Rheumatology

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.

sworcester@mdedge.com

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.

sworcester@mdedge.com

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.

sworcester@mdedge.com

A safety signal of pulmonary embolism and increased mortality has emerged in a postmarketing trial of tofacitinib (Xeljanz) in patients with rheumatoid arthritis, 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.

A safety signal of pulmonary embolism and increased mortality has emerged in a postmarketing trial of tofacitinib (Xeljanz) in patients with rheumatoid arthritis, 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.

A safety signal of pulmonary embolism and increased mortality has emerged in a postmarketing trial of tofacitinib (Xeljanz) in patients with rheumatoid arthritis, 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 is a significant risk factor for seropositive rheumatoid arthritis, and quitting may delay or even prevent the disease, a study has found.

American Heart Association

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.

American Heart Association

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.

American Heart Association

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.

The gout drug febuxostat (Uloric) poses a significantly higher risk of all-cause and heart-related death than does the popular alternative drug allopurinol, the Food and Drug Administration declared on Feb. 21. The agency is now mandating a black-box warning.

“Health care professionals should reserve Uloric for use only in patients who have failed or do not tolerate allopurinol,” the FDA announced. “Counsel patients about the cardiovascular risk with Uloric,” the agency suggested, and advise them to seek medical attention at once if they have cardiac symptoms such as chest pain, shortness of breath, rapid or irregular heartbeat, or dizziness.

The FDA’s move comes a decade after it approved febuxostat as a gout treatment. As the FDA noted in its announcement, “the number of medicines to treat gout is limited, and there is an unmet need for treatments for this disease.”

Research has suggested that both febuxostat and allopurinol have similar efficacy. Some experts have recommended febuxostat as an alternative for patients who shouldn’t take allopurinol (Semin Arthritis Rheum. 2013 Dec;43[3]:367-75).

However, research has raised concerns about febuxostat’s cardiac risk. In its Feb. 21 statement, the FDA pointed to the findings of a 2010-2017 postmarket clinical trial of 6,190 patients with gout who were treated with febuxostat or allopurinol (N Engl J Med. 2018;378:1200-10).

“In patients treated with Uloric, 15 deaths from heart-related causes were observed for every 1,000 patients treated for a year compared to 11 deaths from heart-related causes per 1,000 patients treated with allopurinol for a year,” the FDA said. “In addition, there were 26 deaths from any cause per 1,000 patients treated for a year with Uloric compared to 22 deaths per 1,000 patients treated for a year with allopurinol.”

The gout drug febuxostat (Uloric) poses a significantly higher risk of all-cause and heart-related death than does the popular alternative drug allopurinol, the Food and Drug Administration declared on Feb. 21. The agency is now mandating a black-box warning.

“Health care professionals should reserve Uloric for use only in patients who have failed or do not tolerate allopurinol,” the FDA announced. “Counsel patients about the cardiovascular risk with Uloric,” the agency suggested, and advise them to seek medical attention at once if they have cardiac symptoms such as chest pain, shortness of breath, rapid or irregular heartbeat, or dizziness.

The FDA’s move comes a decade after it approved febuxostat as a gout treatment. As the FDA noted in its announcement, “the number of medicines to treat gout is limited, and there is an unmet need for treatments for this disease.”

Research has suggested that both febuxostat and allopurinol have similar efficacy. Some experts have recommended febuxostat as an alternative for patients who shouldn’t take allopurinol (Semin Arthritis Rheum. 2013 Dec;43[3]:367-75).

However, research has raised concerns about febuxostat’s cardiac risk. In its Feb. 21 statement, the FDA pointed to the findings of a 2010-2017 postmarket clinical trial of 6,190 patients with gout who were treated with febuxostat or allopurinol (N Engl J Med. 2018;378:1200-10).

