taking a 10-mg dose of tofacitinib twice daily, the FDA said in a safety announcement.
Pfizer, the trial’s sponsor, took “immediate action” to transition patients in the ongoing trial from the 10-mg, twice-daily dose to 5 mg twice daily, which is the approved dose for adult patients with moderate to severe rheumatoid arthritis, the agency said. The 10-mg, twice-daily dose is approved only in the dosing regimen for patients with ulcerative colitis. Xeljanz is also approved to treat psoriatic arthritis. The 11-mg, once-daily dose of Xeljanz XR that is approved to treat rheumatoid arthritis and psoriatic arthritis was not tested in the trial.
The ongoing study was designed to assess risks of cardiovascular events, cancer, and opportunistic infections with tofacitinib 10 mg twice daily or 5 mg twice daily versus the risks in a control group treated with a tumor necrosis factor (TNF) inhibitor, according to the statement.
Patients had to be 50 years of age or older and have at least one cardiovascular risk factor to be eligible for the study, which was required by the agency in 2012 when it approved tofacitinib, the statement says.
The FDA is reviewing trial data and working with Pfizer to better understand the safety signal, its effect on patients, and how tofacitinib should be used, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a news release. The trial will continue and is expected to be completed by the end of 2019.
“The agency will take appropriate action, as warranted, to ensure patients enrolled in this and other trials are protected and that health care professionals and clinical trial researchers understand the risks associated with this use,” she added.
Health care professionals should follow tofacitinib prescribing information, monitor patients for the signs and symptoms of pulmonary embolism, and advise patients to seek medical attention immediately if they experience those signs and symptoms, according to the statement.
“We are communicating now, given the serious nature of the safety issue, to ensure that patients taking tofacitinib are aware that the FDA still believes the benefits of taking tofacitinib for its approved uses continue to outweigh the risks,” Dr. Woodcock said in the release.
While not approved in rheumatoid arthritis, the 10-mg, twice-daily dose of tofacitinib is approved in the dosing regimen for patients with ulcerative colitis, the release says.
the Food and Drug Administration reported.
The trial’s Data Safety and Monitoring Board identified the signal in patients taking a 10-mg dose of tofacitinib twice daily, the FDA said in a safety announcement.
Pfizer, the trial’s sponsor, took “immediate action” to transition patients in the ongoing trial from the 10-mg, twice-daily dose to 5 mg twice daily, which is the approved dose for adult patients with moderate to severe rheumatoid arthritis, the agency said. The 10-mg, twice-daily dose is approved only in the dosing regimen for patients with ulcerative colitis. Xeljanz is also approved to treat psoriatic arthritis. The 11-mg, once-daily dose of Xeljanz XR that is approved to treat rheumatoid arthritis and psoriatic arthritis was not tested in the trial.
The ongoing study was designed to assess risks of cardiovascular events, cancer, and opportunistic infections with tofacitinib 10 mg twice daily or 5 mg twice daily versus the risks in a control group treated with a tumor necrosis factor (TNF) inhibitor, according to the statement.
Patients had to be 50 years of age or older and have at least one cardiovascular risk factor to be eligible for the study, which was required by the agency in 2012 when it approved tofacitinib, the statement says.
The FDA is reviewing trial data and working with Pfizer to better understand the safety signal, its effect on patients, and how tofacitinib should be used, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a news release. The trial will continue and is expected to be completed by the end of 2019.
“The agency will take appropriate action, as warranted, to ensure patients enrolled in this and other trials are protected and that health care professionals and clinical trial researchers understand the risks associated with this use,” she added.
Health care professionals should follow tofacitinib prescribing information, monitor patients for the signs and symptoms of pulmonary embolism, and advise patients to seek medical attention immediately if they experience those signs and symptoms, according to the statement.
“We are communicating now, given the serious nature of the safety issue, to ensure that patients taking tofacitinib are aware that the FDA still believes the benefits of taking tofacitinib for its approved uses continue to outweigh the risks,” Dr. Woodcock said in the release.
While not approved in rheumatoid arthritis, the 10-mg, twice-daily dose of tofacitinib is approved in the dosing regimen for patients with ulcerative colitis, the release says.
Smoking cessation could delay or prevent rheumatoid arthritis
Smoking is a significant risk factor for seropositive rheumatoid arthritis, and quitting may delay or even prevent the disease, a study has found.
In a paper published in Arthritis Care & Research, researchers report the analysis of data from 230,732 women – including 1,528 individuals with rheumatoid arthritis – participating in the Nurses’ Health Study (NHS) and NHS II.
They saw that current smokers had a significant 67% increased risk for seropositive rheumatoid arthritis (RA), compared with never smokers, while those who smoked 25 or more cigarettes per day had a 92% higher risk.
There was an increasing trend of association between pack-years of smoking and seropositive RA such that 35 pack-years of exposure was associated with a 2.3-fold higher risk for seropositive RA, compared with never smokers (P less than .0001).
Xinyi Liu of the division of rheumatology, immunology, and allergy at Brigham and Women’s Hospital, Boston, and her coauthors noted that the population attributable risk of RA from smoking was 14% and that smoking could contribute up to 35% of seropositive RA risk.
“Although the biologic mechanisms linking smoking with increased risk for developing RA are still not clear, components in cigarette smoke, such as nicotine, hydrocarbons, and carbon monoxide, are known to have aberrant effects on the immune system,” the authors wrote.
The good news was that sustained smoking cessation significantly reduced the risk of RA and seropositive RA, and those benefits increased with the amount of time since the individual stopped smoking.
Women who had quit smoking at least 30 years prior showed a 22% lower risk of all RA and a 37% lower risk of seropositive RA, compared with those who had quit within the previous 5 years. However, even 30 years after quitting, there was still a 30% higher risk of seropositive rheumatoid arthritis, compared with the risk among women who had never smoked.
“While smoking cessation may not decrease RA risk to the level of a never smoker, our findings provide evidence that a behavior change of smoking cessation may delay or even prevent the onset of seropositive RA,” the authors wrote. “These results could provide rationale for a smoking intervention trial among active smokers to prevent the formation of RA-related autoantibodies or to prevent the progression to RA among those at elevated risk for seropositive RA.”
Commenting on the difference in associations with seropositive and seronegative rheumatoid arthritis and smoking behavior, the authors wrote this suggested these two types of the disease may represent separate phenotypes with different risk factors.
The National Institutes of Health supported the study. No conflicts of interest were declared.
SOURCE: Liu X et al. Arthritis Care Res. 2019 Feb 21. doi: 10.1002/acr.23837.
Smoking is a significant risk factor for seropositive rheumatoid arthritis, and quitting may delay or even prevent the disease, a study has found.
In a paper published in Arthritis Care & Research, researchers report the analysis of data from 230,732 women – including 1,528 individuals with rheumatoid arthritis – participating in the Nurses’ Health Study (NHS) and NHS II.
They saw that current smokers had a significant 67% increased risk for seropositive rheumatoid arthritis (RA), compared with never smokers, while those who smoked 25 or more cigarettes per day had a 92% higher risk.
There was an increasing trend of association between pack-years of smoking and seropositive RA such that 35 pack-years of exposure was associated with a 2.3-fold higher risk for seropositive RA, compared with never smokers (P less than .0001).
Xinyi Liu of the division of rheumatology, immunology, and allergy at Brigham and Women’s Hospital, Boston, and her coauthors noted that the population attributable risk of RA from smoking was 14% and that smoking could contribute up to 35% of seropositive RA risk.
