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Methotrexate for RA: A 'fascinating drug’
SNOWMASS, COLO. – “When I started working with methotrexate in 1982, I never would have predicted that methotrexate would become the standard of care in treating rheumatoid arthritis. There’s just no way,” Michael E. Weinblatt, MD, recalled at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Even now, 35 years later, we continue to learn more about this fascinating drug,” added Dr. Weinblatt, professor of medicine at Harvard Medical School, Boston.
He highlighted recent developments in this ongoing story and presented some tricks of the trade gained in 35 years of up-close experience with the drug.
Enhancing effectiveness of biologics
One of the hottest topics in methotrexate research is the drug’s ability to enhance the effectiveness of many, but not all, biologic agents. All of the anti–tumor necrosis factor (anti-TNF) biologics as well as rituximab (Rituxan) are demonstrably more effective when used in combination with methotrexate. Dr. Weinblatt considers the widespread underutilization of this combination strategy scandalous.
“This is an incredibly important point: All of you use biologics and all of you use methotrexate, but I’ve been depressed by the fact that up to 30%-40% of patients – no matter which data set you look at – are on monotherapy biological therapy,” he said.
He cited data from the ongoing BRASS Registry (Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Registry) to underscore his point that good things happen when biologics and methotrexate are used together. Of 1,395 BRASS Registry participants prospectively followed since 2003, the proportion on biologic therapy has climbed steadily from 41% at the outset to 68% in 2016. Remarkably, 82% of patients on biologic therapy remain on their first biologic agent. Fewer than 4% have switched biologics more than twice. That’s very unlike the experiences reported elsewhere.
“I think one of the reasons we have such positive data is that we have a high percentage of patients staying on their background methotrexate,” said Dr. Weinblatt, codirector of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston.
He noted that Dutch investigators reported at the 2016 annual meeting of the American College of Rheumatology that among 1,230 consecutive rheumatoid arthritis patients started on etanercept (Enbrel) or adalimumab (Humira), 28% in the etanercept group were on concomitant methotrexate, as were 64% of those who started on adalimumab. The patients spent a median of 1.3-1.6 years and a maximum of 9.2-9.3 years on their biologic agent. Patients on adalimumab monotherapy were 2.61-fold more likely to drop out than were those on dual therapy with methotrexate. Patients on etanercept monotherapy were 1.2-fold more likely to drop out, a difference that didn’t achieve statistical significance.
Although the investigators did not study the mechanism of prolonged on-treatment survival, they speculated that it probably involved methotrexate’s documented ability to prevent formation of anti-adalimumab antibodies. In contrast, patients on etanercept don’t develop blocking antibodies, Dr. Weinblatt observed.
The randomized, double-blind CONCERTO trial conducted in 395 methotrexate- and biologic-naive RA patients demonstrated that methotrexate reduces the immunogenicity of adalimumab in dose-dependent fashion. Participants were randomized to open-label adalimumab at 40 mg every 2 weeks plus weekly double-blind methotrexate at 2.5, 5, 10, or 20 mg. Clinical outcomes at 26 weeks as reflected in 28-joint count disease activity score and the Clinical Disease Activity Index were significantly better in patients on 10 or 20 mg/week of methotrexate than in those on 2.5 or 5 mg/week. Serum adalimumab levels were higher in patients on the two higher doses of methotrexate as well (Ann Rheum Dis. 2015 Jun;74[6]:1037-44).
“It ends up that if you don’t use methotrexate or you use a very low dose you increase the risk of developing antibodies against adalimumab and decrease the efficacy of the drug. So in clinical practice, if you’re going to be working with dose titration of methotrexate and your patient is on adalimumab, there’s a threshold below which you probably shouldn’t go. In this study, doses of 10 mg/week or more induced a greater clinical response,” he said.
With infliximab (Remicade), based upon 20-year-old studies, the threshold is 7.5 mg of methotrexate per week.
“With etanercept, we don’t know what the threshold is. You don’t develop blocking anti-drug antibodies with etanercept, but we do know that methotrexate enhances the efficacy of etanercept, and it doesn’t do it by changing the biologic’s pharmacokinetics and there’s no increase in methotrexate blood levels,” the rheumatologist continued.
Unlike the anti-TNF biologics and rituximab, the efficacy of the Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib is not enhanced when the drugs are used in combination with methotrexate, studies indicate.
The efficacy of certolizumab pegol (Cimzia) wasn’t affected by methotrexate dose category in a prespecified pooled subgroup analysis of the phase III RAPID 1 and RAPID 2 clinical trials. In the 1,273 certolizumab-treated patients, the week-24 treatment response was similar regardless of whether patients were on methotrexate at 10 mg/week or less, 10-15 mg/week, or more than 15 mg/week. The investigators concluded that to minimize treatment-emergent adverse events, physicians can tailor background methotrexate dosing based upon individual patient tolerance without affecting certolizumab’s efficacy (Arthritis Care Res [Hoboken]. 2016 Mar;68[3]:299-307).
An important aspect of this analysis was that among the 325 subjects randomized to placebo rather than certolizumab, the treatment response at week 24 was significantly better in those on more than 15 mg/week of methotrexate than with lower doses of the drug.
“Most patients on methotrexate need more than 15 mg/week. So it astonishes me that such a high percentage of patients enrolled in clinical trials around the world are on, like, 14 mg/week. I mean, most patients need somewhere between 15 and 25 mg/week for a response, although over time you might be able to decrease that dose,” Dr. Weinblatt said.
Side effects of methotrexate
“The biggest issue with methotrexate is the tolerability problem, since serious adverse events are incredibly rare with this molecule,” he said.
Hepatotoxicity is a concern, but Dr. Weinblatt emphasized that elevated liver function tests do not equal cirrhosis.
“Historically, during the first 6 months on methotrexate 20%-25% of patients increase their transaminases in every clinical trial where that’s been looked at. Over time, the liver compensates for the drug. But 5%-6% of patients experience repeated moderate elevations more than 1.5 times the upper limit of normal,” he said.
Key risk factors for methotrexate-related hepatotoxicity were identified in a national observational cohort study of 659 military veterans over age 65 when they started methotrexate for rheumatic diseases. The investigators found a 6% incidence of moderately elevated liver enzymes during a mean follow-up period of 7 months. Obesity was associated with a 1.9-fold increased risk, a serum total cholesterol greater than 240 mg/dL conferred a 5.8-fold elevated risk, and abnormal liver function tests at baseline were associated with a 3.2-fold increased risk (Arthritis Care Res [Hoboken]. 2014 Aug;66[8]:1159-66).
“No surprise: It’s patients who weigh more who are at increased risk for methotrexate-related transaminase increases. I actually think the biggest factor with regard to methotrexate liver disease is the patient’s [body mass index]. Patients in North America aren’t getting any slimmer, so you need to look at this with your patients. If you have a morbidly obese patient on methotrexate whose transaminases suddenly start going up, that’s the patient who’s at greatest risk for methotrexate hepatotoxicity,” he cautioned.
The 3.2-fold increased risk of repeated elevated transaminases associated with abnormal baseline liver function tests in the Veterans Affairs study should be a red flag for rheumatologists.
“I personally think patients shouldn’t start on methotrexate if they have elevated transaminases. They ought to be normal at the start. There are too many other good options now to treat our patients,” Dr. Weinblatt said.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
SNOWMASS, COLO. – “When I started working with methotrexate in 1982, I never would have predicted that methotrexate would become the standard of care in treating rheumatoid arthritis. There’s just no way,” Michael E. Weinblatt, MD, recalled at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Even now, 35 years later, we continue to learn more about this fascinating drug,” added Dr. Weinblatt, professor of medicine at Harvard Medical School, Boston.
He highlighted recent developments in this ongoing story and presented some tricks of the trade gained in 35 years of up-close experience with the drug.
Enhancing effectiveness of biologics
One of the hottest topics in methotrexate research is the drug’s ability to enhance the effectiveness of many, but not all, biologic agents. All of the anti–tumor necrosis factor (anti-TNF) biologics as well as rituximab (Rituxan) are demonstrably more effective when used in combination with methotrexate. Dr. Weinblatt considers the widespread underutilization of this combination strategy scandalous.
“This is an incredibly important point: All of you use biologics and all of you use methotrexate, but I’ve been depressed by the fact that up to 30%-40% of patients – no matter which data set you look at – are on monotherapy biological therapy,” he said.
He cited data from the ongoing BRASS Registry (Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Registry) to underscore his point that good things happen when biologics and methotrexate are used together. Of 1,395 BRASS Registry participants prospectively followed since 2003, the proportion on biologic therapy has climbed steadily from 41% at the outset to 68% in 2016. Remarkably, 82% of patients on biologic therapy remain on their first biologic agent. Fewer than 4% have switched biologics more than twice. That’s very unlike the experiences reported elsewhere.
“I think one of the reasons we have such positive data is that we have a high percentage of patients staying on their background methotrexate,” said Dr. Weinblatt, codirector of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston.
He noted that Dutch investigators reported at the 2016 annual meeting of the American College of Rheumatology that among 1,230 consecutive rheumatoid arthritis patients started on etanercept (Enbrel) or adalimumab (Humira), 28% in the etanercept group were on concomitant methotrexate, as were 64% of those who started on adalimumab. The patients spent a median of 1.3-1.6 years and a maximum of 9.2-9.3 years on their biologic agent. Patients on adalimumab monotherapy were 2.61-fold more likely to drop out than were those on dual therapy with methotrexate. Patients on etanercept monotherapy were 1.2-fold more likely to drop out, a difference that didn’t achieve statistical significance.
Although the investigators did not study the mechanism of prolonged on-treatment survival, they speculated that it probably involved methotrexate’s documented ability to prevent formation of anti-adalimumab antibodies. In contrast, patients on etanercept don’t develop blocking antibodies, Dr. Weinblatt observed.
The randomized, double-blind CONCERTO trial conducted in 395 methotrexate- and biologic-naive RA patients demonstrated that methotrexate reduces the immunogenicity of adalimumab in dose-dependent fashion. Participants were randomized to open-label adalimumab at 40 mg every 2 weeks plus weekly double-blind methotrexate at 2.5, 5, 10, or 20 mg. Clinical outcomes at 26 weeks as reflected in 28-joint count disease activity score and the Clinical Disease Activity Index were significantly better in patients on 10 or 20 mg/week of methotrexate than in those on 2.5 or 5 mg/week. Serum adalimumab levels were higher in patients on the two higher doses of methotrexate as well (Ann Rheum Dis. 2015 Jun;74[6]:1037-44).
“It ends up that if you don’t use methotrexate or you use a very low dose you increase the risk of developing antibodies against adalimumab and decrease the efficacy of the drug. So in clinical practice, if you’re going to be working with dose titration of methotrexate and your patient is on adalimumab, there’s a threshold below which you probably shouldn’t go. In this study, doses of 10 mg/week or more induced a greater clinical response,” he said.
With infliximab (Remicade), based upon 20-year-old studies, the threshold is 7.5 mg of methotrexate per week.
“With etanercept, we don’t know what the threshold is. You don’t develop blocking anti-drug antibodies with etanercept, but we do know that methotrexate enhances the efficacy of etanercept, and it doesn’t do it by changing the biologic’s pharmacokinetics and there’s no increase in methotrexate blood levels,” the rheumatologist continued.
Unlike the anti-TNF biologics and rituximab, the efficacy of the Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib is not enhanced when the drugs are used in combination with methotrexate, studies indicate.
The efficacy of certolizumab pegol (Cimzia) wasn’t affected by methotrexate dose category in a prespecified pooled subgroup analysis of the phase III RAPID 1 and RAPID 2 clinical trials. In the 1,273 certolizumab-treated patients, the week-24 treatment response was similar regardless of whether patients were on methotrexate at 10 mg/week or less, 10-15 mg/week, or more than 15 mg/week. The investigators concluded that to minimize treatment-emergent adverse events, physicians can tailor background methotrexate dosing based upon individual patient tolerance without affecting certolizumab’s efficacy (Arthritis Care Res [Hoboken]. 2016 Mar;68[3]:299-307).
An important aspect of this analysis was that among the 325 subjects randomized to placebo rather than certolizumab, the treatment response at week 24 was significantly better in those on more than 15 mg/week of methotrexate than with lower doses of the drug.
“Most patients on methotrexate need more than 15 mg/week. So it astonishes me that such a high percentage of patients enrolled in clinical trials around the world are on, like, 14 mg/week. I mean, most patients need somewhere between 15 and 25 mg/week for a response, although over time you might be able to decrease that dose,” Dr. Weinblatt said.