“In patients treated with Uloric, 15 deaths from heart-related causes were observed for every 1,000 patients treated for a year compared to 11 deaths from heart-related causes per 1,000 patients treated with allopurinol for a year,” the FDA said. “In addition, there were 26 deaths from any cause per 1,000 patients treated for a year with Uloric compared to 22 deaths per 1,000 patients treated for a year with allopurinol.”

The gout drug febuxostat (Uloric) poses a significantly higher risk of all-cause and heart-related death than does the popular alternative drug allopurinol, the Food and Drug Administration declared on Feb. 21. The agency is now mandating a black-box warning.

“Health care professionals should reserve Uloric for use only in patients who have failed or do not tolerate allopurinol,” the FDA announced. “Counsel patients about the cardiovascular risk with Uloric,” the agency suggested, and advise them to seek medical attention at once if they have cardiac symptoms such as chest pain, shortness of breath, rapid or irregular heartbeat, or dizziness.

The FDA’s move comes a decade after it approved febuxostat as a gout treatment. As the FDA noted in its announcement, “the number of medicines to treat gout is limited, and there is an unmet need for treatments for this disease.”

Research has suggested that both febuxostat and allopurinol have similar efficacy. Some experts have recommended febuxostat as an alternative for patients who shouldn’t take allopurinol (Semin Arthritis Rheum. 2013 Dec;43[3]:367-75).

However, research has raised concerns about febuxostat’s cardiac risk. In its Feb. 21 statement, the FDA pointed to the findings of a 2010-2017 postmarket clinical trial of 6,190 patients with gout who were treated with febuxostat or allopurinol (N Engl J Med. 2018;378:1200-10).

“In patients treated with Uloric, 15 deaths from heart-related causes were observed for every 1,000 patients treated for a year compared to 11 deaths from heart-related causes per 1,000 patients treated with allopurinol for a year,” the FDA said. “In addition, there were 26 deaths from any cause per 1,000 patients treated for a year with Uloric compared to 22 deaths per 1,000 patients treated for a year with allopurinol.”

The American Academy of Dermatology and the National Psoriasis Foundation have jointly released two new guidelines on the management and treatment of psoriasis with a focus on biologics and comorbidities.

Courtesy National Psoriasis Foundation

These guidelines are the first of two papers to be published in the Journal of the American Academy of Dermatology (JAAD), with four more guidelines on psoriasis to be published later this year in JAAD on phototherapy, topical therapy, nonbiologic systemic medications, and treatment of pediatric patients.

The guideline on biologics updates the 2008 AAD guidelines on psoriasis. In an interview, Alan Menter, MD, cochair of the guidelines work group and lead author of the biologics paper, said the guidelines for biologics were needed because of major advances with the availability of new biologics over the last decade. For example, three tumor necrosis factor–alpha (TNF-alpha) inhibitors were available in 2008, but that number has increased to 10 biologics and now includes agents such as those targeting interleukin (IL)-12/IL-23, IL-17 and IL-23.

In addition, the new guidelines from AAD were developed to represent improvements in the management of patients with moderate to severe psoriasis as well as the relationship between psoriasis and related comorbidities.

“Major advances in new biologic drugs [are] now available to patients, plus [there have been] significant advances in our understanding of comorbid conditions,” such as cardiovascular comorbidities, said Dr. Menter, chairman of the division of dermatology, Baylor University Medical Center, and clinical professor of dermatology, University of Texas, both in Dallas.

The working group for each set of guidelines consisted of dermatologists, patient representatives, a cardiologist, and a rheumatologist. The biologic guidelines working group analyzed studies published between January 2008 and December 2018 and issued a series of recommendations based on published evidence for the effectiveness, adverse events, and switching for Food and Drug Administration–approved TNF-alpha inhibitors (etanercept, infliximab, adalimumab, certolizumab, and TNF-alpha biosimilars); IL-12/IL-23 inhibitors (ustekinumab); IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab); and IL-23 inhibitors (guselkumab and tildrakizumab, and risankizumab, which is still under FDA review) for monotherapy or combination therapy in patients with moderate to severe psoriasis.