“Although the biologic mechanisms linking smoking with increased risk for developing RA are still not clear, components in cigarette smoke, such as nicotine, hydrocarbons, and carbon monoxide, are known to have aberrant effects on the immune system,” the authors wrote.
The good news was that sustained smoking cessation significantly reduced the risk of RA and seropositive RA, and those benefits increased with the amount of time since the individual stopped smoking.
Women who had quit smoking at least 30 years prior showed a 22% lower risk of all RA and a 37% lower risk of seropositive RA, compared with those who had quit within the previous 5 years. However, even 30 years after quitting, there was still a 30% higher risk of seropositive rheumatoid arthritis, compared with the risk among women who had never smoked.
“While smoking cessation may not decrease RA risk to the level of a never smoker, our findings provide evidence that a behavior change of smoking cessation may delay or even prevent the onset of seropositive RA,” the authors wrote. “These results could provide rationale for a smoking intervention trial among active smokers to prevent the formation of RA-related autoantibodies or to prevent the progression to RA among those at elevated risk for seropositive RA.”
Commenting on the difference in associations with seropositive and seronegative rheumatoid arthritis and smoking behavior, the authors wrote this suggested these two types of the disease may represent separate phenotypes with different risk factors.
The National Institutes of Health supported the study. No conflicts of interest were declared.
SOURCE: Liu X et al. Arthritis Care Res. 2019 Feb 21. doi: 10.1002/acr.23837.
Smoking is a significant risk factor for seropositive rheumatoid arthritis, and quitting may delay or even prevent the disease, a study has found.
In a paper published in Arthritis Care & Research, researchers report the analysis of data from 230,732 women – including 1,528 individuals with rheumatoid arthritis – participating in the Nurses’ Health Study (NHS) and NHS II.
They saw that current smokers had a significant 67% increased risk for seropositive rheumatoid arthritis (RA), compared with never smokers, while those who smoked 25 or more cigarettes per day had a 92% higher risk.
There was an increasing trend of association between pack-years of smoking and seropositive RA such that 35 pack-years of exposure was associated with a 2.3-fold higher risk for seropositive RA, compared with never smokers (P less than .0001).
Xinyi Liu of the division of rheumatology, immunology, and allergy at Brigham and Women’s Hospital, Boston, and her coauthors noted that the population attributable risk of RA from smoking was 14% and that smoking could contribute up to 35% of seropositive RA risk.
“Although the biologic mechanisms linking smoking with increased risk for developing RA are still not clear, components in cigarette smoke, such as nicotine, hydrocarbons, and carbon monoxide, are known to have aberrant effects on the immune system,” the authors wrote.
The good news was that sustained smoking cessation significantly reduced the risk of RA and seropositive RA, and those benefits increased with the amount of time since the individual stopped smoking.
Women who had quit smoking at least 30 years prior showed a 22% lower risk of all RA and a 37% lower risk of seropositive RA, compared with those who had quit within the previous 5 years. However, even 30 years after quitting, there was still a 30% higher risk of seropositive rheumatoid arthritis, compared with the risk among women who had never smoked.
“While smoking cessation may not decrease RA risk to the level of a never smoker, our findings provide evidence that a behavior change of smoking cessation may delay or even prevent the onset of seropositive RA,” the authors wrote. “These results could provide rationale for a smoking intervention trial among active smokers to prevent the formation of RA-related autoantibodies or to prevent the progression to RA among those at elevated risk for seropositive RA.”
Commenting on the difference in associations with seropositive and seronegative rheumatoid arthritis and smoking behavior, the authors wrote this suggested these two types of the disease may represent separate phenotypes with different risk factors.
The National Institutes of Health supported the study. No conflicts of interest were declared.
SOURCE: Liu X et al. Arthritis Care Res. 2019 Feb 21. doi: 10.1002/acr.23837.
FROM ARTHRITIS CARE & RESEARCH
TNF inhibitor prices rose despite increased drug class competition
according to a new analysis of Medicare claims data and wholesale acquisition costs published online in JAMA Internal Medicine.
A research team led by Alvaro San-Juan-Rodriguez, PharmD, of the University of Pittsburgh said their analysis illustrates “a market failure contributing to the rising costs of prescription drugs.”
Before 2009, etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) were the only tumor necrosis factor (TNF) inhibitors approved by the Food and Drug Administration for treating rheumatoid arthritis; infliximab and adalimumab are also approved to treat inflammatory bowel disease. In 2009, subcutaneous golimumab (Simponi) and certolizumab pegol (Cimzia) entered the market, followed by intravenous golimumab (Simponi ARIA) in 2013.
The researchers used an interrupted time series analysis with a linear model that “regressed the annual cost of existing TNF inhibitors against a continuous variable for month, two indicator variables for each period after market entry of new drugs, and the interactions between them.”
Using estimates from this model, the researchers calculated the trends in costs that would have been expected if new anti-TNFs had not entered the market. They examined costs for TNF inhibitors typically reimbursed under Medicare Part D (Enbrel, Humira, Simponi, and Cimzia) and adjusted the data for increases in manufacturer rebates, but “owing to lack of data,” they could not “assess how purchasing prices for drugs typically reimbursed under Medicare Part B [Remicade and Simponi ARIA] changed over time.” All estimates for annual costs of treatment were based on dosing recommendations for a standard 80-kg patient with rheumatoid arthritis.
The annual treatment costs with existing TNF inhibitors increased after the three new agents entered the market. For example, when wholesale acquisition cost data was applied, annual treatment costs with existing TNF inhibitors increased by 144% from April 2009 to December 2016 after new drug entry (from $15.809 to $38,574). However, in the absence of new drugs’ entry, the researchers estimated that annual treatment costs would have increased by 34% (from $15,809 to $21,184).
Medicare annual treatment costs increased by 139% (from $14,901 to $35,613), compared with a 43% increase expected in the absence of new drugs’ entry (from $14,901 to $21,308). Medicare spending increased in parallel with increases in annual treatment costs, but out-of-pocket costs and manufacturer coverage gap discounts remained relatively constant over time.
The research team noted that if cost trends had not changed after the entry of new products, the costs of Enbrel, Remicade, and Humira in December 2016 would have been 40%-45% lower.
“These increases were born solely by Medicare, while patient out-of-pocket spending remained flat. In addition, these increases were not offset by manufacturer discounts in the Medicare Part D coverage gap. The rising costs of existing products may reflect manufacturers’ opportunism in response to payers’ increased willingness to pay for TNF inhibitors after market entry of new, more expensive agents,” the research team noted.
The study was funded in part by the Myers Family Foundation and one author reported funding from the National Heart, Lung, and Blood Institute.
SOURCE: San-Juan-Rodriguez A et al. JAMA Intern Med. 2019 Feb 18. doi: 10.1001/jamainternmed.2018.7656
according to a new analysis of Medicare claims data and wholesale acquisition costs published online in JAMA Internal Medicine.
A research team led by Alvaro San-Juan-Rodriguez, PharmD, of the University of Pittsburgh said their analysis illustrates “a market failure contributing to the rising costs of prescription drugs.”
Before 2009, etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) were the only tumor necrosis factor (TNF) inhibitors approved by the Food and Drug Administration for treating rheumatoid arthritis; infliximab and adalimumab are also approved to treat inflammatory bowel disease. In 2009, subcutaneous golimumab (Simponi) and certolizumab pegol (Cimzia) entered the market, followed by intravenous golimumab (Simponi ARIA) in 2013.
The researchers used an interrupted time series analysis with a linear model that “regressed the annual cost of existing TNF inhibitors against a continuous variable for month, two indicator variables for each period after market entry of new drugs, and the interactions between them.”