Side effects of methotrexate
“The biggest issue with methotrexate is the tolerability problem, since serious adverse events are incredibly rare with this molecule,” he said.
Hepatotoxicity is a concern, but Dr. Weinblatt emphasized that elevated liver function tests do not equal cirrhosis.
“Historically, during the first 6 months on methotrexate 20%-25% of patients increase their transaminases in every clinical trial where that’s been looked at. Over time, the liver compensates for the drug. But 5%-6% of patients experience repeated moderate elevations more than 1.5 times the upper limit of normal,” he said.
Key risk factors for methotrexate-related hepatotoxicity were identified in a national observational cohort study of 659 military veterans over age 65 when they started methotrexate for rheumatic diseases. The investigators found a 6% incidence of moderately elevated liver enzymes during a mean follow-up period of 7 months. Obesity was associated with a 1.9-fold increased risk, a serum total cholesterol greater than 240 mg/dL conferred a 5.8-fold elevated risk, and abnormal liver function tests at baseline were associated with a 3.2-fold increased risk (Arthritis Care Res [Hoboken]. 2014 Aug;66[8]:1159-66).
“No surprise: It’s patients who weigh more who are at increased risk for methotrexate-related transaminase increases. I actually think the biggest factor with regard to methotrexate liver disease is the patient’s [body mass index]. Patients in North America aren’t getting any slimmer, so you need to look at this with your patients. If you have a morbidly obese patient on methotrexate whose transaminases suddenly start going up, that’s the patient who’s at greatest risk for methotrexate hepatotoxicity,” he cautioned.
The 3.2-fold increased risk of repeated elevated transaminases associated with abnormal baseline liver function tests in the Veterans Affairs study should be a red flag for rheumatologists.
“I personally think patients shouldn’t start on methotrexate if they have elevated transaminases. They ought to be normal at the start. There are too many other good options now to treat our patients,” Dr. Weinblatt said.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
SNOWMASS, COLO. – “When I started working with methotrexate in 1982, I never would have predicted that methotrexate would become the standard of care in treating rheumatoid arthritis. There’s just no way,” Michael E. Weinblatt, MD, recalled at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Even now, 35 years later, we continue to learn more about this fascinating drug,” added Dr. Weinblatt, professor of medicine at Harvard Medical School, Boston.
He highlighted recent developments in this ongoing story and presented some tricks of the trade gained in 35 years of up-close experience with the drug.
Enhancing effectiveness of biologics
One of the hottest topics in methotrexate research is the drug’s ability to enhance the effectiveness of many, but not all, biologic agents. All of the anti–tumor necrosis factor (anti-TNF) biologics as well as rituximab (Rituxan) are demonstrably more effective when used in combination with methotrexate. Dr. Weinblatt considers the widespread underutilization of this combination strategy scandalous.
“This is an incredibly important point: All of you use biologics and all of you use methotrexate, but I’ve been depressed by the fact that up to 30%-40% of patients – no matter which data set you look at – are on monotherapy biological therapy,” he said.
He cited data from the ongoing BRASS Registry (Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Registry) to underscore his point that good things happen when biologics and methotrexate are used together. Of 1,395 BRASS Registry participants prospectively followed since 2003, the proportion on biologic therapy has climbed steadily from 41% at the outset to 68% in 2016. Remarkably, 82% of patients on biologic therapy remain on their first biologic agent. Fewer than 4% have switched biologics more than twice. That’s very unlike the experiences reported elsewhere.
“I think one of the reasons we have such positive data is that we have a high percentage of patients staying on their background methotrexate,” said Dr. Weinblatt, codirector of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston.
He noted that Dutch investigators reported at the 2016 annual meeting of the American College of Rheumatology that among 1,230 consecutive rheumatoid arthritis patients started on etanercept (Enbrel) or adalimumab (Humira), 28% in the etanercept group were on concomitant methotrexate, as were 64% of those who started on adalimumab. The patients spent a median of 1.3-1.6 years and a maximum of 9.2-9.3 years on their biologic agent. Patients on adalimumab monotherapy were 2.61-fold more likely to drop out than were those on dual therapy with methotrexate. Patients on etanercept monotherapy were 1.2-fold more likely to drop out, a difference that didn’t achieve statistical significance.
Although the investigators did not study the mechanism of prolonged on-treatment survival, they speculated that it probably involved methotrexate’s documented ability to prevent formation of anti-adalimumab antibodies. In contrast, patients on etanercept don’t develop blocking antibodies, Dr. Weinblatt observed.
The randomized, double-blind CONCERTO trial conducted in 395 methotrexate- and biologic-naive RA patients demonstrated that methotrexate reduces the immunogenicity of adalimumab in dose-dependent fashion. Participants were randomized to open-label adalimumab at 40 mg every 2 weeks plus weekly double-blind methotrexate at 2.5, 5, 10, or 20 mg. Clinical outcomes at 26 weeks as reflected in 28-joint count disease activity score and the Clinical Disease Activity Index were significantly better in patients on 10 or 20 mg/week of methotrexate than in those on 2.5 or 5 mg/week. Serum adalimumab levels were higher in patients on the two higher doses of methotrexate as well (Ann Rheum Dis. 2015 Jun;74[6]:1037-44).
“It ends up that if you don’t use methotrexate or you use a very low dose you increase the risk of developing antibodies against adalimumab and decrease the efficacy of the drug. So in clinical practice, if you’re going to be working with dose titration of methotrexate and your patient is on adalimumab, there’s a threshold below which you probably shouldn’t go. In this study, doses of 10 mg/week or more induced a greater clinical response,” he said.
With infliximab (Remicade), based upon 20-year-old studies, the threshold is 7.5 mg of methotrexate per week.
“With etanercept, we don’t know what the threshold is. You don’t develop blocking anti-drug antibodies with etanercept, but we do know that methotrexate enhances the efficacy of etanercept, and it doesn’t do it by changing the biologic’s pharmacokinetics and there’s no increase in methotrexate blood levels,” the rheumatologist continued.
Unlike the anti-TNF biologics and rituximab, the efficacy of the Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib is not enhanced when the drugs are used in combination with methotrexate, studies indicate.
The efficacy of certolizumab pegol (Cimzia) wasn’t affected by methotrexate dose category in a prespecified pooled subgroup analysis of the phase III RAPID 1 and RAPID 2 clinical trials. In the 1,273 certolizumab-treated patients, the week-24 treatment response was similar regardless of whether patients were on methotrexate at 10 mg/week or less, 10-15 mg/week, or more than 15 mg/week. The investigators concluded that to minimize treatment-emergent adverse events, physicians can tailor background methotrexate dosing based upon individual patient tolerance without affecting certolizumab’s efficacy (Arthritis Care Res [Hoboken]. 2016 Mar;68[3]:299-307).
An important aspect of this analysis was that among the 325 subjects randomized to placebo rather than certolizumab, the treatment response at week 24 was significantly better in those on more than 15 mg/week of methotrexate than with lower doses of the drug.
“Most patients on methotrexate need more than 15 mg/week. So it astonishes me that such a high percentage of patients enrolled in clinical trials around the world are on, like, 14 mg/week. I mean, most patients need somewhere between 15 and 25 mg/week for a response, although over time you might be able to decrease that dose,” Dr. Weinblatt said.
Side effects of methotrexate
“The biggest issue with methotrexate is the tolerability problem, since serious adverse events are incredibly rare with this molecule,” he said.
Hepatotoxicity is a concern, but Dr. Weinblatt emphasized that elevated liver function tests do not equal cirrhosis.
“Historically, during the first 6 months on methotrexate 20%-25% of patients increase their transaminases in every clinical trial where that’s been looked at. Over time, the liver compensates for the drug. But 5%-6% of patients experience repeated moderate elevations more than 1.5 times the upper limit of normal,” he said.
Key risk factors for methotrexate-related hepatotoxicity were identified in a national observational cohort study of 659 military veterans over age 65 when they started methotrexate for rheumatic diseases. The investigators found a 6% incidence of moderately elevated liver enzymes during a mean follow-up period of 7 months. Obesity was associated with a 1.9-fold increased risk, a serum total cholesterol greater than 240 mg/dL conferred a 5.8-fold elevated risk, and abnormal liver function tests at baseline were associated with a 3.2-fold increased risk (Arthritis Care Res [Hoboken]. 2014 Aug;66[8]:1159-66).
“No surprise: It’s patients who weigh more who are at increased risk for methotrexate-related transaminase increases. I actually think the biggest factor with regard to methotrexate liver disease is the patient’s [body mass index]. Patients in North America aren’t getting any slimmer, so you need to look at this with your patients. If you have a morbidly obese patient on methotrexate whose transaminases suddenly start going up, that’s the patient who’s at greatest risk for methotrexate hepatotoxicity,” he cautioned.
The 3.2-fold increased risk of repeated elevated transaminases associated with abnormal baseline liver function tests in the Veterans Affairs study should be a red flag for rheumatologists.
“I personally think patients shouldn’t start on methotrexate if they have elevated transaminases. They ought to be normal at the start. There are too many other good options now to treat our patients,” Dr. Weinblatt said.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
When to screen asymptomatic diabetics for CAD
SNOWMASS, COLO. – The use of coronary artery calcium screening in the subset of asymptomatic diabetes patients at higher clinical risk of CAD appears to offer a practical strategy for identifying a subgroup in whom costlier stress cardiac imaging may be justified, Marcelo F. di Carli, MD, said at the Annual Cardiovascular Conference at Snowmass.
The ultimate goal is to reliably identify those patients who have asymptomatic diabetes with significant CAD warranting revascularization or maximal medical therapy for primary cardiovascular prevention.
“Coronary artery calcium is a simple test that’s accessible and inexpensive and can give us a quick read on the extent of atherosclerosis in the coronary arteries,” said Dr. di Carli, professor of radiology and medicine at Harvard University in Boston. “There’s good data that in diabetic patients there’s a gradation of risk across the spectrum of calcium scores. Risk increases exponentially from a coronary artery calcium score of 0 to more than 400. The calcium score can also provide a snapshot of which patients are more likely to have flow-limiting coronary disease.”
Atherosclerotic cardiovascular disease is the biggest contributor to the direct and indirect costs of diabetes, and diabetes experts are eager to avoid jacking up those costs further by routinely ordering stress nuclear imaging, stress echocardiography, cardiac magnetic resonance, and other expensive noninvasive imaging methods unless they can be shown to lead to improved outcomes. There is general agreement on the value of noninvasive imaging in diabetic patients with CAD symptoms. However, the routine use of such testing in asymptomatic diabetic patients has been controversial.
Indeed, according to the 2017 American Diabetes Association Standards of Medical Care in Diabetes: “In asymptomatic patients, routine screening for coronary artery disease is not recommended as it does not improve outcomes as long as atherosclerotic cardiovascular disease risk factors are treated (Diabetes Care. 2017 Jan;40[Suppl. 1]:S75-87). That’s a Level A recommendation.
But Dr. di Carli is among many cardiologists who believe this statement paints with too broad a brush. He considers it an overgeneralization that’s based on the negative results of two randomized trials of routine screening in asymptomatic diabetics: DIAD, which utilized stress single-photon emission CT (SPECT) imaging (JAMA. 2009 Apr 15;301[15]:1547-55), and FACTOR-64, which relied upon coronary CT angiography (JAMA. 2014 Dec 3;312[21]: 2234-43). Both studies found relatively low yields of severe CAD and showed no survival benefit for screening. And of course, these are also costly and inconvenient tests.
The problem in generalizing from DIAD and FACTOR-64 to the overall population of asymptomatic diabetic patients is that both studies were conducted in asymptomatic patients at the lower end of the cardiovascular risk spectrum. They were young, with an average age of 60 years. They had a history of diabetes of less than 10 years, and their diabetes was reasonably well controlled. They had normal ECGs and preserved renal function. Peripheral artery disease (PAD) was present in only 9% of the DIAD population and no one in FACTOR-64. So this would not be expected to be a high-risk/high-yield population, according to Dr. di Carli, executive director of the cardiovascular imaging program at Brigham and Women’s Hospital, Boston.
An earlier study from the Mayo Clinic identified the clinical factors that can potentially be used to identify a higher-risk cohort of asymptomatic diabetic patients in whom high-tech noninvasive testing for significant CAD may be justified, he continued. This was a nonrandomized study of 1,427 asymptomatic diabetic patients without known CAD who underwent SPECT imaging. Compared with the study populations in DIAD and FACTOR-64, the Mayo Clinic patients had a longer duration of diabetes and substantially higher rates of poor diabetes control, renal dysfunction, hypertension, and dyslipidemia. One-third of them had PAD.