“Both the comorbidities guidelines and the biologic guidelines will help educate the psoriasis population with input from dermatologists in clinical practices,” Dr. Menter said.

However, both working groups noted there are still significant gaps in research, such as the effects of treatment combinations for new biologics and the lack of biomarkers that would identify which biologics are best suited for individual psoriasis patients.

There is also little known about the complex relationship between psoriasis and its comorbidities, and how psoriasis treatment can potentially prevent future disease. To ensure treatment of psoriasis-related comorbidities, dermatologists should consider psoriasis as a systemic disease with multiple comorbidities and interact with primary care doctors, cardiologists, and other providers involved in the care of the patients, Dr. Menter said.

There were no specific funding sources reported for the guidelines. Several authors reported relationships with industry, including pharmaceutical companies with drugs and products involving psoriasis, during the development of the guidelines. If a potential conflict was noted, the working group member recused himself or herself from discussion and drafting of recommendations, according to the paper. Dr. Menter’s disclosure includes serving as a consultant, speaker, investigator, and adviser, and receiving honoraria, from multiple pharmaceutical companies.

SOURCE: Menter A et al. J Am Acad Dermatol. 2019 Feb 13. doi: 10.1016/j.jaad.2018.11.057. Elmets CA et al. J Am Acad Dermatol. 2019 Feb 13. doi: 10.1016/j.jaad.2018.11.058.

The American Academy of Dermatology and the National Psoriasis Foundation have jointly released two new guidelines on the management and treatment of psoriasis with a focus on biologics and comorbidities.

Courtesy National Psoriasis Foundation

These guidelines are the first of two papers to be published in the Journal of the American Academy of Dermatology (JAAD), with four more guidelines on psoriasis to be published later this year in JAAD on phototherapy, topical therapy, nonbiologic systemic medications, and treatment of pediatric patients.

The guideline on biologics updates the 2008 AAD guidelines on psoriasis. In an interview, Alan Menter, MD, cochair of the guidelines work group and lead author of the biologics paper, said the guidelines for biologics were needed because of major advances with the availability of new biologics over the last decade. For example, three tumor necrosis factor–alpha (TNF-alpha) inhibitors were available in 2008, but that number has increased to 10 biologics and now includes agents such as those targeting interleukin (IL)-12/IL-23, IL-17 and IL-23.

In addition, the new guidelines from AAD were developed to represent improvements in the management of patients with moderate to severe psoriasis as well as the relationship between psoriasis and related comorbidities.

“Major advances in new biologic drugs [are] now available to patients, plus [there have been] significant advances in our understanding of comorbid conditions,” such as cardiovascular comorbidities, said Dr. Menter, chairman of the division of dermatology, Baylor University Medical Center, and clinical professor of dermatology, University of Texas, both in Dallas.

The working group for each set of guidelines consisted of dermatologists, patient representatives, a cardiologist, and a rheumatologist. The biologic guidelines working group analyzed studies published between January 2008 and December 2018 and issued a series of recommendations based on published evidence for the effectiveness, adverse events, and switching for Food and Drug Administration–approved TNF-alpha inhibitors (etanercept, infliximab, adalimumab, certolizumab, and TNF-alpha biosimilars); IL-12/IL-23 inhibitors (ustekinumab); IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab); and IL-23 inhibitors (guselkumab and tildrakizumab, and risankizumab, which is still under FDA review) for monotherapy or combination therapy in patients with moderate to severe psoriasis.

“Both the comorbidities guidelines and the biologic guidelines will help educate the psoriasis population with input from dermatologists in clinical practices,” Dr. Menter said.

However, both working groups noted there are still significant gaps in research, such as the effects of treatment combinations for new biologics and the lack of biomarkers that would identify which biologics are best suited for individual psoriasis patients.