Using estimates from this model, the researchers calculated the trends in costs that would have been expected if new anti-TNFs had not entered the market. They examined costs for TNF inhibitors typically reimbursed under Medicare Part D (Enbrel, Humira, Simponi, and Cimzia) and adjusted the data for increases in manufacturer rebates, but “owing to lack of data,” they could not “assess how purchasing prices for drugs typically reimbursed under Medicare Part B [Remicade and Simponi ARIA] changed over time.” All estimates for annual costs of treatment were based on dosing recommendations for a standard 80-kg patient with rheumatoid arthritis.
The annual treatment costs with existing TNF inhibitors increased after the three new agents entered the market. For example, when wholesale acquisition cost data was applied, annual treatment costs with existing TNF inhibitors increased by 144% from April 2009 to December 2016 after new drug entry (from $15.809 to $38,574). However, in the absence of new drugs’ entry, the researchers estimated that annual treatment costs would have increased by 34% (from $15,809 to $21,184).
Medicare annual treatment costs increased by 139% (from $14,901 to $35,613), compared with a 43% increase expected in the absence of new drugs’ entry (from $14,901 to $21,308). Medicare spending increased in parallel with increases in annual treatment costs, but out-of-pocket costs and manufacturer coverage gap discounts remained relatively constant over time.
The research team noted that if cost trends had not changed after the entry of new products, the costs of Enbrel, Remicade, and Humira in December 2016 would have been 40%-45% lower.
“These increases were born solely by Medicare, while patient out-of-pocket spending remained flat. In addition, these increases were not offset by manufacturer discounts in the Medicare Part D coverage gap. The rising costs of existing products may reflect manufacturers’ opportunism in response to payers’ increased willingness to pay for TNF inhibitors after market entry of new, more expensive agents,” the research team noted.
The study was funded in part by the Myers Family Foundation and one author reported funding from the National Heart, Lung, and Blood Institute.
SOURCE: San-Juan-Rodriguez A et al. JAMA Intern Med. 2019 Feb 18. doi: 10.1001/jamainternmed.2018.7656
according to a new analysis of Medicare claims data and wholesale acquisition costs published online in JAMA Internal Medicine.
A research team led by Alvaro San-Juan-Rodriguez, PharmD, of the University of Pittsburgh said their analysis illustrates “a market failure contributing to the rising costs of prescription drugs.”
Before 2009, etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) were the only tumor necrosis factor (TNF) inhibitors approved by the Food and Drug Administration for treating rheumatoid arthritis; infliximab and adalimumab are also approved to treat inflammatory bowel disease. In 2009, subcutaneous golimumab (Simponi) and certolizumab pegol (Cimzia) entered the market, followed by intravenous golimumab (Simponi ARIA) in 2013.
The researchers used an interrupted time series analysis with a linear model that “regressed the annual cost of existing TNF inhibitors against a continuous variable for month, two indicator variables for each period after market entry of new drugs, and the interactions between them.”
Using estimates from this model, the researchers calculated the trends in costs that would have been expected if new anti-TNFs had not entered the market. They examined costs for TNF inhibitors typically reimbursed under Medicare Part D (Enbrel, Humira, Simponi, and Cimzia) and adjusted the data for increases in manufacturer rebates, but “owing to lack of data,” they could not “assess how purchasing prices for drugs typically reimbursed under Medicare Part B [Remicade and Simponi ARIA] changed over time.” All estimates for annual costs of treatment were based on dosing recommendations for a standard 80-kg patient with rheumatoid arthritis.
The annual treatment costs with existing TNF inhibitors increased after the three new agents entered the market. For example, when wholesale acquisition cost data was applied, annual treatment costs with existing TNF inhibitors increased by 144% from April 2009 to December 2016 after new drug entry (from $15.809 to $38,574). However, in the absence of new drugs’ entry, the researchers estimated that annual treatment costs would have increased by 34% (from $15,809 to $21,184).
Medicare annual treatment costs increased by 139% (from $14,901 to $35,613), compared with a 43% increase expected in the absence of new drugs’ entry (from $14,901 to $21,308). Medicare spending increased in parallel with increases in annual treatment costs, but out-of-pocket costs and manufacturer coverage gap discounts remained relatively constant over time.
The research team noted that if cost trends had not changed after the entry of new products, the costs of Enbrel, Remicade, and Humira in December 2016 would have been 40%-45% lower.
“These increases were born solely by Medicare, while patient out-of-pocket spending remained flat. In addition, these increases were not offset by manufacturer discounts in the Medicare Part D coverage gap. The rising costs of existing products may reflect manufacturers’ opportunism in response to payers’ increased willingness to pay for TNF inhibitors after market entry of new, more expensive agents,” the research team noted.
The study was funded in part by the Myers Family Foundation and one author reported funding from the National Heart, Lung, and Blood Institute.
SOURCE: San-Juan-Rodriguez A et al. JAMA Intern Med. 2019 Feb 18. doi: 10.1001/jamainternmed.2018.7656
FROM JAMA INTERNAL MEDICINE
Mediterranean diet cut Parkinson’s risk
‘Telereferrals’ improved mental health referral follow-through for children. How to take action to cut cardiovascular disease risk in rheumatoid patients. And the U.S. Preventive Services Task Force recommends counseling for perinatal depression prevention.
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‘Telereferrals’ improved mental health referral follow-through for children. How to take action to cut cardiovascular disease risk in rheumatoid patients. And the U.S. Preventive Services Task Force recommends counseling for perinatal depression prevention.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
‘Telereferrals’ improved mental health referral follow-through for children. How to take action to cut cardiovascular disease risk in rheumatoid patients. And the U.S. Preventive Services Task Force recommends counseling for perinatal depression prevention.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
TNFi use may not affect joint replacement rates for RA patients
Patients with rheumatoid arthritis using tumor necrosis factor inhibitors do not appear to have a lower rate of joint replacement when compared with patients taking conventional synthetic disease-modifying antirheumatic drugs, according to an analysis of data in the British Society for Rheumatology Biologics Register for RA.
Although there was not a general protective effect, patients with rheumatoid arthritis (RA) who were 60 years or older had a 40% reduction in total hip replacement (THR) when using tumor necrosis factor inhibitors (TNFi), according to first author Samuel Hawley from the Nuffield Department of Orthopaedics in the Rheumatology and Musculoskeletal Sciences at the University of Oxford (England) and his colleagues.
“While a reduction in THR amongst older TNFi users offers some support for biologics playing a role in reducing need for joint replacement, it must also be noted that the lack of an overall protective effect is suggestive that other factors apart from TNFi are likely to be involved in the ... downward population trends in joint replacement rates in RA,” Mr. Hawley and his colleagues wrote in their report published in the journal Rheumatology.
The researchers analyzed prospectively collected data on 11,202 RA patients from the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) from 2001-2016 who were using TNFi (n = 9,558) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; n = 1,644). Patients had a median disease duration of 11.0 years in the TNFi group and 10.8 years in the csDMARD group. TNFi and csDMARD users were matched based on their propensity to receive treatment, and researchers used a Cox regression analysis to compare the rates of total knee replacement (TKR), THR, and other joint replacement. The researchers utilized each csDMARD user a median of three times (interquartile range, one to six) in the comparisons.