Fifty-eight percent of the 1,427 patients in the Mayo cohort proved to have an abnormal SPECT imaging scan, and 18% had a high-risk scan. In a multivariate analysis, the investigators identified several factors independently associated with a high-risk scan. Q waves were present on the ECGs of 9% of the asymptomatic diabetes patients, and 43% of that subgroup had a high-risk scan. Thirty-eight percent of patients had other ECG abnormalities, and 28% of them had a high-risk scan. Age greater than 65 was associated with an increased likelihood of a high-risk SPECT result. And 28% of patients with PAD had a high-risk scan.
On the other hand, the likelihood of a high-risk scan in the 69% of subjects without PAD was 14% (J Am Coll Cardiol. 2005 Jan 4;45[1]:43-9).
The 2017 ADA guidelines acknowledge this and similar evidence by providing as a relatively weak Level E recommendation: “Consider screening for CAD in the presence of any of the following: atypical cardiac symptoms (e.g., unexplained dyspnea, chest discomfort); signs of symptoms of associated vascular disease including carotid bruits, transient ischemic attack, stroke, claudication, or PAD; or electrogram abnormalities (e.g., Q waves).”
Dr. di Carli would add to that list age older than 65, diabetes duration of greater than 10 years, poor diabetes control, and a high burden of standard cardiovascular risk factors. And he proposed the coronary artery calcium (CAC) score as a sensible gateway to selective use of further screening tests, citing as support a report from the National Institutes of Health–sponsored Multi-Ethnic Study of Atherosclerosis (MESA).
The MESA investigators assessed CAC in 6,603 persons aged 45-84 free of known CAD at baseline, including 881 with diabetes. Participants were subsequently followed prospectively for an average of 6.4 years. Compared with diabetes patients who had a baseline CAC score of 0, those with a score of 1-99 were at a risk factor– and ethnicity-adjusted 2.9-fold increased risk for developing coronary heart disease during the follow-up period. The CHD risk climbed stepwise with an increasing CAC score such that subjects with a score of 400 or higher were at 9.5-fold increased risk (Diabetes Care. 2011 Oct;34[10]L2285-90).
Using CAC measurement in this way as a screening tool in asymptomatic diabetes patients with clinical factors placing them at higher risk of significant CAD is consistent with appropriate use criteria for the detection and risk assessment of stable ischemic heart disease. The criteria were provided in a 2014 joint report by the American College of Cardiology, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons.
The report rates CAC testing as “May Be Appropriate” for asymptomatic patients of intermediate or high global risk. As such, CAC “can be an option for further evaluation of potential SIHD [stable ischemic heart disease] in an individual patient when deemed reasonable by the patient’s physician,” according to the appropriate use criteria guidance, which was created with the express purpose of developing standards to avoid overuse of costly cardiovascular testing (J Am Coll Cardiol. 2014 Feb 4;63[4]:380-406).
Dr. di Carli reported having no financial conflicts.
SNOWMASS, COLO. – The use of coronary artery calcium screening in the subset of asymptomatic diabetes patients at higher clinical risk of CAD appears to offer a practical strategy for identifying a subgroup in whom costlier stress cardiac imaging may be justified, Marcelo F. di Carli, MD, said at the Annual Cardiovascular Conference at Snowmass.
The ultimate goal is to reliably identify those patients who have asymptomatic diabetes with significant CAD warranting revascularization or maximal medical therapy for primary cardiovascular prevention.
“Coronary artery calcium is a simple test that’s accessible and inexpensive and can give us a quick read on the extent of atherosclerosis in the coronary arteries,” said Dr. di Carli, professor of radiology and medicine at Harvard University in Boston. “There’s good data that in diabetic patients there’s a gradation of risk across the spectrum of calcium scores. Risk increases exponentially from a coronary artery calcium score of 0 to more than 400. The calcium score can also provide a snapshot of which patients are more likely to have flow-limiting coronary disease.”
Atherosclerotic cardiovascular disease is the biggest contributor to the direct and indirect costs of diabetes, and diabetes experts are eager to avoid jacking up those costs further by routinely ordering stress nuclear imaging, stress echocardiography, cardiac magnetic resonance, and other expensive noninvasive imaging methods unless they can be shown to lead to improved outcomes. There is general agreement on the value of noninvasive imaging in diabetic patients with CAD symptoms. However, the routine use of such testing in asymptomatic diabetic patients has been controversial.
Indeed, according to the 2017 American Diabetes Association Standards of Medical Care in Diabetes: “In asymptomatic patients, routine screening for coronary artery disease is not recommended as it does not improve outcomes as long as atherosclerotic cardiovascular disease risk factors are treated (Diabetes Care. 2017 Jan;40[Suppl. 1]:S75-87). That’s a Level A recommendation.
But Dr. di Carli is among many cardiologists who believe this statement paints with too broad a brush. He considers it an overgeneralization that’s based on the negative results of two randomized trials of routine screening in asymptomatic diabetics: DIAD, which utilized stress single-photon emission CT (SPECT) imaging (JAMA. 2009 Apr 15;301[15]:1547-55), and FACTOR-64, which relied upon coronary CT angiography (JAMA. 2014 Dec 3;312[21]: 2234-43). Both studies found relatively low yields of severe CAD and showed no survival benefit for screening. And of course, these are also costly and inconvenient tests.
The problem in generalizing from DIAD and FACTOR-64 to the overall population of asymptomatic diabetic patients is that both studies were conducted in asymptomatic patients at the lower end of the cardiovascular risk spectrum. They were young, with an average age of 60 years. They had a history of diabetes of less than 10 years, and their diabetes was reasonably well controlled. They had normal ECGs and preserved renal function. Peripheral artery disease (PAD) was present in only 9% of the DIAD population and no one in FACTOR-64. So this would not be expected to be a high-risk/high-yield population, according to Dr. di Carli, executive director of the cardiovascular imaging program at Brigham and Women’s Hospital, Boston.
An earlier study from the Mayo Clinic identified the clinical factors that can potentially be used to identify a higher-risk cohort of asymptomatic diabetic patients in whom high-tech noninvasive testing for significant CAD may be justified, he continued. This was a nonrandomized study of 1,427 asymptomatic diabetic patients without known CAD who underwent SPECT imaging. Compared with the study populations in DIAD and FACTOR-64, the Mayo Clinic patients had a longer duration of diabetes and substantially higher rates of poor diabetes control, renal dysfunction, hypertension, and dyslipidemia. One-third of them had PAD.
Fifty-eight percent of the 1,427 patients in the Mayo cohort proved to have an abnormal SPECT imaging scan, and 18% had a high-risk scan. In a multivariate analysis, the investigators identified several factors independently associated with a high-risk scan. Q waves were present on the ECGs of 9% of the asymptomatic diabetes patients, and 43% of that subgroup had a high-risk scan. Thirty-eight percent of patients had other ECG abnormalities, and 28% of them had a high-risk scan. Age greater than 65 was associated with an increased likelihood of a high-risk SPECT result. And 28% of patients with PAD had a high-risk scan.
On the other hand, the likelihood of a high-risk scan in the 69% of subjects without PAD was 14% (J Am Coll Cardiol. 2005 Jan 4;45[1]:43-9).
The 2017 ADA guidelines acknowledge this and similar evidence by providing as a relatively weak Level E recommendation: “Consider screening for CAD in the presence of any of the following: atypical cardiac symptoms (e.g., unexplained dyspnea, chest discomfort); signs of symptoms of associated vascular disease including carotid bruits, transient ischemic attack, stroke, claudication, or PAD; or electrogram abnormalities (e.g., Q waves).”
Dr. di Carli would add to that list age older than 65, diabetes duration of greater than 10 years, poor diabetes control, and a high burden of standard cardiovascular risk factors. And he proposed the coronary artery calcium (CAC) score as a sensible gateway to selective use of further screening tests, citing as support a report from the National Institutes of Health–sponsored Multi-Ethnic Study of Atherosclerosis (MESA).
The MESA investigators assessed CAC in 6,603 persons aged 45-84 free of known CAD at baseline, including 881 with diabetes. Participants were subsequently followed prospectively for an average of 6.4 years. Compared with diabetes patients who had a baseline CAC score of 0, those with a score of 1-99 were at a risk factor– and ethnicity-adjusted 2.9-fold increased risk for developing coronary heart disease during the follow-up period. The CHD risk climbed stepwise with an increasing CAC score such that subjects with a score of 400 or higher were at 9.5-fold increased risk (Diabetes Care. 2011 Oct;34[10]L2285-90).
Using CAC measurement in this way as a screening tool in asymptomatic diabetes patients with clinical factors placing them at higher risk of significant CAD is consistent with appropriate use criteria for the detection and risk assessment of stable ischemic heart disease. The criteria were provided in a 2014 joint report by the American College of Cardiology, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons.
The report rates CAC testing as “May Be Appropriate” for asymptomatic patients of intermediate or high global risk. As such, CAC “can be an option for further evaluation of potential SIHD [stable ischemic heart disease] in an individual patient when deemed reasonable by the patient’s physician,” according to the appropriate use criteria guidance, which was created with the express purpose of developing standards to avoid overuse of costly cardiovascular testing (J Am Coll Cardiol. 2014 Feb 4;63[4]:380-406).
Dr. di Carli reported having no financial conflicts.
SNOWMASS, COLO. – The use of coronary artery calcium screening in the subset of asymptomatic diabetes patients at higher clinical risk of CAD appears to offer a practical strategy for identifying a subgroup in whom costlier stress cardiac imaging may be justified, Marcelo F. di Carli, MD, said at the Annual Cardiovascular Conference at Snowmass.
The ultimate goal is to reliably identify those patients who have asymptomatic diabetes with significant CAD warranting revascularization or maximal medical therapy for primary cardiovascular prevention.
“Coronary artery calcium is a simple test that’s accessible and inexpensive and can give us a quick read on the extent of atherosclerosis in the coronary arteries,” said Dr. di Carli, professor of radiology and medicine at Harvard University in Boston. “There’s good data that in diabetic patients there’s a gradation of risk across the spectrum of calcium scores. Risk increases exponentially from a coronary artery calcium score of 0 to more than 400. The calcium score can also provide a snapshot of which patients are more likely to have flow-limiting coronary disease.”
Atherosclerotic cardiovascular disease is the biggest contributor to the direct and indirect costs of diabetes, and diabetes experts are eager to avoid jacking up those costs further by routinely ordering stress nuclear imaging, stress echocardiography, cardiac magnetic resonance, and other expensive noninvasive imaging methods unless they can be shown to lead to improved outcomes. There is general agreement on the value of noninvasive imaging in diabetic patients with CAD symptoms. However, the routine use of such testing in asymptomatic diabetic patients has been controversial.
Indeed, according to the 2017 American Diabetes Association Standards of Medical Care in Diabetes: “In asymptomatic patients, routine screening for coronary artery disease is not recommended as it does not improve outcomes as long as atherosclerotic cardiovascular disease risk factors are treated (Diabetes Care. 2017 Jan;40[Suppl. 1]:S75-87). That’s a Level A recommendation.
But Dr. di Carli is among many cardiologists who believe this statement paints with too broad a brush. He considers it an overgeneralization that’s based on the negative results of two randomized trials of routine screening in asymptomatic diabetics: DIAD, which utilized stress single-photon emission CT (SPECT) imaging (JAMA. 2009 Apr 15;301[15]:1547-55), and FACTOR-64, which relied upon coronary CT angiography (JAMA. 2014 Dec 3;312[21]: 2234-43). Both studies found relatively low yields of severe CAD and showed no survival benefit for screening. And of course, these are also costly and inconvenient tests.
The problem in generalizing from DIAD and FACTOR-64 to the overall population of asymptomatic diabetic patients is that both studies were conducted in asymptomatic patients at the lower end of the cardiovascular risk spectrum. They were young, with an average age of 60 years. They had a history of diabetes of less than 10 years, and their diabetes was reasonably well controlled. They had normal ECGs and preserved renal function. Peripheral artery disease (PAD) was present in only 9% of the DIAD population and no one in FACTOR-64. So this would not be expected to be a high-risk/high-yield population, according to Dr. di Carli, executive director of the cardiovascular imaging program at Brigham and Women’s Hospital, Boston.