There is also little known about the complex relationship between psoriasis and its comorbidities, and how psoriasis treatment can potentially prevent future disease. To ensure treatment of psoriasis-related comorbidities, dermatologists should consider psoriasis as a systemic disease with multiple comorbidities and interact with primary care doctors, cardiologists, and other providers involved in the care of the patients, Dr. Menter said.

There were no specific funding sources reported for the guidelines. Several authors reported relationships with industry, including pharmaceutical companies with drugs and products involving psoriasis, during the development of the guidelines. If a potential conflict was noted, the working group member recused himself or herself from discussion and drafting of recommendations, according to the paper. Dr. Menter’s disclosure includes serving as a consultant, speaker, investigator, and adviser, and receiving honoraria, from multiple pharmaceutical companies.

SOURCE: Menter A et al. J Am Acad Dermatol. 2019 Feb 13. doi: 10.1016/j.jaad.2018.11.057. Elmets CA et al. J Am Acad Dermatol. 2019 Feb 13. doi: 10.1016/j.jaad.2018.11.058.

The American Academy of Dermatology and the National Psoriasis Foundation have jointly released two new guidelines on the management and treatment of psoriasis with a focus on biologics and comorbidities.

Courtesy National Psoriasis Foundation

These guidelines are the first of two papers to be published in the Journal of the American Academy of Dermatology (JAAD), with four more guidelines on psoriasis to be published later this year in JAAD on phototherapy, topical therapy, nonbiologic systemic medications, and treatment of pediatric patients.

The guideline on biologics updates the 2008 AAD guidelines on psoriasis. In an interview, Alan Menter, MD, cochair of the guidelines work group and lead author of the biologics paper, said the guidelines for biologics were needed because of major advances with the availability of new biologics over the last decade. For example, three tumor necrosis factor–alpha (TNF-alpha) inhibitors were available in 2008, but that number has increased to 10 biologics and now includes agents such as those targeting interleukin (IL)-12/IL-23, IL-17 and IL-23.

In addition, the new guidelines from AAD were developed to represent improvements in the management of patients with moderate to severe psoriasis as well as the relationship between psoriasis and related comorbidities.

“Major advances in new biologic drugs [are] now available to patients, plus [there have been] significant advances in our understanding of comorbid conditions,” such as cardiovascular comorbidities, said Dr. Menter, chairman of the division of dermatology, Baylor University Medical Center, and clinical professor of dermatology, University of Texas, both in Dallas.

The working group for each set of guidelines consisted of dermatologists, patient representatives, a cardiologist, and a rheumatologist. The biologic guidelines working group analyzed studies published between January 2008 and December 2018 and issued a series of recommendations based on published evidence for the effectiveness, adverse events, and switching for Food and Drug Administration–approved TNF-alpha inhibitors (etanercept, infliximab, adalimumab, certolizumab, and TNF-alpha biosimilars); IL-12/IL-23 inhibitors (ustekinumab); IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab); and IL-23 inhibitors (guselkumab and tildrakizumab, and risankizumab, which is still under FDA review) for monotherapy or combination therapy in patients with moderate to severe psoriasis.

“Both the comorbidities guidelines and the biologic guidelines will help educate the psoriasis population with input from dermatologists in clinical practices,” Dr. Menter said.

However, both working groups noted there are still significant gaps in research, such as the effects of treatment combinations for new biologics and the lack of biomarkers that would identify which biologics are best suited for individual psoriasis patients.

There is also little known about the complex relationship between psoriasis and its comorbidities, and how psoriasis treatment can potentially prevent future disease. To ensure treatment of psoriasis-related comorbidities, dermatologists should consider psoriasis as a systemic disease with multiple comorbidities and interact with primary care doctors, cardiologists, and other providers involved in the care of the patients, Dr. Menter said.