The incidence rate for THR was 5.22/1,000 person-years for TNFi users and 6.30/1,000 person-years for csDMARD users, while the incidence rate for TKR was 8.89/1,000 person-years for TNFi users and 8.09/1,000 person-years for csDMARD users. Mr. Hawley and his colleagues found no association between TNFi use and THR when compared with csDMARD users (adjusted pooled hazard ratio, 0.86; 95% confidence interval, 0.60-1.22; P = .39) based on 589 THRs during follow-up. There was also no association between the incidence of TKR and TNFi use when compared with csDMARD users (adjusted pooled HR, 1.11; 95% CI, 0.84-1.47; P = .46) based on 846 TKRs during follow-up. When the researchers examined 336 other joint replacements performed during follow-up, there was also no significant difference in incidence between TNFi and csDMARD users (HR, 1.15; 95% CI, 0.75-1.77).
For patients 60 years or older, TNFi use was associated with a 40% reduction in THR incidence (HR, 0.60; 95% CI, 0.41-0.87; P = .008), but not in TKR incidence. However, younger patients using TNFi did not have a reduced incidence of THR, and there were no associations between TNFi use and incidence of TKR or other joint replacements.
“It could be that the relatively long disease duration at our baseline meant there was greater potential for prevention of joint destruction at the hip over knee, although details of differential natural history of RA disease at these two joints are not well established,” the researchers wrote. “It is also very difficult to disentangle the impact of TNFi on improved function and overall quality of life and how this may have mediated effects on longer-term progression of joint damage, potentially differentially at the knee and hip.”
The researchers said the study was limited by the potential for residual confounding by indication, and the long disease duration of patients means that the results would not be generalizable to patients with early RA. In addition, underreporting of joint replacement could create bias because the registry information is a combination of physician-reported and self-reported incidences, they added.
This study was funded by an award from the National Institute for Health Research (NIHR) and support from the Oxford NIHR Biomedical Research Unit. Four authors disclosed financial relationships with industry, including many companies marketing biologics for RA. Other authors reported no relevant conflicts of interest.
SOURCE: Hawley S et al. Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/key424.
The arrival and widespread use of tumor necrosis factor inhibitors (TNFi) in the late 1990s has “created a perception of causality” that led many to believe that TNFi use was associated with decreased rates of joint replacement. However, the decline in total hip arthroplasties (THAs), total knee arthroplasties (TKAs), and other joint replacements is likely because of a confluence of factors, Susan M. Goodman, MD, and Anne R. Bass, MD, wrote in an editorial accompanying the report by Hawley et al. (Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/kez022).
Although Hawley et al. attempted to mitigate confounding in their study by using a propensity score when comparing TNFi and conventional synthetic disease-modifying antirheumatic drug (csDMARD) users, there was a preference for physicians prescribing biologics at a rate of 87% versus 13%, and the biologic preference was associated with disease severity, which is “a strong driver of the need for surgery.” In addition, in patients 60 years or older for whom TNFi reduced indications for joint replacement, “[t]he differential effect of TNFi use on THA utilization in the elderly is especially curious because a previous study by the same authors demonstrated that TKA, but not THA, rates were impacted by introduction of NICE guidance in 2002.”
The authors also noted clinicians should exercise caution in extrapolating the results of Hawley et al. because the effects of biologic treatment in patients with a long disease duration, such as in this study, may not be generalizable to most RA patients.
Dr. Goodman and Dr. Bass are rheumatologists and professors of clinical medicine at Cornell University and the Hospital for Special Surgery, both in New York. Dr. Goodman disclosed financial relationships with Novartis and UCB outside the scope of this work.
The arrival and widespread use of tumor necrosis factor inhibitors (TNFi) in the late 1990s has “created a perception of causality” that led many to believe that TNFi use was associated with decreased rates of joint replacement. However, the decline in total hip arthroplasties (THAs), total knee arthroplasties (TKAs), and other joint replacements is likely because of a confluence of factors, Susan M. Goodman, MD, and Anne R. Bass, MD, wrote in an editorial accompanying the report by Hawley et al. (Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/kez022).
Although Hawley et al. attempted to mitigate confounding in their study by using a propensity score when comparing TNFi and conventional synthetic disease-modifying antirheumatic drug (csDMARD) users, there was a preference for physicians prescribing biologics at a rate of 87% versus 13%, and the biologic preference was associated with disease severity, which is “a strong driver of the need for surgery.” In addition, in patients 60 years or older for whom TNFi reduced indications for joint replacement, “[t]he differential effect of TNFi use on THA utilization in the elderly is especially curious because a previous study by the same authors demonstrated that TKA, but not THA, rates were impacted by introduction of NICE guidance in 2002.”
The authors also noted clinicians should exercise caution in extrapolating the results of Hawley et al. because the effects of biologic treatment in patients with a long disease duration, such as in this study, may not be generalizable to most RA patients.
Dr. Goodman and Dr. Bass are rheumatologists and professors of clinical medicine at Cornell University and the Hospital for Special Surgery, both in New York. Dr. Goodman disclosed financial relationships with Novartis and UCB outside the scope of this work.
The arrival and widespread use of tumor necrosis factor inhibitors (TNFi) in the late 1990s has “created a perception of causality” that led many to believe that TNFi use was associated with decreased rates of joint replacement. However, the decline in total hip arthroplasties (THAs), total knee arthroplasties (TKAs), and other joint replacements is likely because of a confluence of factors, Susan M. Goodman, MD, and Anne R. Bass, MD, wrote in an editorial accompanying the report by Hawley et al. (Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/kez022).
Although Hawley et al. attempted to mitigate confounding in their study by using a propensity score when comparing TNFi and conventional synthetic disease-modifying antirheumatic drug (csDMARD) users, there was a preference for physicians prescribing biologics at a rate of 87% versus 13%, and the biologic preference was associated with disease severity, which is “a strong driver of the need for surgery.” In addition, in patients 60 years or older for whom TNFi reduced indications for joint replacement, “[t]he differential effect of TNFi use on THA utilization in the elderly is especially curious because a previous study by the same authors demonstrated that TKA, but not THA, rates were impacted by introduction of NICE guidance in 2002.”
The authors also noted clinicians should exercise caution in extrapolating the results of Hawley et al. because the effects of biologic treatment in patients with a long disease duration, such as in this study, may not be generalizable to most RA patients.
Dr. Goodman and Dr. Bass are rheumatologists and professors of clinical medicine at Cornell University and the Hospital for Special Surgery, both in New York. Dr. Goodman disclosed financial relationships with Novartis and UCB outside the scope of this work.
Patients with rheumatoid arthritis using tumor necrosis factor inhibitors do not appear to have a lower rate of joint replacement when compared with patients taking conventional synthetic disease-modifying antirheumatic drugs, according to an analysis of data in the British Society for Rheumatology Biologics Register for RA.
Although there was not a general protective effect, patients with rheumatoid arthritis (RA) who were 60 years or older had a 40% reduction in total hip replacement (THR) when using tumor necrosis factor inhibitors (TNFi), according to first author Samuel Hawley from the Nuffield Department of Orthopaedics in the Rheumatology and Musculoskeletal Sciences at the University of Oxford (England) and his colleagues.
“While a reduction in THR amongst older TNFi users offers some support for biologics playing a role in reducing need for joint replacement, it must also be noted that the lack of an overall protective effect is suggestive that other factors apart from TNFi are likely to be involved in the ... downward population trends in joint replacement rates in RA,” Mr. Hawley and his colleagues wrote in their report published in the journal Rheumatology.
The researchers analyzed prospectively collected data on 11,202 RA patients from the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) from 2001-2016 who were using TNFi (n = 9,558) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; n = 1,644). Patients had a median disease duration of 11.0 years in the TNFi group and 10.8 years in the csDMARD group. TNFi and csDMARD users were matched based on their propensity to receive treatment, and researchers used a Cox regression analysis to compare the rates of total knee replacement (TKR), THR, and other joint replacement. The researchers utilized each csDMARD user a median of three times (interquartile range, one to six) in the comparisons.