An earlier study from the Mayo Clinic identified the clinical factors that can potentially be used to identify a higher-risk cohort of asymptomatic diabetic patients in whom high-tech noninvasive testing for significant CAD may be justified, he continued. This was a nonrandomized study of 1,427 asymptomatic diabetic patients without known CAD who underwent SPECT imaging. Compared with the study populations in DIAD and FACTOR-64, the Mayo Clinic patients had a longer duration of diabetes and substantially higher rates of poor diabetes control, renal dysfunction, hypertension, and dyslipidemia. One-third of them had PAD.
Fifty-eight percent of the 1,427 patients in the Mayo cohort proved to have an abnormal SPECT imaging scan, and 18% had a high-risk scan. In a multivariate analysis, the investigators identified several factors independently associated with a high-risk scan. Q waves were present on the ECGs of 9% of the asymptomatic diabetes patients, and 43% of that subgroup had a high-risk scan. Thirty-eight percent of patients had other ECG abnormalities, and 28% of them had a high-risk scan. Age greater than 65 was associated with an increased likelihood of a high-risk SPECT result. And 28% of patients with PAD had a high-risk scan.
On the other hand, the likelihood of a high-risk scan in the 69% of subjects without PAD was 14% (J Am Coll Cardiol. 2005 Jan 4;45[1]:43-9).
The 2017 ADA guidelines acknowledge this and similar evidence by providing as a relatively weak Level E recommendation: “Consider screening for CAD in the presence of any of the following: atypical cardiac symptoms (e.g., unexplained dyspnea, chest discomfort); signs of symptoms of associated vascular disease including carotid bruits, transient ischemic attack, stroke, claudication, or PAD; or electrogram abnormalities (e.g., Q waves).”
Dr. di Carli would add to that list age older than 65, diabetes duration of greater than 10 years, poor diabetes control, and a high burden of standard cardiovascular risk factors. And he proposed the coronary artery calcium (CAC) score as a sensible gateway to selective use of further screening tests, citing as support a report from the National Institutes of Health–sponsored Multi-Ethnic Study of Atherosclerosis (MESA).
The MESA investigators assessed CAC in 6,603 persons aged 45-84 free of known CAD at baseline, including 881 with diabetes. Participants were subsequently followed prospectively for an average of 6.4 years. Compared with diabetes patients who had a baseline CAC score of 0, those with a score of 1-99 were at a risk factor– and ethnicity-adjusted 2.9-fold increased risk for developing coronary heart disease during the follow-up period. The CHD risk climbed stepwise with an increasing CAC score such that subjects with a score of 400 or higher were at 9.5-fold increased risk (Diabetes Care. 2011 Oct;34[10]L2285-90).
Using CAC measurement in this way as a screening tool in asymptomatic diabetes patients with clinical factors placing them at higher risk of significant CAD is consistent with appropriate use criteria for the detection and risk assessment of stable ischemic heart disease. The criteria were provided in a 2014 joint report by the American College of Cardiology, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons.
The report rates CAC testing as “May Be Appropriate” for asymptomatic patients of intermediate or high global risk. As such, CAC “can be an option for further evaluation of potential SIHD [stable ischemic heart disease] in an individual patient when deemed reasonable by the patient’s physician,” according to the appropriate use criteria guidance, which was created with the express purpose of developing standards to avoid overuse of costly cardiovascular testing (J Am Coll Cardiol. 2014 Feb 4;63[4]:380-406).
Dr. di Carli reported having no financial conflicts.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Hypertension in SLE pregnancy: Is it lupus flare or preeclampsia?
SNOWMASS, COLO. – No hard and fast test exists that would enable a physician to tell a flare of systemic lupus erythematosus from preeclampsia in a pregnant lupus patient who becomes hypertensive and ill, but there are highly useful clues, Bonnie L. Bermas, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“There is no perfect way of distinguishing between a lupus flare and preeclampsia. I’ve never walked away from the labor floor and said, ‘This is great – I know this is a lupus flare,’ or ‘I know this is preeclampsia.’ But you make your best guess as to which one it is, and that will inform your management,” explained Dr. Bermas, a rheumatologist and director of the clinical lupus program at Brigham and Women’s Hospital in Boston.
“Why do we care? Because if it’s preeclampsia the mother needs to be delivered immediately for her safety, while if it’s an SLE flare sometimes you can treat it and get the fetus to a more viable age. A 23-week-old baby isn’t at all likely to make it, but a 27-week-old could,” Dr. Bermas said.
The fact that the patient has thrombocytopenia isn’t helpful in making the distinction, since that feature is shared in common by SLE flares and preeclampsia. But the uric acid level is a useful clue.
It’s quite possible that much of the current guesswork in predicting preeclampsia and other adverse pregnancy outcomes in lupus patients will give way to reliable risk testing within the next several years. Investigators in the U.S. multicenter prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE) study have reported that circulating levels of the angiogenic factors soluble fms-like tyrosine kinase-1 and placental growth factor were abnormal as early as gestational weeks 12-15 in patients who went on to develop preeclampsia or other adverse pregnancy outcomes.
Indeed, monthly testing demonstrated that SLE patients in the top quartile for soluble fms-like tyrosine kinase-1 at weeks 12-15 had an adjusted 17.3-fold greater likelihood of experiencing a severe adverse pregnancy outcome than did those in the lowest quartile. A high level had a positive predictive value of 61% and a negative predictive value of 93% (Am J Obstet Gynecol. 2016 Jan;214[1]:108.e1-14). These findings are being further explored in ongoing studies.
“Hopefully, in another few years we’re going to be able to say early in pregnancy, ‘This person is set up to get preeclampsia.’ Maybe that will lead to better treatment as well,” Dr. Bermas said.
The risk of preeclampsia has been shown to be threefold higher in women with SLE than in the general population of pregnant women in a study of more than 16.7 million admissions for childbirth in the United States during a 4-year period. The SLE patients were also at 2.4-fold increased risk for preterm labor. Their risks of infection, thrombosis, thrombocytopenia, and transfusion were each three- to seven-fold higher as well (Am J Obstet Gynecol. 2008 Aug;199[2]:127.e1-16).
Dr. Bermas reported serving as a consultant to UCB.
SNOWMASS, COLO. – No hard and fast test exists that would enable a physician to tell a flare of systemic lupus erythematosus from preeclampsia in a pregnant lupus patient who becomes hypertensive and ill, but there are highly useful clues, Bonnie L. Bermas, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“There is no perfect way of distinguishing between a lupus flare and preeclampsia. I’ve never walked away from the labor floor and said, ‘This is great – I know this is a lupus flare,’ or ‘I know this is preeclampsia.’ But you make your best guess as to which one it is, and that will inform your management,” explained Dr. Bermas, a rheumatologist and director of the clinical lupus program at Brigham and Women’s Hospital in Boston.
“Why do we care? Because if it’s preeclampsia the mother needs to be delivered immediately for her safety, while if it’s an SLE flare sometimes you can treat it and get the fetus to a more viable age. A 23-week-old baby isn’t at all likely to make it, but a 27-week-old could,” Dr. Bermas said.
The fact that the patient has thrombocytopenia isn’t helpful in making the distinction, since that feature is shared in common by SLE flares and preeclampsia. But the uric acid level is a useful clue.
It’s quite possible that much of the current guesswork in predicting preeclampsia and other adverse pregnancy outcomes in lupus patients will give way to reliable risk testing within the next several years. Investigators in the U.S. multicenter prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE) study have reported that circulating levels of the angiogenic factors soluble fms-like tyrosine kinase-1 and placental growth factor were abnormal as early as gestational weeks 12-15 in patients who went on to develop preeclampsia or other adverse pregnancy outcomes.
Indeed, monthly testing demonstrated that SLE patients in the top quartile for soluble fms-like tyrosine kinase-1 at weeks 12-15 had an adjusted 17.3-fold greater likelihood of experiencing a severe adverse pregnancy outcome than did those in the lowest quartile. A high level had a positive predictive value of 61% and a negative predictive value of 93% (Am J Obstet Gynecol. 2016 Jan;214[1]:108.e1-14). These findings are being further explored in ongoing studies.
“Hopefully, in another few years we’re going to be able to say early in pregnancy, ‘This person is set up to get preeclampsia.’ Maybe that will lead to better treatment as well,” Dr. Bermas said.
The risk of preeclampsia has been shown to be threefold higher in women with SLE than in the general population of pregnant women in a study of more than 16.7 million admissions for childbirth in the United States during a 4-year period. The SLE patients were also at 2.4-fold increased risk for preterm labor. Their risks of infection, thrombosis, thrombocytopenia, and transfusion were each three- to seven-fold higher as well (Am J Obstet Gynecol. 2008 Aug;199[2]:127.e1-16).
Dr. Bermas reported serving as a consultant to UCB.
SNOWMASS, COLO. – No hard and fast test exists that would enable a physician to tell a flare of systemic lupus erythematosus from preeclampsia in a pregnant lupus patient who becomes hypertensive and ill, but there are highly useful clues, Bonnie L. Bermas, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“There is no perfect way of distinguishing between a lupus flare and preeclampsia. I’ve never walked away from the labor floor and said, ‘This is great – I know this is a lupus flare,’ or ‘I know this is preeclampsia.’ But you make your best guess as to which one it is, and that will inform your management,” explained Dr. Bermas, a rheumatologist and director of the clinical lupus program at Brigham and Women’s Hospital in Boston.
“Why do we care? Because if it’s preeclampsia the mother needs to be delivered immediately for her safety, while if it’s an SLE flare sometimes you can treat it and get the fetus to a more viable age. A 23-week-old baby isn’t at all likely to make it, but a 27-week-old could,” Dr. Bermas said.
The fact that the patient has thrombocytopenia isn’t helpful in making the distinction, since that feature is shared in common by SLE flares and preeclampsia. But the uric acid level is a useful clue.
It’s quite possible that much of the current guesswork in predicting preeclampsia and other adverse pregnancy outcomes in lupus patients will give way to reliable risk testing within the next several years. Investigators in the U.S. multicenter prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE) study have reported that circulating levels of the angiogenic factors soluble fms-like tyrosine kinase-1 and placental growth factor were abnormal as early as gestational weeks 12-15 in patients who went on to develop preeclampsia or other adverse pregnancy outcomes.
Indeed, monthly testing demonstrated that SLE patients in the top quartile for soluble fms-like tyrosine kinase-1 at weeks 12-15 had an adjusted 17.3-fold greater likelihood of experiencing a severe adverse pregnancy outcome than did those in the lowest quartile. A high level had a positive predictive value of 61% and a negative predictive value of 93% (Am J Obstet Gynecol. 2016 Jan;214[1]:108.e1-14). These findings are being further explored in ongoing studies.
“Hopefully, in another few years we’re going to be able to say early in pregnancy, ‘This person is set up to get preeclampsia.’ Maybe that will lead to better treatment as well,” Dr. Bermas said.
The risk of preeclampsia has been shown to be threefold higher in women with SLE than in the general population of pregnant women in a study of more than 16.7 million admissions for childbirth in the United States during a 4-year period. The SLE patients were also at 2.4-fold increased risk for preterm labor. Their risks of infection, thrombosis, thrombocytopenia, and transfusion were each three- to seven-fold higher as well (Am J Obstet Gynecol. 2008 Aug;199[2]:127.e1-16).
Dr. Bermas reported serving as a consultant to UCB.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
New AJCC guidance brings melanoma staging changes
WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.
The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.
The eighth edition breaks new ground, moving beyond TNM (Tumor, Node, Metastasis) anatomic staging to incorporate new evidence-based prognostic factors.
“There are some subtle differences here to be aware of. It can be a little bit tricky at first glance. You should become familiar with this,” advised Dr. Marchetti, a dermatologist at Memorial Sloan-Kettering Cancer Center in New York.
In addition to highlighting the changes in melanoma staging included in the new AJCC manual, he outlined key recommendations – some of them controversial – on the use of sentinel lymph node biopsy (SLNB) in melanoma patients incorporated in the 2017 National Comprehensive Cancer Network (NCCN) guidelines.
The biggest change for the dermatology community contained in the new edition of the AJCC staging manual is that the T1 classification of melanoma has changed. In the seventh edition, a melanoma was categorized as T1 if less than or equal to 1.0 mm thickness. The cancer was T1a if nonulcerated and had a mitosis rate of less than 1/mm2 and T1b if ulcerated or had at least 1 mitosis/mm2.
The eighth edition makes an evidence-based subcategorization of T1 based upon thickness in light of the prognostic implications of this distinction. A melanoma is defined as T1a if nonulcerated and less than 0.8 mm in thickness, and T1b if it is 0.8-1.0 mm thick or less than 0.8 mm with ulceration.