There were no specific funding sources reported for the guidelines. Several authors reported relationships with industry, including pharmaceutical companies with drugs and products involving psoriasis, during the development of the guidelines. If a potential conflict was noted, the working group member recused himself or herself from discussion and drafting of recommendations, according to the paper. Dr. Menter’s disclosure includes serving as a consultant, speaker, investigator, and adviser, and receiving honoraria, from multiple pharmaceutical companies.

SOURCE: Menter A et al. J Am Acad Dermatol. 2019 Feb 13. doi: 10.1016/j.jaad.2018.11.057. Elmets CA et al. J Am Acad Dermatol. 2019 Feb 13. doi: 10.1016/j.jaad.2018.11.058.

Increased competition when new tumor necrosis factor inhibitors entered the market did not translate into price reductions during 2009-2016, according to a new analysis of Medicare claims data and wholesale acquisition costs published online in JAMA Internal Medicine.

utah778/Thinkstock

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

Increased competition when new tumor necrosis factor inhibitors entered the market did not translate into price reductions during 2009-2016, according to a new analysis of Medicare claims data and wholesale acquisition costs published online in JAMA Internal Medicine.

utah778/Thinkstock

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

Increased competition when new tumor necrosis factor inhibitors entered the market did not translate into price reductions during 2009-2016, according to a new analysis of Medicare claims data and wholesale acquisition costs published online in JAMA Internal Medicine.

utah778/Thinkstock

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

A total of 42 new drugs have been associated with drug-induced lupus in a study that mined the World Health Organization’s international pharmacovigilance drug monitoring database, leaving the overall number now standing at 118.

Artfoliophoto/Thinkstock

Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.

Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).

In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.

“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.

Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.

The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.

They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.

Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.

“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.

The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.

“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.

“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.

The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.

The authors had no outside funding for the study and reported having no conflicts of interest.

SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.

A total of 42 new drugs have been associated with drug-induced lupus in a study that mined the World Health Organization’s international pharmacovigilance drug monitoring database, leaving the overall number now standing at 118.

Artfoliophoto/Thinkstock

Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.

Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).

In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.

“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.

Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.

The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.

They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.

Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.

“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.

The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.

“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.

“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.

The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.

The authors had no outside funding for the study and reported having no conflicts of interest.

SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.

A total of 42 new drugs have been associated with drug-induced lupus in a study that mined the World Health Organization’s international pharmacovigilance drug monitoring database, leaving the overall number now standing at 118.

Artfoliophoto/Thinkstock

Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.

Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).

In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.

“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.

Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.

The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.

They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.

Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.

“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.

The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.

“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.

“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.

The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.

The authors had no outside funding for the study and reported having no conflicts of interest.

SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.

Does adherence to a Mediterranean diet reduce the risk of Parkinson’s disease? ‘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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Does adherence to a Mediterranean diet reduce the risk of Parkinson’s disease? ‘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

Does adherence to a Mediterranean diet reduce the risk of Parkinson’s disease? ‘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

LAS VEGAS – Women with Ehlers-Danlos syndrome who became pregnant were more likely to experience antepartum hemorrhage, placenta previa, cervical incompetence, and preterm birth, according to a retrospective cohort study of national birth data. Long hospital stays also were more likely among these women.

Kari Oakes/MDedge News

Infants born to women with Ehlers-Danlos syndrome (EDS) were significantly more likely to have intrauterine growth retardation (IUGR) as well, an unexpected and as-yet unexplained finding, said the study’s first author, Laura Nicholls-Dempsey, MD, speaking at a poster session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Complications were infrequent overall, with a very low rate of intrauterine demise and no maternal mortality seen in the 910 women with EDS who were studied, said Dr. Nicholls-Dempsey, an ob.gyn. resident at McGill University, Montreal.

In counseling women with EDS, Dr. Nicholls-Dempsey said that she would advise them that “these are the types of things we’re going to watch out for, and we’ll see how the pregnancy goes. But we have to be careful about these: preterm birth, antepartum bleeding, placenta previa. We’ll watch the growth of the baby; we just have to be more careful about these specific things.”