The incidence rate for THR was 5.22/1,000 person-years for TNFi users and 6.30/1,000 person-years for csDMARD users, while the incidence rate for TKR was 8.89/1,000 person-years for TNFi users and 8.09/1,000 person-years for csDMARD users. Mr. Hawley and his colleagues found no association between TNFi use and THR when compared with csDMARD users (adjusted pooled hazard ratio, 0.86; 95% confidence interval, 0.60-1.22; P = .39) based on 589 THRs during follow-up. There was also no association between the incidence of TKR and TNFi use when compared with csDMARD users (adjusted pooled HR, 1.11; 95% CI, 0.84-1.47; P = .46) based on 846 TKRs during follow-up. When the researchers examined 336 other joint replacements performed during follow-up, there was also no significant difference in incidence between TNFi and csDMARD users (HR, 1.15; 95% CI, 0.75-1.77).
For patients 60 years or older, TNFi use was associated with a 40% reduction in THR incidence (HR, 0.60; 95% CI, 0.41-0.87; P = .008), but not in TKR incidence. However, younger patients using TNFi did not have a reduced incidence of THR, and there were no associations between TNFi use and incidence of TKR or other joint replacements.
“It could be that the relatively long disease duration at our baseline meant there was greater potential for prevention of joint destruction at the hip over knee, although details of differential natural history of RA disease at these two joints are not well established,” the researchers wrote. “It is also very difficult to disentangle the impact of TNFi on improved function and overall quality of life and how this may have mediated effects on longer-term progression of joint damage, potentially differentially at the knee and hip.”
The researchers said the study was limited by the potential for residual confounding by indication, and the long disease duration of patients means that the results would not be generalizable to patients with early RA. In addition, underreporting of joint replacement could create bias because the registry information is a combination of physician-reported and self-reported incidences, they added.
This study was funded by an award from the National Institute for Health Research (NIHR) and support from the Oxford NIHR Biomedical Research Unit. Four authors disclosed financial relationships with industry, including many companies marketing biologics for RA. Other authors reported no relevant conflicts of interest.
SOURCE: Hawley S et al. Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/key424.
Patients with rheumatoid arthritis using tumor necrosis factor inhibitors do not appear to have a lower rate of joint replacement when compared with patients taking conventional synthetic disease-modifying antirheumatic drugs, according to an analysis of data in the British Society for Rheumatology Biologics Register for RA.
Although there was not a general protective effect, patients with rheumatoid arthritis (RA) who were 60 years or older had a 40% reduction in total hip replacement (THR) when using tumor necrosis factor inhibitors (TNFi), according to first author Samuel Hawley from the Nuffield Department of Orthopaedics in the Rheumatology and Musculoskeletal Sciences at the University of Oxford (England) and his colleagues.
“While a reduction in THR amongst older TNFi users offers some support for biologics playing a role in reducing need for joint replacement, it must also be noted that the lack of an overall protective effect is suggestive that other factors apart from TNFi are likely to be involved in the ... downward population trends in joint replacement rates in RA,” Mr. Hawley and his colleagues wrote in their report published in the journal Rheumatology.
The researchers analyzed prospectively collected data on 11,202 RA patients from the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) from 2001-2016 who were using TNFi (n = 9,558) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; n = 1,644). Patients had a median disease duration of 11.0 years in the TNFi group and 10.8 years in the csDMARD group. TNFi and csDMARD users were matched based on their propensity to receive treatment, and researchers used a Cox regression analysis to compare the rates of total knee replacement (TKR), THR, and other joint replacement. The researchers utilized each csDMARD user a median of three times (interquartile range, one to six) in the comparisons.
The incidence rate for THR was 5.22/1,000 person-years for TNFi users and 6.30/1,000 person-years for csDMARD users, while the incidence rate for TKR was 8.89/1,000 person-years for TNFi users and 8.09/1,000 person-years for csDMARD users. Mr. Hawley and his colleagues found no association between TNFi use and THR when compared with csDMARD users (adjusted pooled hazard ratio, 0.86; 95% confidence interval, 0.60-1.22; P = .39) based on 589 THRs during follow-up. There was also no association between the incidence of TKR and TNFi use when compared with csDMARD users (adjusted pooled HR, 1.11; 95% CI, 0.84-1.47; P = .46) based on 846 TKRs during follow-up. When the researchers examined 336 other joint replacements performed during follow-up, there was also no significant difference in incidence between TNFi and csDMARD users (HR, 1.15; 95% CI, 0.75-1.77).
For patients 60 years or older, TNFi use was associated with a 40% reduction in THR incidence (HR, 0.60; 95% CI, 0.41-0.87; P = .008), but not in TKR incidence. However, younger patients using TNFi did not have a reduced incidence of THR, and there were no associations between TNFi use and incidence of TKR or other joint replacements.
“It could be that the relatively long disease duration at our baseline meant there was greater potential for prevention of joint destruction at the hip over knee, although details of differential natural history of RA disease at these two joints are not well established,” the researchers wrote. “It is also very difficult to disentangle the impact of TNFi on improved function and overall quality of life and how this may have mediated effects on longer-term progression of joint damage, potentially differentially at the knee and hip.”
The researchers said the study was limited by the potential for residual confounding by indication, and the long disease duration of patients means that the results would not be generalizable to patients with early RA. In addition, underreporting of joint replacement could create bias because the registry information is a combination of physician-reported and self-reported incidences, they added.
This study was funded by an award from the National Institute for Health Research (NIHR) and support from the Oxford NIHR Biomedical Research Unit. Four authors disclosed financial relationships with industry, including many companies marketing biologics for RA. Other authors reported no relevant conflicts of interest.
SOURCE: Hawley S et al. Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/key424.
FROM RHEUMATOLOGY
Key clinical point: The rate of joint replacement did not differ among patients with RA using conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or tumor necrosis factor inhibitors (TNFis).
Major finding: There was no association between TNFi use and total hip replacement when compared with csDMARD users based on an adjusted pooled hazard ratio of 0.86 (95% confidence interval, 0.60-1.22), but patients older than 60 years using TNFi had a significantly greater reduction in total hip replacement.
Study details: An observational study of 11,202 prospectively collected RA patients in the British Society for Rheumatology Biologics Register for RA.
Disclosures: This study was funded by an award from the National Institute for Health Research (NIHR) and support from the Oxford NIHR Biomedical Research Unit. Four authors disclosed financial relationships with industry, including many companies marketing biologics for RA. Other authors reported no relevant conflicts of interest.
Source: Hawley S et al. Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/key424.
Take action to mitigate CVD risk in RA patients
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
ICYMI: MRI-based treat-to-target approach offers no benefit for RA patients
Patients with RA in clinical remission who received an MRI-based treat-to-target strategy did not achieve superior disease activity remission rates (85% vs. 88%) or reduced radiographic progression (66% vs. 62%), compared with a conventional treat-to-target strategy, according to results of the Danish, 2-year, investigator-initiated, randomized, multicenter IMAGINE-RA trial published in JAMA (2019 Feb 5. doi: 10.1001/jama.2018.21362).
We covered this study at the 2018 European Congress of Rheumatology before it was published in the journal. Read the story at the link above.
Patients with RA in clinical remission who received an MRI-based treat-to-target strategy did not achieve superior disease activity remission rates (85% vs. 88%) or reduced radiographic progression (66% vs. 62%), compared with a conventional treat-to-target strategy, according to results of the Danish, 2-year, investigator-initiated, randomized, multicenter IMAGINE-RA trial published in JAMA (2019 Feb 5. doi: 10.1001/jama.2018.21362).