Of note, tumor mitotic rate has been dropped as a staging criterion for T1 tumors.
What this means is, for example, in 2017, a patient with a 0.9-mm nonulcerated melanoma with 1 mitosis/mm2 and a negative sentinel lymph node biopsy with wide local excision is T1bN0M0, pathologic Stage IB. Under the eighth edition of AJCC, the same patient is T1bN0M0, pathologic Stage IA, because that mitosis rate isn’t a factor.
Today, a patient with a 0.5-mm melanoma with 1 mitosis/mm2 with wide local excision is T1bN0M0, Pathologic Stage IB. Under the new system, the same tumor is downstaged to Pathologic Stage IA, Dr. Marchetti explained.
In the eighth edition, tumor thickness measurements are recorded with rounding to the nearest 0.1 mm, not to the nearest 0.01 mm as before. This change was prompted by the inherent lack of precision in measuring melanomas, especially thicker ones.
The T category definitions of primary tumors have been clarified in the eighth edition. A tumor should be classified as T0 only if there is no evidence of a primary tumor. T is utilized for melanoma in situ. TX is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained through curettage.
The N categorization of regional lymph node status has become much more complicated in the eighth edition, the dermatologist cautioned. Plus, the terminology for nodal disease has changed. The term micrometastasis has been replaced by “clinically occult disease” as detected by SLNB. Macrometastasis has been supplanted by “clinically detected disease.” And while in-transit or satellite node metastasis or microsatellite metastasis with satellite nodes was formerly listed simply as N3, in the new system there are subcategories for N3 based upon the number of metastatic nodes involved. For example, in the eighth edition, a melanoma is pathologic Stage N3a if there are four or more clinically occult regional lymph nodes and no in-transit, satellite, or matted nodes. Pathologic Stage N3b is shorthand for four or more tumor-involved regional lymph nodes, at least one of which was clinically detected, or any number of matted lymph nodes, with no in-transit or satellite nodal involvement. Stage N3c is reserved for melanomas with two or more clinically occult or clinically detected regional lymph nodes and/or any number of matted nodes, plus the presence of in-transit or satellite nodal metastasis.
As a result of the changes in the N classification, there are now four pathologic Stage III groups rather than three. Stages IIIA-C have been joined by pathologic Stage IIID, reserved for patients who are T4b, N3a, b, or c, and M0.
The M categorization of distant metastatic disease status has also become more elaborate. In the AJCC seventh edition, if serum lactate dehydrogenase (LDH) is elevated and a patient has any distant metastatic disease, that’s automatically category M1c. Not any longer, though.
Under the eighth edition, if a patient has distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes and the LDH is unspecified, the categorization is M1a. If serum LDH is not elevated, it’s M1a(0). If elevated, then M1a(1).
Similarly, for distant metastasis to the lung, the range of possibilities based upon LDH is M1b, M1b(0), and M1b(1). For distant metastasis to non-CNS visceral sites, the possibilities are M1c, M1c(0), and M1c(1).
M1d is a new classification, a clear departure from the seventh edition. It applies to patients with distant metastasis to the CNS. The classification is M1d if LDH isn’t recorded, M1d(0) if LDH isn’t elevated, and M1d(1) if it is.
Turning to the updated 2017 NCCN guidelines Version 1.2017 on the role of SLNB in melanoma, Dr. Marchetti noted that the procedure is not recommended in patients with melanoma in situ or Stage IA or IB disease 0.75 mm or less in thickness, regardless of features. Neither are routine imaging or lab tests. That’s because the pretest probability of a positive SLNB is so low, at around 3%.
For Clinicopathologic Stage IA disease, 0.76-1.0 mm in thickness with no ulceration and a mitotic rate of less than 1 per mm2, the guidelines recommend that physicians “discuss and consider” SLNB, which the available evidence suggests has roughly a 7% pretest probability of a positive result.
For Stage IB disease, 0.76-1.0 mm in thickness with ulceration or a mitotic rate of at least 1 per mm2, as well as for Stage IB or Stage II disease greater than 1.0 mm in thickness, with any feature, the language of the recommendation shifts to “discuss and offer” rather than “discuss and consider” SLNB, since various studies have reported pretest probabilities of a positive result as high as 35%.
“The rationale here for performing sentinel lymph node biopsy is primarily to acquire more staging information. Is it a perfect test? Absolutely not. But it’s the current standard of care in terms of providing additional information for staging,” according to Dr. Marchetti.
If the SLNB generates a positive result, by definition the patient now has Stage III melanoma. The NCCN guidelines recommend consideration of imaging to establish a baseline, and state further that the primary treatment is to discuss and offer complete lymph node dissection in order to control the regional nodal basin and because of a possible favorable impact on overall survival. But the question of a survival benefit has been controversial for many years, and it’s unlikely to be resolved soon, Dr. Marchetti predicted.
The final report from the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–1 (MSLT-1) concluded that patients with primary cutaneous melanomas 1.2 mm or more in thickness who were randomized to undergo SLNB and, if positive, immediate complete lymphadenectomy, fared significantly better in terms of 10-year disease-free survival, compared with those assigned to observation and lymphadenectomy in the event of nodal relapse (N Engl J Med. 2014 Feb 13;370[7]:599-609).
This conclusion has generated numerous letters to the editor from melanoma experts who took issue with the analysis and conclusion. To try to put the MSLT-1 results in perspective, Dr. Marchetti applied the results to a hypothetical cohort of 100 patients with intermediate-thickness melanomas of 1.2-3.5 mm undergoing SLNB.
Eighty of these patients would be true SLNB-negative for regional nodal disease. Five others would have a false-negative SLNB and would later develop clinically detectable nodal disease. Fifteen patients with a positive SLNB would undergo prompt complete lymph node dissection, of whom 12 or 13 would derive no mortality benefit at 10 years, assuming the MSLT-1 investigators are correct in their analysis.
“Two or three patients with a positive SLNB will derive mortality benefit at 10 years, but we have no way to identify who those people are from the original 100,” he said.
Since the MSLT-1 report, a phase III German multicenter randomized trial of 241 melanoma patients with a positive screening SLNB has reported results. The participants assigned to complete lymph node dissection didn’t differ in terms of 3-year overall survival, distant metastasis-free survival, or recurrence-free survival, compared with those assigned to observation and lymphadenectomy if nodal disease occurred (Lancet Oncol. 2016 Jun;17[6]:757-67). However, as the investigators noted, the study, known as DeCOG-SLT, was underpowered, and Dr. Marchetti’s view is that it can’t be considered definitive.
“Ultimately I don’t think we’ll have a definitive answer to this question until the final results of the MSLT-II trial in the fall of 2022,” he said.
The MSLT-II trial has the same design as DeCOG-SLT.
Dr. Marchetti reported having no financial conflicts of interest regarding his presentation.
SDEF and this news organization are owned by the same parent company.
WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.
The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.
The eighth edition breaks new ground, moving beyond TNM (Tumor, Node, Metastasis) anatomic staging to incorporate new evidence-based prognostic factors.
“There are some subtle differences here to be aware of. It can be a little bit tricky at first glance. You should become familiar with this,” advised Dr. Marchetti, a dermatologist at Memorial Sloan-Kettering Cancer Center in New York.
In addition to highlighting the changes in melanoma staging included in the new AJCC manual, he outlined key recommendations – some of them controversial – on the use of sentinel lymph node biopsy (SLNB) in melanoma patients incorporated in the 2017 National Comprehensive Cancer Network (NCCN) guidelines.
The biggest change for the dermatology community contained in the new edition of the AJCC staging manual is that the T1 classification of melanoma has changed. In the seventh edition, a melanoma was categorized as T1 if less than or equal to 1.0 mm thickness. The cancer was T1a if nonulcerated and had a mitosis rate of less than 1/mm2 and T1b if ulcerated or had at least 1 mitosis/mm2.
The eighth edition makes an evidence-based subcategorization of T1 based upon thickness in light of the prognostic implications of this distinction. A melanoma is defined as T1a if nonulcerated and less than 0.8 mm in thickness, and T1b if it is 0.8-1.0 mm thick or less than 0.8 mm with ulceration.
Of note, tumor mitotic rate has been dropped as a staging criterion for T1 tumors.
What this means is, for example, in 2017, a patient with a 0.9-mm nonulcerated melanoma with 1 mitosis/mm2 and a negative sentinel lymph node biopsy with wide local excision is T1bN0M0, pathologic Stage IB. Under the eighth edition of AJCC, the same patient is T1bN0M0, pathologic Stage IA, because that mitosis rate isn’t a factor.
Today, a patient with a 0.5-mm melanoma with 1 mitosis/mm2 with wide local excision is T1bN0M0, Pathologic Stage IB. Under the new system, the same tumor is downstaged to Pathologic Stage IA, Dr. Marchetti explained.
In the eighth edition, tumor thickness measurements are recorded with rounding to the nearest 0.1 mm, not to the nearest 0.01 mm as before. This change was prompted by the inherent lack of precision in measuring melanomas, especially thicker ones.
The T category definitions of primary tumors have been clarified in the eighth edition. A tumor should be classified as T0 only if there is no evidence of a primary tumor. T is utilized for melanoma in situ. TX is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained through curettage.
The N categorization of regional lymph node status has become much more complicated in the eighth edition, the dermatologist cautioned. Plus, the terminology for nodal disease has changed. The term micrometastasis has been replaced by “clinically occult disease” as detected by SLNB. Macrometastasis has been supplanted by “clinically detected disease.” And while in-transit or satellite node metastasis or microsatellite metastasis with satellite nodes was formerly listed simply as N3, in the new system there are subcategories for N3 based upon the number of metastatic nodes involved. For example, in the eighth edition, a melanoma is pathologic Stage N3a if there are four or more clinically occult regional lymph nodes and no in-transit, satellite, or matted nodes. Pathologic Stage N3b is shorthand for four or more tumor-involved regional lymph nodes, at least one of which was clinically detected, or any number of matted lymph nodes, with no in-transit or satellite nodal involvement. Stage N3c is reserved for melanomas with two or more clinically occult or clinically detected regional lymph nodes and/or any number of matted nodes, plus the presence of in-transit or satellite nodal metastasis.
As a result of the changes in the N classification, there are now four pathologic Stage III groups rather than three. Stages IIIA-C have been joined by pathologic Stage IIID, reserved for patients who are T4b, N3a, b, or c, and M0.
The M categorization of distant metastatic disease status has also become more elaborate. In the AJCC seventh edition, if serum lactate dehydrogenase (LDH) is elevated and a patient has any distant metastatic disease, that’s automatically category M1c. Not any longer, though.
Under the eighth edition, if a patient has distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes and the LDH is unspecified, the categorization is M1a. If serum LDH is not elevated, it’s M1a(0). If elevated, then M1a(1).
Similarly, for distant metastasis to the lung, the range of possibilities based upon LDH is M1b, M1b(0), and M1b(1). For distant metastasis to non-CNS visceral sites, the possibilities are M1c, M1c(0), and M1c(1).
M1d is a new classification, a clear departure from the seventh edition. It applies to patients with distant metastasis to the CNS. The classification is M1d if LDH isn’t recorded, M1d(0) if LDH isn’t elevated, and M1d(1) if it is.
Turning to the updated 2017 NCCN guidelines Version 1.2017 on the role of SLNB in melanoma, Dr. Marchetti noted that the procedure is not recommended in patients with melanoma in situ or Stage IA or IB disease 0.75 mm or less in thickness, regardless of features. Neither are routine imaging or lab tests. That’s because the pretest probability of a positive SLNB is so low, at around 3%.
For Clinicopathologic Stage IA disease, 0.76-1.0 mm in thickness with no ulceration and a mitotic rate of less than 1 per mm2, the guidelines recommend that physicians “discuss and consider” SLNB, which the available evidence suggests has roughly a 7% pretest probability of a positive result.
For Stage IB disease, 0.76-1.0 mm in thickness with ulceration or a mitotic rate of at least 1 per mm2, as well as for Stage IB or Stage II disease greater than 1.0 mm in thickness, with any feature, the language of the recommendation shifts to “discuss and offer” rather than “discuss and consider” SLNB, since various studies have reported pretest probabilities of a positive result as high as 35%.
“The rationale here for performing sentinel lymph node biopsy is primarily to acquire more staging information. Is it a perfect test? Absolutely not. But it’s the current standard of care in terms of providing additional information for staging,” according to Dr. Marchetti.