Compared with women without EDS, those with the inherited connective tissue disorder had adjusted odds ratios (AORs) of 3.2 for cervical incompetence (95% confidence interval, 2.0-5.1) and 2.2 for placenta previa (95% CI, 1.3-3.9; P less than .01 for both). Absolute rates for these complications were 0.8% and 0.7% for women without EDS and 2.1% and 1.4% for women with EDS, respectively.

koakes@mdedge.com

SOURCE: Nicholls-Dempsey L et al. Am J Obstet Gynecol. 2019 Jan;220(1):S381-382. Abstract 574

LAS VEGAS – Women with Ehlers-Danlos syndrome who became pregnant were more likely to experience antepartum hemorrhage, placenta previa, cervical incompetence, and preterm birth, according to a retrospective cohort study of national birth data. Long hospital stays also were more likely among these women.

Kari Oakes/MDedge News

Infants born to women with Ehlers-Danlos syndrome (EDS) were significantly more likely to have intrauterine growth retardation (IUGR) as well, an unexpected and as-yet unexplained finding, said the study’s first author, Laura Nicholls-Dempsey, MD, speaking at a poster session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Complications were infrequent overall, with a very low rate of intrauterine demise and no maternal mortality seen in the 910 women with EDS who were studied, said Dr. Nicholls-Dempsey, an ob.gyn. resident at McGill University, Montreal.

In counseling women with EDS, Dr. Nicholls-Dempsey said that she would advise them that “these are the types of things we’re going to watch out for, and we’ll see how the pregnancy goes. But we have to be careful about these: preterm birth, antepartum bleeding, placenta previa. We’ll watch the growth of the baby; we just have to be more careful about these specific things.”

Compared with women without EDS, those with the inherited connective tissue disorder had adjusted odds ratios (AORs) of 3.2 for cervical incompetence (95% confidence interval, 2.0-5.1) and 2.2 for placenta previa (95% CI, 1.3-3.9; P less than .01 for both). Absolute rates for these complications were 0.8% and 0.7% for women without EDS and 2.1% and 1.4% for women with EDS, respectively.

koakes@mdedge.com

SOURCE: Nicholls-Dempsey L et al. Am J Obstet Gynecol. 2019 Jan;220(1):S381-382. Abstract 574

LAS VEGAS – Women with Ehlers-Danlos syndrome who became pregnant were more likely to experience antepartum hemorrhage, placenta previa, cervical incompetence, and preterm birth, according to a retrospective cohort study of national birth data. Long hospital stays also were more likely among these women.

Kari Oakes/MDedge News

Infants born to women with Ehlers-Danlos syndrome (EDS) were significantly more likely to have intrauterine growth retardation (IUGR) as well, an unexpected and as-yet unexplained finding, said the study’s first author, Laura Nicholls-Dempsey, MD, speaking at a poster session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Complications were infrequent overall, with a very low rate of intrauterine demise and no maternal mortality seen in the 910 women with EDS who were studied, said Dr. Nicholls-Dempsey, an ob.gyn. resident at McGill University, Montreal.

In counseling women with EDS, Dr. Nicholls-Dempsey said that she would advise them that “these are the types of things we’re going to watch out for, and we’ll see how the pregnancy goes. But we have to be careful about these: preterm birth, antepartum bleeding, placenta previa. We’ll watch the growth of the baby; we just have to be more careful about these specific things.”

Compared with women without EDS, those with the inherited connective tissue disorder had adjusted odds ratios (AORs) of 3.2 for cervical incompetence (95% confidence interval, 2.0-5.1) and 2.2 for placenta previa (95% CI, 1.3-3.9; P less than .01 for both). Absolute rates for these complications were 0.8% and 0.7% for women without EDS and 2.1% and 1.4% for women with EDS, respectively.

koakes@mdedge.com

SOURCE: Nicholls-Dempsey L et al. Am J Obstet Gynecol. 2019 Jan;220(1):S381-382. Abstract 574

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.

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.