We covered this study at the 2018 European Congress of Rheumatology before it was published in the journal. Read the story at the link above.
Patients with RA in clinical remission who received an MRI-based treat-to-target strategy did not achieve superior disease activity remission rates (85% vs. 88%) or reduced radiographic progression (66% vs. 62%), compared with a conventional treat-to-target strategy, according to results of the Danish, 2-year, investigator-initiated, randomized, multicenter IMAGINE-RA trial published in JAMA (2019 Feb 5. doi: 10.1001/jama.2018.21362).
We covered this study at the 2018 European Congress of Rheumatology before it was published in the journal. Read the story at the link above.
FROM JAMA
Findings in seropositive arthralgia patients may help to predict RA
Findings from an ongoing study of individuals with seropositive arthralgia, as well as from numerous other ongoing research efforts, suggest that it will soon be possible to predict a future rheumatoid arthritis diagnosis, according to Douglas J. Veale, MD.
Evidence also suggests that disease onset can be delayed, and that there is potential for disease prevention in those cases, Dr. Veale, a professor and consultant rheumatologist at St. Vincent’s University Hospital in Dublin said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Cellular and molecular profiling of RA risk
Dr. Veale’s current research focuses on patients presenting with joint pain but no joint swelling or clinical evidence of soft tissue swelling, who are found to be seropositive for anticitrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF).
“We have termed these patients [as having] ‘seropositive arthralgia,’ and we started a study in our institution because we started seeing more of these patients being referred in by the general practitioners,” said Dr. Veale, who is also director of translational research at the Dublin Academic Medical Centre of University College Dublin.
The aim of the study is to biopsy synovial tissue obtained during knee joint arthroscopy (which has been shown in prior studies to provide the same synovial findings as can be obtained through wrist and ankle biopsies) and to assess cellular and molecular profiles and clinical outcomes in these subjects, he said.
Of 36 seropositive arthralgia patients recruited to date, 22 are women, and 19 developed RA by 2010 ACR criteria within 12 months; most of those did so within 2-3 months, he said.
Median swollen joint counts were zero, and tender joint counts were slightly raised (median = 0, interquartile range = 0-4) in the subjects at baseline. Overall, 82% were RF positive, 91% were ACPA positive, and 73% were both RF and ACPA positive.
“The median [C-reactive protein (CRP) level] was 3 [mg/dL] with a range of 2-7, so most of these are normal when they’re coming to see us,” he said.
The level of synovitis seen on knee arthroscopy was a median of 60 on a visual analog scale of 0-100.
“So the level of synovitis that we’re seeing is certainly over a median of 50%,” he added.
Of 22 patients who were followed for at least 1 year – including the 19 who developed RA – none were on therapy at baseline, and none had CRP over 5 mg/dL at baseline. Two of the 19 who later developed RA elected to begin treatment before they developed the disease – one with hydroxychloroquine and one with methotrexate – and treatment was initiated in the remaining 17 RA patients as soon as they met the ACR RA criteria. Currently, 14 are on synthetic disease-modifying antirheumatic drugs (DMARDs), and 5 are on biologic DMARDs. Overall, 13 of the 22 patients followed for 1 year have no disease activity, 5 have low disease activity, and 4 have moderate disease activity, he said.
One question addressed in this study is whether immunostaining predicts arthritis, Dr. Veale noted.
“The short answer is ‘no,’ ” he said, explaining that activated T and B cells are seen in the biopsies of subjects who remain as seropositive arthralgia patients, and also in patients who actually develop RA. “So the immunohistology of these biopsies is not telling us a great deal.”
Immunophenotyping to establish RA risk
Another finding of interest is an increase in the synovial tissue CD38 plasmablasts as detected by RNA sequencing in seropositive arthralgia subjects.
“Their pattern looks more like early RA or established RA,” he noted.
Similarly, the proportion of B cells is already increased in the seropositive arthralgia subjects, compared with healthy subjects, and is similar to that seen in established seropositive and seronegative RA patients.
After looking at “a whole range of immunophenotypes,” Dr. Veale and his colleagues found that several other genes (not just for CD38) are expressed at increased levels in the arthralgia patients.
“The pattern that we’re seeing is that the seropositive arthralgia patients look more like the early rheumatoid and the established rheumatoid patients when we actually analyze their gene signatures using immunophenotyping,” he said.
The patients in this study were all referred by general practitioners, but another study – the PRAIRI study – recruited seropositive arthralgia patients from the community and randomized them to receive a single rituximab infusion or placebo (Ann Rheum Dis. 2019;78:179-85).
“What they showed is that patients who received one dose of rituximab actually developed rheumatoid arthritis at a slower rate and at a later time than the patients who received placebo,” he said.
At 1-year follow-up, there was no difference in the rate of development of RA between the groups; rituximab had merely delayed the onset of RA, he said.
“They do discuss in this paper what the effect would be if you continued treatment in these patients: Would we actually prevent the onset of rheumatoid arthritis in a significant cohort of patients?” he said. “But we don’t know that.”
Could immune checkpoint inhibition reveal RA risk?
Recent findings from work with immune checkpoint therapy in the hematology/oncology arena, however, raise other interesting possibilities with respect to early treatment and prevention of RA.
A number of case reports have documented the development of autoimmune diseases in patients with cancer who have undergone treatment with checkpoint inhibitors.
“Essentially what happens in cancer is that the activated T cells upregulate immune checkpoint molecules. ... and what these molecules do is they make the T cells essentially resistant to attacking the tumor cells,” he explained, noting that the molecules include programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).
Checkpoint inhibitors bind to these molecules and “free up these activated T cells to attack the tumor cells” both through cytokines (interferon release) and direct cell cytotoxicity, he said.
This is relevant for rheumatology patients, because the PD-1 checkpoint molecule is overexpressed in pathogenic T cells in RA and systemic lupus erythematosus.
A closer look at his own RA patients showed that those who were ACPA positive had higher levels of soluble PD-1 than did the ACPA-negative RA patients – a finding that has been replicated in two other cohorts, he noted.
“So we wanted to look at our seropositive arthralgia subjects and see if there is something in their gene signatures on immunophenotyping which actually would give us a clue in terms of this checkpoint inhibitor pathway,” he said. “What we found is that the anti–PD-1 signature is increased in our arthralgia patients, and again, the pattern of expression is more similar to early rheumatoid arthritis and established rheumatoid arthritis, and is significantly different from both healthy controls and patients with osteoarthritis.”
PD-1 expression was also found to be increased on CD4- and CD8-positive T cells taken from the synovial tissues in these patients, he said.
Immunostaining of the T cells showed, interestingly, that the ligand for PD-1 is “almost absent,” he noted.
“So there’s an overexpression of PD-1, but there’s a downregulation of the ligand for PD-1, so that means that the PD-1 pathway is not active in these patients because the PD-1 ... has no ligand to actually bind on to.”
This suggests that “something else may happen that will upregulate the ligand – maybe a second hit,” thereby allowing PD-1 to bind and become active, he said.
“I realize what I’ve been talking about is fairly controversial, but I think it may be possible soon to predict a diagnosis of rheumatoid arthritis before clinical arthritis develops, but not in everybody,” he said, noting that current diagnostic tools are often unreliable.
For example, CRP levels in most of his study subjects remained normal even after converting to meet RA criteria, he explained.
However, “the checkpoint inhibitor story is absolutely fascinating,” he said.
“It’s unmasked an RA phenotype in patients who are receiving these drugs, and we have identified that the PD-1 pathway is altered in the synovial tissue, not just in patients with established rheumatoid arthritis, but also in subjects before they have developed arthritis and they have circulating autoantibodies,” he said.