If the SLNB generates a positive result, by definition the patient now has Stage III melanoma. The NCCN guidelines recommend consideration of imaging to establish a baseline, and state further that the primary treatment is to discuss and offer complete lymph node dissection in order to control the regional nodal basin and because of a possible favorable impact on overall survival. But the question of a survival benefit has been controversial for many years, and it’s unlikely to be resolved soon, Dr. Marchetti predicted.
The final report from the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–1 (MSLT-1) concluded that patients with primary cutaneous melanomas 1.2 mm or more in thickness who were randomized to undergo SLNB and, if positive, immediate complete lymphadenectomy, fared significantly better in terms of 10-year disease-free survival, compared with those assigned to observation and lymphadenectomy in the event of nodal relapse (N Engl J Med. 2014 Feb 13;370[7]:599-609).
This conclusion has generated numerous letters to the editor from melanoma experts who took issue with the analysis and conclusion. To try to put the MSLT-1 results in perspective, Dr. Marchetti applied the results to a hypothetical cohort of 100 patients with intermediate-thickness melanomas of 1.2-3.5 mm undergoing SLNB.
Eighty of these patients would be true SLNB-negative for regional nodal disease. Five others would have a false-negative SLNB and would later develop clinically detectable nodal disease. Fifteen patients with a positive SLNB would undergo prompt complete lymph node dissection, of whom 12 or 13 would derive no mortality benefit at 10 years, assuming the MSLT-1 investigators are correct in their analysis.
“Two or three patients with a positive SLNB will derive mortality benefit at 10 years, but we have no way to identify who those people are from the original 100,” he said.
Since the MSLT-1 report, a phase III German multicenter randomized trial of 241 melanoma patients with a positive screening SLNB has reported results. The participants assigned to complete lymph node dissection didn’t differ in terms of 3-year overall survival, distant metastasis-free survival, or recurrence-free survival, compared with those assigned to observation and lymphadenectomy if nodal disease occurred (Lancet Oncol. 2016 Jun;17[6]:757-67). However, as the investigators noted, the study, known as DeCOG-SLT, was underpowered, and Dr. Marchetti’s view is that it can’t be considered definitive.
“Ultimately I don’t think we’ll have a definitive answer to this question until the final results of the MSLT-II trial in the fall of 2022,” he said.
The MSLT-II trial has the same design as DeCOG-SLT.
Dr. Marchetti reported having no financial conflicts of interest regarding his presentation.
SDEF and this news organization are owned by the same parent company.
WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.
The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.
The eighth edition breaks new ground, moving beyond TNM (Tumor, Node, Metastasis) anatomic staging to incorporate new evidence-based prognostic factors.
“There are some subtle differences here to be aware of. It can be a little bit tricky at first glance. You should become familiar with this,” advised Dr. Marchetti, a dermatologist at Memorial Sloan-Kettering Cancer Center in New York.
In addition to highlighting the changes in melanoma staging included in the new AJCC manual, he outlined key recommendations – some of them controversial – on the use of sentinel lymph node biopsy (SLNB) in melanoma patients incorporated in the 2017 National Comprehensive Cancer Network (NCCN) guidelines.
The biggest change for the dermatology community contained in the new edition of the AJCC staging manual is that the T1 classification of melanoma has changed. In the seventh edition, a melanoma was categorized as T1 if less than or equal to 1.0 mm thickness. The cancer was T1a if nonulcerated and had a mitosis rate of less than 1/mm2 and T1b if ulcerated or had at least 1 mitosis/mm2.
The eighth edition makes an evidence-based subcategorization of T1 based upon thickness in light of the prognostic implications of this distinction. A melanoma is defined as T1a if nonulcerated and less than 0.8 mm in thickness, and T1b if it is 0.8-1.0 mm thick or less than 0.8 mm with ulceration.
Of note, tumor mitotic rate has been dropped as a staging criterion for T1 tumors.
What this means is, for example, in 2017, a patient with a 0.9-mm nonulcerated melanoma with 1 mitosis/mm2 and a negative sentinel lymph node biopsy with wide local excision is T1bN0M0, pathologic Stage IB. Under the eighth edition of AJCC, the same patient is T1bN0M0, pathologic Stage IA, because that mitosis rate isn’t a factor.
Today, a patient with a 0.5-mm melanoma with 1 mitosis/mm2 with wide local excision is T1bN0M0, Pathologic Stage IB. Under the new system, the same tumor is downstaged to Pathologic Stage IA, Dr. Marchetti explained.
In the eighth edition, tumor thickness measurements are recorded with rounding to the nearest 0.1 mm, not to the nearest 0.01 mm as before. This change was prompted by the inherent lack of precision in measuring melanomas, especially thicker ones.
The T category definitions of primary tumors have been clarified in the eighth edition. A tumor should be classified as T0 only if there is no evidence of a primary tumor. T is utilized for melanoma in situ. TX is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained through curettage.
The N categorization of regional lymph node status has become much more complicated in the eighth edition, the dermatologist cautioned. Plus, the terminology for nodal disease has changed. The term micrometastasis has been replaced by “clinically occult disease” as detected by SLNB. Macrometastasis has been supplanted by “clinically detected disease.” And while in-transit or satellite node metastasis or microsatellite metastasis with satellite nodes was formerly listed simply as N3, in the new system there are subcategories for N3 based upon the number of metastatic nodes involved. For example, in the eighth edition, a melanoma is pathologic Stage N3a if there are four or more clinically occult regional lymph nodes and no in-transit, satellite, or matted nodes. Pathologic Stage N3b is shorthand for four or more tumor-involved regional lymph nodes, at least one of which was clinically detected, or any number of matted lymph nodes, with no in-transit or satellite nodal involvement. Stage N3c is reserved for melanomas with two or more clinically occult or clinically detected regional lymph nodes and/or any number of matted nodes, plus the presence of in-transit or satellite nodal metastasis.
As a result of the changes in the N classification, there are now four pathologic Stage III groups rather than three. Stages IIIA-C have been joined by pathologic Stage IIID, reserved for patients who are T4b, N3a, b, or c, and M0.
The M categorization of distant metastatic disease status has also become more elaborate. In the AJCC seventh edition, if serum lactate dehydrogenase (LDH) is elevated and a patient has any distant metastatic disease, that’s automatically category M1c. Not any longer, though.
Under the eighth edition, if a patient has distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes and the LDH is unspecified, the categorization is M1a. If serum LDH is not elevated, it’s M1a(0). If elevated, then M1a(1).
Similarly, for distant metastasis to the lung, the range of possibilities based upon LDH is M1b, M1b(0), and M1b(1). For distant metastasis to non-CNS visceral sites, the possibilities are M1c, M1c(0), and M1c(1).
M1d is a new classification, a clear departure from the seventh edition. It applies to patients with distant metastasis to the CNS. The classification is M1d if LDH isn’t recorded, M1d(0) if LDH isn’t elevated, and M1d(1) if it is.
Turning to the updated 2017 NCCN guidelines Version 1.2017 on the role of SLNB in melanoma, Dr. Marchetti noted that the procedure is not recommended in patients with melanoma in situ or Stage IA or IB disease 0.75 mm or less in thickness, regardless of features. Neither are routine imaging or lab tests. That’s because the pretest probability of a positive SLNB is so low, at around 3%.
For Clinicopathologic Stage IA disease, 0.76-1.0 mm in thickness with no ulceration and a mitotic rate of less than 1 per mm2, the guidelines recommend that physicians “discuss and consider” SLNB, which the available evidence suggests has roughly a 7% pretest probability of a positive result.
For Stage IB disease, 0.76-1.0 mm in thickness with ulceration or a mitotic rate of at least 1 per mm2, as well as for Stage IB or Stage II disease greater than 1.0 mm in thickness, with any feature, the language of the recommendation shifts to “discuss and offer” rather than “discuss and consider” SLNB, since various studies have reported pretest probabilities of a positive result as high as 35%.
“The rationale here for performing sentinel lymph node biopsy is primarily to acquire more staging information. Is it a perfect test? Absolutely not. But it’s the current standard of care in terms of providing additional information for staging,” according to Dr. Marchetti.
If the SLNB generates a positive result, by definition the patient now has Stage III melanoma. The NCCN guidelines recommend consideration of imaging to establish a baseline, and state further that the primary treatment is to discuss and offer complete lymph node dissection in order to control the regional nodal basin and because of a possible favorable impact on overall survival. But the question of a survival benefit has been controversial for many years, and it’s unlikely to be resolved soon, Dr. Marchetti predicted.
The final report from the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–1 (MSLT-1) concluded that patients with primary cutaneous melanomas 1.2 mm or more in thickness who were randomized to undergo SLNB and, if positive, immediate complete lymphadenectomy, fared significantly better in terms of 10-year disease-free survival, compared with those assigned to observation and lymphadenectomy in the event of nodal relapse (N Engl J Med. 2014 Feb 13;370[7]:599-609).
This conclusion has generated numerous letters to the editor from melanoma experts who took issue with the analysis and conclusion. To try to put the MSLT-1 results in perspective, Dr. Marchetti applied the results to a hypothetical cohort of 100 patients with intermediate-thickness melanomas of 1.2-3.5 mm undergoing SLNB.
Eighty of these patients would be true SLNB-negative for regional nodal disease. Five others would have a false-negative SLNB and would later develop clinically detectable nodal disease. Fifteen patients with a positive SLNB would undergo prompt complete lymph node dissection, of whom 12 or 13 would derive no mortality benefit at 10 years, assuming the MSLT-1 investigators are correct in their analysis.
“Two or three patients with a positive SLNB will derive mortality benefit at 10 years, but we have no way to identify who those people are from the original 100,” he said.
Since the MSLT-1 report, a phase III German multicenter randomized trial of 241 melanoma patients with a positive screening SLNB has reported results. The participants assigned to complete lymph node dissection didn’t differ in terms of 3-year overall survival, distant metastasis-free survival, or recurrence-free survival, compared with those assigned to observation and lymphadenectomy if nodal disease occurred (Lancet Oncol. 2016 Jun;17[6]:757-67). However, as the investigators noted, the study, known as DeCOG-SLT, was underpowered, and Dr. Marchetti’s view is that it can’t be considered definitive.
“Ultimately I don’t think we’ll have a definitive answer to this question until the final results of the MSLT-II trial in the fall of 2022,” he said.
The MSLT-II trial has the same design as DeCOG-SLT.
Dr. Marchetti reported having no financial conflicts of interest regarding his presentation.
SDEF and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM THE SDEF HAWAII DERMATOLOGY SEMINAR
Ultrasound guidance of early RA therapy doesn’t improve outcomes
SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.
The stepped treatment escalation regimen began with methotrexate monotherapy, followed by the addition of sulfasalazine and hydroxychloroquine to methotrexate as triple therapy, then etanercept plus triple therapy.
The primary outcome was improvement in DAS44 at 18 months. Both groups experienced similarly robust improvements: a mean 2.69-point reduction in the ultrasound group and a 2.59-point decrease in the control arm. Nor were there any between-group differences in radiographic or MRI erosions. This was the case even though the ultrasound group received more intensive therapy (Ann Rheum Dis. 2016 Jun;75[6]:1043-50).
“This doesn’t mean that there’s not great value in ultrasound to evaluate disease activity, but I’m not convinced that using ultrasound to guide your treatment per se shows any advantages over a good clinical evaluation of the patient,” concluded Dr. Weinblatt, professor of medicine at Harvard Medical School in Boston.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.
The stepped treatment escalation regimen began with methotrexate monotherapy, followed by the addition of sulfasalazine and hydroxychloroquine to methotrexate as triple therapy, then etanercept plus triple therapy.
The primary outcome was improvement in DAS44 at 18 months. Both groups experienced similarly robust improvements: a mean 2.69-point reduction in the ultrasound group and a 2.59-point decrease in the control arm. Nor were there any between-group differences in radiographic or MRI erosions. This was the case even though the ultrasound group received more intensive therapy (Ann Rheum Dis. 2016 Jun;75[6]:1043-50).
“This doesn’t mean that there’s not great value in ultrasound to evaluate disease activity, but I’m not convinced that using ultrasound to guide your treatment per se shows any advantages over a good clinical evaluation of the patient,” concluded Dr. Weinblatt, professor of medicine at Harvard Medical School in Boston.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.
The stepped treatment escalation regimen began with methotrexate monotherapy, followed by the addition of sulfasalazine and hydroxychloroquine to methotrexate as triple therapy, then etanercept plus triple therapy.