The CD38 plasmablasts found to be present in the synovial tissue before RA presents clinically may also represent a therapeutic target, he added.
Dr. Veale disclosed financial relationships (research grants, consulting fees, speaker’s bureau, and “other” relationships) with AbbVie, Pfizer, UCB, Roche, and Janssen.
Findings from an ongoing study of individuals with seropositive arthralgia, as well as from numerous other ongoing research efforts, suggest that it will soon be possible to predict a future rheumatoid arthritis diagnosis, according to Douglas J. Veale, MD.
Evidence also suggests that disease onset can be delayed, and that there is potential for disease prevention in those cases, Dr. Veale, a professor and consultant rheumatologist at St. Vincent’s University Hospital in Dublin said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Cellular and molecular profiling of RA risk
Dr. Veale’s current research focuses on patients presenting with joint pain but no joint swelling or clinical evidence of soft tissue swelling, who are found to be seropositive for anticitrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF).
“We have termed these patients [as having] ‘seropositive arthralgia,’ and we started a study in our institution because we started seeing more of these patients being referred in by the general practitioners,” said Dr. Veale, who is also director of translational research at the Dublin Academic Medical Centre of University College Dublin.
The aim of the study is to biopsy synovial tissue obtained during knee joint arthroscopy (which has been shown in prior studies to provide the same synovial findings as can be obtained through wrist and ankle biopsies) and to assess cellular and molecular profiles and clinical outcomes in these subjects, he said.
Of 36 seropositive arthralgia patients recruited to date, 22 are women, and 19 developed RA by 2010 ACR criteria within 12 months; most of those did so within 2-3 months, he said.
Median swollen joint counts were zero, and tender joint counts were slightly raised (median = 0, interquartile range = 0-4) in the subjects at baseline. Overall, 82% were RF positive, 91% were ACPA positive, and 73% were both RF and ACPA positive.
“The median [C-reactive protein (CRP) level] was 3 [mg/dL] with a range of 2-7, so most of these are normal when they’re coming to see us,” he said.
The level of synovitis seen on knee arthroscopy was a median of 60 on a visual analog scale of 0-100.
“So the level of synovitis that we’re seeing is certainly over a median of 50%,” he added.
Of 22 patients who were followed for at least 1 year – including the 19 who developed RA – none were on therapy at baseline, and none had CRP over 5 mg/dL at baseline. Two of the 19 who later developed RA elected to begin treatment before they developed the disease – one with hydroxychloroquine and one with methotrexate – and treatment was initiated in the remaining 17 RA patients as soon as they met the ACR RA criteria. Currently, 14 are on synthetic disease-modifying antirheumatic drugs (DMARDs), and 5 are on biologic DMARDs. Overall, 13 of the 22 patients followed for 1 year have no disease activity, 5 have low disease activity, and 4 have moderate disease activity, he said.
One question addressed in this study is whether immunostaining predicts arthritis, Dr. Veale noted.
“The short answer is ‘no,’ ” he said, explaining that activated T and B cells are seen in the biopsies of subjects who remain as seropositive arthralgia patients, and also in patients who actually develop RA. “So the immunohistology of these biopsies is not telling us a great deal.”
Immunophenotyping to establish RA risk
Another finding of interest is an increase in the synovial tissue CD38 plasmablasts as detected by RNA sequencing in seropositive arthralgia subjects.
“Their pattern looks more like early RA or established RA,” he noted.
Similarly, the proportion of B cells is already increased in the seropositive arthralgia subjects, compared with healthy subjects, and is similar to that seen in established seropositive and seronegative RA patients.
After looking at “a whole range of immunophenotypes,” Dr. Veale and his colleagues found that several other genes (not just for CD38) are expressed at increased levels in the arthralgia patients.
“The pattern that we’re seeing is that the seropositive arthralgia patients look more like the early rheumatoid and the established rheumatoid patients when we actually analyze their gene signatures using immunophenotyping,” he said.
The patients in this study were all referred by general practitioners, but another study – the PRAIRI study – recruited seropositive arthralgia patients from the community and randomized them to receive a single rituximab infusion or placebo (Ann Rheum Dis. 2019;78:179-85).
“What they showed is that patients who received one dose of rituximab actually developed rheumatoid arthritis at a slower rate and at a later time than the patients who received placebo,” he said.
At 1-year follow-up, there was no difference in the rate of development of RA between the groups; rituximab had merely delayed the onset of RA, he said.
“They do discuss in this paper what the effect would be if you continued treatment in these patients: Would we actually prevent the onset of rheumatoid arthritis in a significant cohort of patients?” he said. “But we don’t know that.”
Could immune checkpoint inhibition reveal RA risk?
Recent findings from work with immune checkpoint therapy in the hematology/oncology arena, however, raise other interesting possibilities with respect to early treatment and prevention of RA.
A number of case reports have documented the development of autoimmune diseases in patients with cancer who have undergone treatment with checkpoint inhibitors.
“Essentially what happens in cancer is that the activated T cells upregulate immune checkpoint molecules. ... and what these molecules do is they make the T cells essentially resistant to attacking the tumor cells,” he explained, noting that the molecules include programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).
Checkpoint inhibitors bind to these molecules and “free up these activated T cells to attack the tumor cells” both through cytokines (interferon release) and direct cell cytotoxicity, he said.
This is relevant for rheumatology patients, because the PD-1 checkpoint molecule is overexpressed in pathogenic T cells in RA and systemic lupus erythematosus.
A closer look at his own RA patients showed that those who were ACPA positive had higher levels of soluble PD-1 than did the ACPA-negative RA patients – a finding that has been replicated in two other cohorts, he noted.
“So we wanted to look at our seropositive arthralgia subjects and see if there is something in their gene signatures on immunophenotyping which actually would give us a clue in terms of this checkpoint inhibitor pathway,” he said. “What we found is that the anti–PD-1 signature is increased in our arthralgia patients, and again, the pattern of expression is more similar to early rheumatoid arthritis and established rheumatoid arthritis, and is significantly different from both healthy controls and patients with osteoarthritis.”
PD-1 expression was also found to be increased on CD4- and CD8-positive T cells taken from the synovial tissues in these patients, he said.
Immunostaining of the T cells showed, interestingly, that the ligand for PD-1 is “almost absent,” he noted.
“So there’s an overexpression of PD-1, but there’s a downregulation of the ligand for PD-1, so that means that the PD-1 pathway is not active in these patients because the PD-1 ... has no ligand to actually bind on to.”
This suggests that “something else may happen that will upregulate the ligand – maybe a second hit,” thereby allowing PD-1 to bind and become active, he said.
“I realize what I’ve been talking about is fairly controversial, but I think it may be possible soon to predict a diagnosis of rheumatoid arthritis before clinical arthritis develops, but not in everybody,” he said, noting that current diagnostic tools are often unreliable.
For example, CRP levels in most of his study subjects remained normal even after converting to meet RA criteria, he explained.
However, “the checkpoint inhibitor story is absolutely fascinating,” he said.
“It’s unmasked an RA phenotype in patients who are receiving these drugs, and we have identified that the PD-1 pathway is altered in the synovial tissue, not just in patients with established rheumatoid arthritis, but also in subjects before they have developed arthritis and they have circulating autoantibodies,” he said.
The CD38 plasmablasts found to be present in the synovial tissue before RA presents clinically may also represent a therapeutic target, he added.
Dr. Veale disclosed financial relationships (research grants, consulting fees, speaker’s bureau, and “other” relationships) with AbbVie, Pfizer, UCB, Roche, and Janssen.
Findings from an ongoing study of individuals with seropositive arthralgia, as well as from numerous other ongoing research efforts, suggest that it will soon be possible to predict a future rheumatoid arthritis diagnosis, according to Douglas J. Veale, MD.
Evidence also suggests that disease onset can be delayed, and that there is potential for disease prevention in those cases, Dr. Veale, a professor and consultant rheumatologist at St. Vincent’s University Hospital in Dublin said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Cellular and molecular profiling of RA risk
Dr. Veale’s current research focuses on patients presenting with joint pain but no joint swelling or clinical evidence of soft tissue swelling, who are found to be seropositive for anticitrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF).
“We have termed these patients [as having] ‘seropositive arthralgia,’ and we started a study in our institution because we started seeing more of these patients being referred in by the general practitioners,” said Dr. Veale, who is also director of translational research at the Dublin Academic Medical Centre of University College Dublin.
The aim of the study is to biopsy synovial tissue obtained during knee joint arthroscopy (which has been shown in prior studies to provide the same synovial findings as can be obtained through wrist and ankle biopsies) and to assess cellular and molecular profiles and clinical outcomes in these subjects, he said.
Of 36 seropositive arthralgia patients recruited to date, 22 are women, and 19 developed RA by 2010 ACR criteria within 12 months; most of those did so within 2-3 months, he said.
Median swollen joint counts were zero, and tender joint counts were slightly raised (median = 0, interquartile range = 0-4) in the subjects at baseline. Overall, 82% were RF positive, 91% were ACPA positive, and 73% were both RF and ACPA positive.
“The median [C-reactive protein (CRP) level] was 3 [mg/dL] with a range of 2-7, so most of these are normal when they’re coming to see us,” he said.
The level of synovitis seen on knee arthroscopy was a median of 60 on a visual analog scale of 0-100.
“So the level of synovitis that we’re seeing is certainly over a median of 50%,” he added.
Of 22 patients who were followed for at least 1 year – including the 19 who developed RA – none were on therapy at baseline, and none had CRP over 5 mg/dL at baseline. Two of the 19 who later developed RA elected to begin treatment before they developed the disease – one with hydroxychloroquine and one with methotrexate – and treatment was initiated in the remaining 17 RA patients as soon as they met the ACR RA criteria. Currently, 14 are on synthetic disease-modifying antirheumatic drugs (DMARDs), and 5 are on biologic DMARDs. Overall, 13 of the 22 patients followed for 1 year have no disease activity, 5 have low disease activity, and 4 have moderate disease activity, he said.
One question addressed in this study is whether immunostaining predicts arthritis, Dr. Veale noted.
“The short answer is ‘no,’ ” he said, explaining that activated T and B cells are seen in the biopsies of subjects who remain as seropositive arthralgia patients, and also in patients who actually develop RA. “So the immunohistology of these biopsies is not telling us a great deal.”
Immunophenotyping to establish RA risk
Another finding of interest is an increase in the synovial tissue CD38 plasmablasts as detected by RNA sequencing in seropositive arthralgia subjects.
“Their pattern looks more like early RA or established RA,” he noted.
Similarly, the proportion of B cells is already increased in the seropositive arthralgia subjects, compared with healthy subjects, and is similar to that seen in established seropositive and seronegative RA patients.
After looking at “a whole range of immunophenotypes,” Dr. Veale and his colleagues found that several other genes (not just for CD38) are expressed at increased levels in the arthralgia patients.
“The pattern that we’re seeing is that the seropositive arthralgia patients look more like the early rheumatoid and the established rheumatoid patients when we actually analyze their gene signatures using immunophenotyping,” he said.
The patients in this study were all referred by general practitioners, but another study – the PRAIRI study – recruited seropositive arthralgia patients from the community and randomized them to receive a single rituximab infusion or placebo (Ann Rheum Dis. 2019;78:179-85).
“What they showed is that patients who received one dose of rituximab actually developed rheumatoid arthritis at a slower rate and at a later time than the patients who received placebo,” he said.
At 1-year follow-up, there was no difference in the rate of development of RA between the groups; rituximab had merely delayed the onset of RA, he said.
“They do discuss in this paper what the effect would be if you continued treatment in these patients: Would we actually prevent the onset of rheumatoid arthritis in a significant cohort of patients?” he said. “But we don’t know that.”
Could immune checkpoint inhibition reveal RA risk?
Recent findings from work with immune checkpoint therapy in the hematology/oncology arena, however, raise other interesting possibilities with respect to early treatment and prevention of RA.
A number of case reports have documented the development of autoimmune diseases in patients with cancer who have undergone treatment with checkpoint inhibitors.
“Essentially what happens in cancer is that the activated T cells upregulate immune checkpoint molecules. ... and what these molecules do is they make the T cells essentially resistant to attacking the tumor cells,” he explained, noting that the molecules include programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).
Checkpoint inhibitors bind to these molecules and “free up these activated T cells to attack the tumor cells” both through cytokines (interferon release) and direct cell cytotoxicity, he said.
This is relevant for rheumatology patients, because the PD-1 checkpoint molecule is overexpressed in pathogenic T cells in RA and systemic lupus erythematosus.
A closer look at his own RA patients showed that those who were ACPA positive had higher levels of soluble PD-1 than did the ACPA-negative RA patients – a finding that has been replicated in two other cohorts, he noted.
“So we wanted to look at our seropositive arthralgia subjects and see if there is something in their gene signatures on immunophenotyping which actually would give us a clue in terms of this checkpoint inhibitor pathway,” he said. “What we found is that the anti–PD-1 signature is increased in our arthralgia patients, and again, the pattern of expression is more similar to early rheumatoid arthritis and established rheumatoid arthritis, and is significantly different from both healthy controls and patients with osteoarthritis.”
PD-1 expression was also found to be increased on CD4- and CD8-positive T cells taken from the synovial tissues in these patients, he said.
Immunostaining of the T cells showed, interestingly, that the ligand for PD-1 is “almost absent,” he noted.
“So there’s an overexpression of PD-1, but there’s a downregulation of the ligand for PD-1, so that means that the PD-1 pathway is not active in these patients because the PD-1 ... has no ligand to actually bind on to.”
This suggests that “something else may happen that will upregulate the ligand – maybe a second hit,” thereby allowing PD-1 to bind and become active, he said.
“I realize what I’ve been talking about is fairly controversial, but I think it may be possible soon to predict a diagnosis of rheumatoid arthritis before clinical arthritis develops, but not in everybody,” he said, noting that current diagnostic tools are often unreliable.
For example, CRP levels in most of his study subjects remained normal even after converting to meet RA criteria, he explained.
However, “the checkpoint inhibitor story is absolutely fascinating,” he said.
“It’s unmasked an RA phenotype in patients who are receiving these drugs, and we have identified that the PD-1 pathway is altered in the synovial tissue, not just in patients with established rheumatoid arthritis, but also in subjects before they have developed arthritis and they have circulating autoantibodies,” he said.
The CD38 plasmablasts found to be present in the synovial tissue before RA presents clinically may also represent a therapeutic target, he added.
Dr. Veale disclosed financial relationships (research grants, consulting fees, speaker’s bureau, and “other” relationships) with AbbVie, Pfizer, UCB, Roche, and Janssen.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Key clinical point:
Major finding: 19 of 36 patients developed RA within 12 months, and 13 of those had no disease activity with treatment initiated at RA onset.
Study details: A study of 36 seropositive arthralgia patients.
Disclosures: Dr. Veale disclosed financial relationships (research grants, consulting fees, speaker’s bureau, and “other” relationships) with AbbVie, Pfizer, UCB, Roche, and Janssen.