The primary outcome was improvement in DAS44 at 18 months. Both groups experienced similarly robust improvements: a mean 2.69-point reduction in the ultrasound group and a 2.59-point decrease in the control arm. Nor were there any between-group differences in radiographic or MRI erosions. This was the case even though the ultrasound group received more intensive therapy (Ann Rheum Dis. 2016 Jun;75[6]:1043-50).
“This doesn’t mean that there’s not great value in ultrasound to evaluate disease activity, but I’m not convinced that using ultrasound to guide your treatment per se shows any advantages over a good clinical evaluation of the patient,” concluded Dr. Weinblatt, professor of medicine at Harvard Medical School in Boston.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
ACR guidelines on HBV screening called inadequate
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
New ACC guidance on periprocedural management of anticoagulation in A-fib falls short
SNOWMASS, COLO. – The 2017 American College of Cardiology Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation is a dense, 28-page document filled with multicolored flow charts and six separate management algorithms. But this complex scheme is no substitute for practical clinical judgment and individualized decision making, N.A. Mark Estes, MD, said at the Annual Cardiovascular Conference at Snowmass.
The decision pathway attempts to guide physicians in making decisions about whether and how to interrupt anticoagulation or bridge with a parenteral agent such as low-molecular-weight heparin, and how to restart oral anticoagulation post-procedure (J Am Coll Cardiol. 2017 Jan 5; doi: 10.1016/j.jacc.2016.11.024).
The document defies concise summary. Dr. Estes chose instead to describe the approach he uses in clinical decision-making regarding anticoagulation in patients with atrial fibrillation undergoing invasive procedures. He relies upon three elements: stroke risk as assessed by CHA2DS2-VASc score; bleeding risk using the HAS-BLED score; and the inherent bleeding risk of the procedure itself.
“An important thing to remember is, any procedure done along the spinal cord or intracranially carries an extremely high risk of bleeding,” the cardiologist noted by way of example.
If a patient with atrial fibrillation has a CHA2DS2-VASc score of 2 or less, he doesn’t offer bridging regardless of the HAS-BLED score. If the stroke risk is high as defined by a CHA2DS2-VASc score of 7 or more, and the patient’s bleeding risk isn’t high, meaning the HAS-BLED score is less than 3, he seriously considers bridging, provided that the patient’s oral anticoagulant is warfarin.
“I don’t think at this point we should be bridging with the DOACs [the direct oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban]. All the available data on bridging with the DOACs indicates that it results in a high risk of bleeding with no reduction in risk of stroke,” Dr. Estes said.
The “vast majority” of patients with atrial fibrillation facing surgery have a CHA2DS2-VASc score of 3-7 and thus fall into a category where individualized consideration of the risks and benefits of bridging rules. The large, randomized, double-blind BRIDGE trial speaks to this population. In this study of atrial fibrillation patients on warfarin prior to their procedure, bridging with low-molecular-weight heparin resulted in an increased risk of major bleeding with no reduction in stroke risk compared with a temporary halt of warfarin with no bridging (N Engl J Med. 2015 Aug 27;373[9]:823-33).
“This is a no-brainer,” Dr. Estes said. “When you bridge, your patients bleed more, and you don’t reduce strokes.”
The real challenge is the type of patient who falls into what he called “the dilemma zone,” with a CHA2DS2-VASc score of 7 or more and a HAS-BLED score of 3 or higher, meaning they are at very high risk for both stroke and bleeding.
“I have a discussion with those patients. I usually do not bridge. I’m biased because of having done a lot more harm than good in bridging,” the cardiologist said.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
In reviewing Dr. Estes’ comments on a consensus statement regarding anticoagulation bridging for patients with atrial fibrillation, the most important point is that there are minimal good data to support decision making; therefore, treatments need to be individualized to the patient. He provides a reasonable paradigm for his own decision making in these complex patients. Ultimately, until there is better evidence, the decision on whether to bridge or not to bridge patients’ anticoagulation will continue to be an individual choice based upon bleeding risk with the planned surgical procedure, potential for significant adverse outcomes if bleeding occurs, and the risk of stroke or other embolic phenomenon with cessation of anticoagulation.
Dr. Linda Harris is the division chief, vascular surgery, at the State University of New York at Buffalo and an associate editor of Vascular Specialist.
In reviewing Dr. Estes’ comments on a consensus statement regarding anticoagulation bridging for patients with atrial fibrillation, the most important point is that there are minimal good data to support decision making; therefore, treatments need to be individualized to the patient. He provides a reasonable paradigm for his own decision making in these complex patients. Ultimately, until there is better evidence, the decision on whether to bridge or not to bridge patients’ anticoagulation will continue to be an individual choice based upon bleeding risk with the planned surgical procedure, potential for significant adverse outcomes if bleeding occurs, and the risk of stroke or other embolic phenomenon with cessation of anticoagulation.
Dr. Linda Harris is the division chief, vascular surgery, at the State University of New York at Buffalo and an associate editor of Vascular Specialist.
In reviewing Dr. Estes’ comments on a consensus statement regarding anticoagulation bridging for patients with atrial fibrillation, the most important point is that there are minimal good data to support decision making; therefore, treatments need to be individualized to the patient. He provides a reasonable paradigm for his own decision making in these complex patients. Ultimately, until there is better evidence, the decision on whether to bridge or not to bridge patients’ anticoagulation will continue to be an individual choice based upon bleeding risk with the planned surgical procedure, potential for significant adverse outcomes if bleeding occurs, and the risk of stroke or other embolic phenomenon with cessation of anticoagulation.
Dr. Linda Harris is the division chief, vascular surgery, at the State University of New York at Buffalo and an associate editor of Vascular Specialist.
SNOWMASS, COLO. – The 2017 American College of Cardiology Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation is a dense, 28-page document filled with multicolored flow charts and six separate management algorithms. But this complex scheme is no substitute for practical clinical judgment and individualized decision making, N.A. Mark Estes, MD, said at the Annual Cardiovascular Conference at Snowmass.
The decision pathway attempts to guide physicians in making decisions about whether and how to interrupt anticoagulation or bridge with a parenteral agent such as low-molecular-weight heparin, and how to restart oral anticoagulation post-procedure (J Am Coll Cardiol. 2017 Jan 5; doi: 10.1016/j.jacc.2016.11.024).
The document defies concise summary. Dr. Estes chose instead to describe the approach he uses in clinical decision-making regarding anticoagulation in patients with atrial fibrillation undergoing invasive procedures. He relies upon three elements: stroke risk as assessed by CHA2DS2-VASc score; bleeding risk using the HAS-BLED score; and the inherent bleeding risk of the procedure itself.
“An important thing to remember is, any procedure done along the spinal cord or intracranially carries an extremely high risk of bleeding,” the cardiologist noted by way of example.
If a patient with atrial fibrillation has a CHA2DS2-VASc score of 2 or less, he doesn’t offer bridging regardless of the HAS-BLED score. If the stroke risk is high as defined by a CHA2DS2-VASc score of 7 or more, and the patient’s bleeding risk isn’t high, meaning the HAS-BLED score is less than 3, he seriously considers bridging, provided that the patient’s oral anticoagulant is warfarin.
“I don’t think at this point we should be bridging with the DOACs [the direct oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban]. All the available data on bridging with the DOACs indicates that it results in a high risk of bleeding with no reduction in risk of stroke,” Dr. Estes said.
The “vast majority” of patients with atrial fibrillation facing surgery have a CHA2DS2-VASc score of 3-7 and thus fall into a category where individualized consideration of the risks and benefits of bridging rules. The large, randomized, double-blind BRIDGE trial speaks to this population. In this study of atrial fibrillation patients on warfarin prior to their procedure, bridging with low-molecular-weight heparin resulted in an increased risk of major bleeding with no reduction in stroke risk compared with a temporary halt of warfarin with no bridging (N Engl J Med. 2015 Aug 27;373[9]:823-33).
“This is a no-brainer,” Dr. Estes said. “When you bridge, your patients bleed more, and you don’t reduce strokes.”
The real challenge is the type of patient who falls into what he called “the dilemma zone,” with a CHA2DS2-VASc score of 7 or more and a HAS-BLED score of 3 or higher, meaning they are at very high risk for both stroke and bleeding.
“I have a discussion with those patients. I usually do not bridge. I’m biased because of having done a lot more harm than good in bridging,” the cardiologist said.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
SNOWMASS, COLO. – The 2017 American College of Cardiology Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation is a dense, 28-page document filled with multicolored flow charts and six separate management algorithms. But this complex scheme is no substitute for practical clinical judgment and individualized decision making, N.A. Mark Estes, MD, said at the Annual Cardiovascular Conference at Snowmass.
The decision pathway attempts to guide physicians in making decisions about whether and how to interrupt anticoagulation or bridge with a parenteral agent such as low-molecular-weight heparin, and how to restart oral anticoagulation post-procedure (J Am Coll Cardiol. 2017 Jan 5; doi: 10.1016/j.jacc.2016.11.024).
The document defies concise summary. Dr. Estes chose instead to describe the approach he uses in clinical decision-making regarding anticoagulation in patients with atrial fibrillation undergoing invasive procedures. He relies upon three elements: stroke risk as assessed by CHA2DS2-VASc score; bleeding risk using the HAS-BLED score; and the inherent bleeding risk of the procedure itself.
“An important thing to remember is, any procedure done along the spinal cord or intracranially carries an extremely high risk of bleeding,” the cardiologist noted by way of example.
If a patient with atrial fibrillation has a CHA2DS2-VASc score of 2 or less, he doesn’t offer bridging regardless of the HAS-BLED score. If the stroke risk is high as defined by a CHA2DS2-VASc score of 7 or more, and the patient’s bleeding risk isn’t high, meaning the HAS-BLED score is less than 3, he seriously considers bridging, provided that the patient’s oral anticoagulant is warfarin.
“I don’t think at this point we should be bridging with the DOACs [the direct oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban]. All the available data on bridging with the DOACs indicates that it results in a high risk of bleeding with no reduction in risk of stroke,” Dr. Estes said.
The “vast majority” of patients with atrial fibrillation facing surgery have a CHA2DS2-VASc score of 3-7 and thus fall into a category where individualized consideration of the risks and benefits of bridging rules. The large, randomized, double-blind BRIDGE trial speaks to this population. In this study of atrial fibrillation patients on warfarin prior to their procedure, bridging with low-molecular-weight heparin resulted in an increased risk of major bleeding with no reduction in stroke risk compared with a temporary halt of warfarin with no bridging (N Engl J Med. 2015 Aug 27;373[9]:823-33).
“This is a no-brainer,” Dr. Estes said. “When you bridge, your patients bleed more, and you don’t reduce strokes.”
The real challenge is the type of patient who falls into what he called “the dilemma zone,” with a CHA2DS2-VASc score of 7 or more and a HAS-BLED score of 3 or higher, meaning they are at very high risk for both stroke and bleeding.
“I have a discussion with those patients. I usually do not bridge. I’m biased because of having done a lot more harm than good in bridging,” the cardiologist said.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Rituximab is dramatically effective in IgG4-related disease
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
IgG4-related disease can strike any organ system
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Trials refine device therapy options for heart failure
SNOWMASS, COLO. – The indication for primary prophylactic implantable cardioverter-defibrillator therapy in patients with nonischemic heart failure is likely to be downgraded in the next iteration of the ACC/AHA heart failure guidelines as a consequence of the negative results of the DANISH trial, William T. Abraham, MD, predicted at the Annual Cardiovascular Conference at Snowmass.
In addition to outlining where the guideline recommendations for implantable cardioverter-defibrillator (ICD) therapy stand today, and how they’re likely to change in response to the DANISH findings, he highlighted the latest patient selection criteria for cardiac resynchronization therapy (CRT), which have grown considerably more complicated over time.
“Following the success of neurohormonal inhibitors and antagonists, our only other breakthroughs for the management of heart failure have been CRT and ICDs,” he noted.
The two device therapies are complementary, and indeed are often employed in combination.
“CRT makes patients feel better and saves lives, while ICDs prolong survival without an effect on improving heart failure per se,” the cardiologist explained.
To put the quality of life benefits of CRT into perspective, studies show that the device therapy results in a placebo-subtracted improvement on the Minnesota Living With Heart Failure Questionnaire of 9-10 points.
“This is a large and clinically meaningful improvement in quality of life. Our best drugs for heart failure – beta blockers and ACE inhibitors – improve this same measure by 4 or 5 points,” Dr. Abraham said.
Current American College of Cardiology/American Heart Association heart failure guidelines give a class I, level of evidence: A, recommendation for prophylactic ICD therapy in patients with an left ventricular ejection fraction (LVEF) of 35% or less and New York Heart Association functional class II or III symptoms despite optimal medical therapy, regardless of whether their heart failure is attributable to ischemic heart disease or nonischemic dilated cardiomyopathy.
The DANISH trial investigators looked at the evidence base for primary prevention ICDs in nonischemic heart failure and concluded it needed shoring up. The recommendation relied mainly on subgroup analyses of larger landmark trials done about 15 years ago, before major improvements in medical therapy had occurred. These reservations were the impetus for the DANISH trial, in which more than 1,100 patients with symptomatic systolic heart failure were randomized to an ICD or usual care.
The primary outcome in the DANISH trial – all-cause mortality – occurred in 21.6% of patients in the ICD group and 23.4% of controls during a median follow-up of 68 months, a nonsignificant difference (N Engl J Med. 2016 Sep 29;375[13]:1221-30).
Turning to the CRT guidelines, Dr. Abraham noted that the simple, broad, class I recommendation for this form of device therapy in patients with cardiac dyssynchrony as defined by a QRS duration greater than 120 msec contained in the 2005 ACC/AHA heart failure guidelines has been whittled down over time as new evidence has unfolded. The only class I recommendation in the current guidelines is in patients with an LVEF of 35% or less, sinus rhythm, left bundle branch block with a QRS duration of 150 msec or longer, and NYHA class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy (Circulation. 2012 Oct 1;126:1784-800). “That’s the money group right there. That’s the group for whom we have the greatest confidence of producing the greatest benefit with the application of cardiac resynchronization therapy,” he explained.
Studies examining the use of CRT in heart failure patients with a non–left bundle branch morphology and a QRS duration of less than 150 msec have yielded negative findings. So have attempts to utilize echocardiographic evidence of mechanical dyssynchrony rather than ECG measurement of QRS duration to guide patient selection for CRT.
“In our practice, any patient with a left bundle branch block gets a CRT device. Our confidence in its efficacy is greater in patients with a QRS of at least 150 msec, but the studies demonstrate clear benefit for patients with left bundle branch block and a QRS of 120-149 msec as well,” according to the cardiologist.
Studies also show that patients who are dependent upon ventricular pacing benefit from CRT.
“If you have a patient who requires at least 40% or more ventricular pacing and also has reduced ejection fraction heart failure, that patient should have a CRT device rather than a dual chamber ICD or standard right-sided right ventricular pacemaker,” he said.
All of this presupposes that first and foremost the patient is already on optimized guideline-directed medical therapy.
“With optimal medical therapy, some of these patients may improve their left ventricular ejection fraction above 35%, or they may become asymptomatic and no longer have an indication for CRT,” Dr. Abraham added.
The rationale for utilizing CRT in combination with an ICD is a bit shaky, resting on a single older landmark study, the COMPANION trial (N Engl J Med. 2004; 350:2140-50).
“That study wasn’t powered to answer the question of whether CRT-D [a combined CRT/ICD device] is better than CRT. Really, this remains somewhat of an unanswered question. So where are we today? Essentially, if a patient has an indication for CRT and an indication for an ICD, we implant a combined device,” he said.
Dr. Abraham reported serving as a consultant to Abbott Vascular, Medtronic, Novartis, and St. Jude Medical.
SNOWMASS, COLO. – The indication for primary prophylactic implantable cardioverter-defibrillator therapy in patients with nonischemic heart failure is likely to be downgraded in the next iteration of the ACC/AHA heart failure guidelines as a consequence of the negative results of the DANISH trial, William T. Abraham, MD, predicted at the Annual Cardiovascular Conference at Snowmass.
In addition to outlining where the guideline recommendations for implantable cardioverter-defibrillator (ICD) therapy stand today, and how they’re likely to change in response to the DANISH findings, he highlighted the latest patient selection criteria for cardiac resynchronization therapy (CRT), which have grown considerably more complicated over time.
“Following the success of neurohormonal inhibitors and antagonists, our only other breakthroughs for the management of heart failure have been CRT and ICDs,” he noted.
The two device therapies are complementary, and indeed are often employed in combination.
“CRT makes patients feel better and saves lives, while ICDs prolong survival without an effect on improving heart failure per se,” the cardiologist explained.
To put the quality of life benefits of CRT into perspective, studies show that the device therapy results in a placebo-subtracted improvement on the Minnesota Living With Heart Failure Questionnaire of 9-10 points.
“This is a large and clinically meaningful improvement in quality of life. Our best drugs for heart failure – beta blockers and ACE inhibitors – improve this same measure by 4 or 5 points,” Dr. Abraham said.
Current American College of Cardiology/American Heart Association heart failure guidelines give a class I, level of evidence: A, recommendation for prophylactic ICD therapy in patients with an left ventricular ejection fraction (LVEF) of 35% or less and New York Heart Association functional class II or III symptoms despite optimal medical therapy, regardless of whether their heart failure is attributable to ischemic heart disease or nonischemic dilated cardiomyopathy.
The DANISH trial investigators looked at the evidence base for primary prevention ICDs in nonischemic heart failure and concluded it needed shoring up. The recommendation relied mainly on subgroup analyses of larger landmark trials done about 15 years ago, before major improvements in medical therapy had occurred. These reservations were the impetus for the DANISH trial, in which more than 1,100 patients with symptomatic systolic heart failure were randomized to an ICD or usual care.
The primary outcome in the DANISH trial – all-cause mortality – occurred in 21.6% of patients in the ICD group and 23.4% of controls during a median follow-up of 68 months, a nonsignificant difference (N Engl J Med. 2016 Sep 29;375[13]:1221-30).
Turning to the CRT guidelines, Dr. Abraham noted that the simple, broad, class I recommendation for this form of device therapy in patients with cardiac dyssynchrony as defined by a QRS duration greater than 120 msec contained in the 2005 ACC/AHA heart failure guidelines has been whittled down over time as new evidence has unfolded. The only class I recommendation in the current guidelines is in patients with an LVEF of 35% or less, sinus rhythm, left bundle branch block with a QRS duration of 150 msec or longer, and NYHA class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy (Circulation. 2012 Oct 1;126:1784-800). “That’s the money group right there. That’s the group for whom we have the greatest confidence of producing the greatest benefit with the application of cardiac resynchronization therapy,” he explained.
Studies examining the use of CRT in heart failure patients with a non–left bundle branch morphology and a QRS duration of less than 150 msec have yielded negative findings. So have attempts to utilize echocardiographic evidence of mechanical dyssynchrony rather than ECG measurement of QRS duration to guide patient selection for CRT.
“In our practice, any patient with a left bundle branch block gets a CRT device. Our confidence in its efficacy is greater in patients with a QRS of at least 150 msec, but the studies demonstrate clear benefit for patients with left bundle branch block and a QRS of 120-149 msec as well,” according to the cardiologist.
Studies also show that patients who are dependent upon ventricular pacing benefit from CRT.
“If you have a patient who requires at least 40% or more ventricular pacing and also has reduced ejection fraction heart failure, that patient should have a CRT device rather than a dual chamber ICD or standard right-sided right ventricular pacemaker,” he said.
All of this presupposes that first and foremost the patient is already on optimized guideline-directed medical therapy.
“With optimal medical therapy, some of these patients may improve their left ventricular ejection fraction above 35%, or they may become asymptomatic and no longer have an indication for CRT,” Dr. Abraham added.
The rationale for utilizing CRT in combination with an ICD is a bit shaky, resting on a single older landmark study, the COMPANION trial (N Engl J Med. 2004; 350:2140-50).
“That study wasn’t powered to answer the question of whether CRT-D [a combined CRT/ICD device] is better than CRT. Really, this remains somewhat of an unanswered question. So where are we today? Essentially, if a patient has an indication for CRT and an indication for an ICD, we implant a combined device,” he said.
Dr. Abraham reported serving as a consultant to Abbott Vascular, Medtronic, Novartis, and St. Jude Medical.
SNOWMASS, COLO. – The indication for primary prophylactic implantable cardioverter-defibrillator therapy in patients with nonischemic heart failure is likely to be downgraded in the next iteration of the ACC/AHA heart failure guidelines as a consequence of the negative results of the DANISH trial, William T. Abraham, MD, predicted at the Annual Cardiovascular Conference at Snowmass.
In addition to outlining where the guideline recommendations for implantable cardioverter-defibrillator (ICD) therapy stand today, and how they’re likely to change in response to the DANISH findings, he highlighted the latest patient selection criteria for cardiac resynchronization therapy (CRT), which have grown considerably more complicated over time.
“Following the success of neurohormonal inhibitors and antagonists, our only other breakthroughs for the management of heart failure have been CRT and ICDs,” he noted.
The two device therapies are complementary, and indeed are often employed in combination.
“CRT makes patients feel better and saves lives, while ICDs prolong survival without an effect on improving heart failure per se,” the cardiologist explained.
To put the quality of life benefits of CRT into perspective, studies show that the device therapy results in a placebo-subtracted improvement on the Minnesota Living With Heart Failure Questionnaire of 9-10 points.
“This is a large and clinically meaningful improvement in quality of life. Our best drugs for heart failure – beta blockers and ACE inhibitors – improve this same measure by 4 or 5 points,” Dr. Abraham said.
Current American College of Cardiology/American Heart Association heart failure guidelines give a class I, level of evidence: A, recommendation for prophylactic ICD therapy in patients with an left ventricular ejection fraction (LVEF) of 35% or less and New York Heart Association functional class II or III symptoms despite optimal medical therapy, regardless of whether their heart failure is attributable to ischemic heart disease or nonischemic dilated cardiomyopathy.
The DANISH trial investigators looked at the evidence base for primary prevention ICDs in nonischemic heart failure and concluded it needed shoring up. The recommendation relied mainly on subgroup analyses of larger landmark trials done about 15 years ago, before major improvements in medical therapy had occurred. These reservations were the impetus for the DANISH trial, in which more than 1,100 patients with symptomatic systolic heart failure were randomized to an ICD or usual care.
The primary outcome in the DANISH trial – all-cause mortality – occurred in 21.6% of patients in the ICD group and 23.4% of controls during a median follow-up of 68 months, a nonsignificant difference (N Engl J Med. 2016 Sep 29;375[13]:1221-30).
Turning to the CRT guidelines, Dr. Abraham noted that the simple, broad, class I recommendation for this form of device therapy in patients with cardiac dyssynchrony as defined by a QRS duration greater than 120 msec contained in the 2005 ACC/AHA heart failure guidelines has been whittled down over time as new evidence has unfolded. The only class I recommendation in the current guidelines is in patients with an LVEF of 35% or less, sinus rhythm, left bundle branch block with a QRS duration of 150 msec or longer, and NYHA class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy (Circulation. 2012 Oct 1;126:1784-800). “That’s the money group right there. That’s the group for whom we have the greatest confidence of producing the greatest benefit with the application of cardiac resynchronization therapy,” he explained.
Studies examining the use of CRT in heart failure patients with a non–left bundle branch morphology and a QRS duration of less than 150 msec have yielded negative findings. So have attempts to utilize echocardiographic evidence of mechanical dyssynchrony rather than ECG measurement of QRS duration to guide patient selection for CRT.
“In our practice, any patient with a left bundle branch block gets a CRT device. Our confidence in its efficacy is greater in patients with a QRS of at least 150 msec, but the studies demonstrate clear benefit for patients with left bundle branch block and a QRS of 120-149 msec as well,” according to the cardiologist.
Studies also show that patients who are dependent upon ventricular pacing benefit from CRT.
“If you have a patient who requires at least 40% or more ventricular pacing and also has reduced ejection fraction heart failure, that patient should have a CRT device rather than a dual chamber ICD or standard right-sided right ventricular pacemaker,” he said.
All of this presupposes that first and foremost the patient is already on optimized guideline-directed medical therapy.
“With optimal medical therapy, some of these patients may improve their left ventricular ejection fraction above 35%, or they may become asymptomatic and no longer have an indication for CRT,” Dr. Abraham added.
The rationale for utilizing CRT in combination with an ICD is a bit shaky, resting on a single older landmark study, the COMPANION trial (N Engl J Med. 2004; 350:2140-50).
“That study wasn’t powered to answer the question of whether CRT-D [a combined CRT/ICD device] is better than CRT. Really, this remains somewhat of an unanswered question. So where are we today? Essentially, if a patient has an indication for CRT and an indication for an ICD, we implant a combined device,” he said.
Dr. Abraham reported serving as a consultant to Abbott Vascular, Medtronic, Novartis, and St. Jude Medical.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
