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Nearly 25% of U.S. adults take an obesogenic prescription drug
LAS VEGAS – based on national U.S. data collected during 2013-2016.
The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.
According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).
The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.
The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.
The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m2), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m2), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m2), and 33% among those with class 3 obesity (BMI, 40 kg/m2 or greater).
In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.
As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.
NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.
SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.
LAS VEGAS – based on national U.S. data collected during 2013-2016.
The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.
According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).
The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.
The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.
The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m2), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m2), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m2), and 33% among those with class 3 obesity (BMI, 40 kg/m2 or greater).
In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.
As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.
NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.
SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.
LAS VEGAS – based on national U.S. data collected during 2013-2016.
The Endocrine Society, the STOP Obesity Alliance, and other medical societies have recommended that clinicians try to minimize use of obesogenic drugs and focus on prescribing agents that are weight neutral or that trigger weight loss when those options are available and appropriate, and the new findings add further evidence that clinicians need to be more mindful of this issue, Craig M. Hales, MD, said at a meeting presented by the Obesity Society and the American Society for Metabolic and Bariatric Surgery.
Among the American adults interviewed for the survey, 40% of those on at least one prescription medication were on at least one drug that is considered obesogenic, said Dr. Hales, a medical epidemiologist at the Centers for Disease Control and Prevention in Hyattsville, Md.
According to practice guidelines published by the Endocrine Society, all drugs in the classes of glucocorticoids, beta-blockers, and antihistamines are obesogenic, as well as selected agents in the classes of antidepressant drugs, antipsychotics, antidepressants, antidiabetics, and contraceptives that are progestin only, said Dr. Hales (J Clin Endocrinol Metab. 2015 Feb;100[2]:342-62).
The data he reported came from the National Health and Nutrition Examination Survey (NHANES) run by the CDC during 2013-2016 that included 11,055 adults who were at least 20 years old. The findings showed that 23% of those adults had taken at least one drug that was considered obesogenic during the 30 days preceding the survey date. By comparison, 35% of the same adults had taken any type of prescription drug during the previous 30 days. That meant that overall, 40% of surveyed adults who had recently used any prescription medication had taken an obesogenic drug.
The 23% prevalence of recent obesogenic drug use was fairly stable at that level during several preceding NHANES surveys going back to 2001, suggesting that the increasing use of obesogenic drugs during the period since 2001 was not a factor in the recent increased prevalence of obesity among U.S. residents, added Dr. Hales.
The 2013-2016 analysis also showed a strong link between obesogenic drug use and increasing obesity severity. Among survey participants with a body mass index (BMI) in the normal range (18.5-24 kg/m2), 16% had recent use of an obesogenic drug. This prevalence increased to 22% among those who were overweight (BMI, 25-29 kg/m2), 29% among those with class 1 or 2 obesity (BMI, 30-39 kg/m2), and 33% among those with class 3 obesity (BMI, 40 kg/m2 or greater).
In contrast, recent use of prescription medications that do not contribute to obesity showed no significant relationship with BMI, with rates that ranged from 34% among those with a normal BMI, to 37% among those with class 3 obesity.
As an example of this relationship for a specific obesogenic drug class, the prevalence of beta-blocker use was about 7% among people with a normal BMI, about 10% among those who were overweight, about 14% among people with class 1 or 2 obesity, and about 17% among people with class 3 obesity, a statistically significant link suggesting that the relationship between use of obesogenic drugs and obesity is “bidirectional,” Dr. Hales said, in that increasing obesogenic drug use likely contributes to obesity, while simultaneously, the more obese people become, the more likely they are to take additional prescription drugs, particularly those that are obesogenic.
NHANES is run by the CDC and receives no commercial funding. The authors reported no conflicts of interest.
SOURCE: Hales CM et al. Obesity Week 2019, Abstract T-OR-2037.
REPORTING FROM OBESITY WEEK 2019
Hydroxychloroquine prevents congenital heart block recurrence in anti-Ro pregnancies
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
REPORTING FROM ACR 2019
ACR and EULAR release first classification criteria for IgG4-related disease
The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.
Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.
“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.
To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).
The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.
If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.
The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.
“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.
Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.
Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.
“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”
The authors reported no relevant conflicts of interest.
SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.
The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.
Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.
“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.
To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).
The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.
If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.
The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.
“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.
Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.
Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.
“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”
The authors reported no relevant conflicts of interest.
SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.
The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.
Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.
“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.
To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).
The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.
If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.
The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.
“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.
Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.
Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.
“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”
The authors reported no relevant conflicts of interest.
SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.
FROM ARTHRITIS & RHEUMATOLOGY
VEDOSS study describes predictors of progression to systemic sclerosis
ATLANTA – , according to recent results from the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) study presented at the annual meeting of the American College of Rheumatology.
“Our data show that thanks [to a] combination of the signs that characterize the various phases of the disease, patients can be diagnosed [with systemic sclerosis] in the very early stages,” first author Silvia Bellando-Randone, MD, PhD, assistant professor in the division of rheumatology at the University of Florence (Italy), said in her presentation.
Dr. Bellando-Randone and colleagues performed a longitudinal, observational study of 742 patients (mean 45.7 years old) at 42 centers in a cohort of mostly women (90%), nearly all of whom had had Raynaud’s phenomenon for longer than 36 months (97.5%). Patients were excluded if they had systemic sclerosis based on ACR 1980 classification criteria and/or ACR–European League Against Rheumatism 2013 criteria, had systemic sclerosis together with other connective-tissue diseases, or were unlikely to be present for three consecutive annual exams. Data collection began in March 2012 with follow-up of 5 years.
The researchers determined the positive predictive values (PPV) and negative predictive values (NPV) of clinical features, systemic sclerosis–specific antibodies, and nailfold video capillaroscopy (NVC) abnormalities on progression from Raynaud’s phenomenon to systemic sclerosis. Laboratory data collected at baseline included presence of antinuclear antibodies (ANA), anticentromere antibodies (ACA), anti-DNA topoisomerase I antibodies (anti-Scl-70), anti-U1RNP antibodies, anti-RNA polymerase III antibodies (ARA), N-terminal pro b-type natriuretic peptides (NT-proBNP), and C-reactive protein/erythrocyte sedimentation rate. Dr. Bellando-Randone and colleagues also collected clinical, pulmonary function, lung high-resolution CT, echocardiographic, and ECG data at baseline.
Predictions were based on these factors alone and in combination. Overall, 65% of patients had positive ANA. Other baseline characteristics present in patients that predicted systemic sclerosis included positive ACA/anti-Scl-70/ARA (32%), NVC abnormalities such as giant capillaries (25%), and puffy fingers (17%).
Using Kaplan-Meier analysis, the researchers found 7.4% of 401 patients who were ANA positive progressed to meet ACR-EULAR 2013 criteria, and the percentage of these patients increased to 29.3% at 3 years and 44.1% at 5 years. When the researchers considered disease-specific antibodies alone, 10.6% of 90 patients progressed from Raynaud’s phenomenon to systemic sclerosis within 1 year, 39.6% within 3 years, and 50.3% within 5 years. When the researchers analyzed disease-specific antibodies and NVC abnormalities together, 16% of 72 patients progressed to systemic sclerosis within 1 year, 61.7% within 3 years, and 77.4% within 5 years.
Puffy fingers also were a predictor of progression, and 14.4% of 69 patients with puffy fingers alone progressed from Raynaud’s phenomenon to systemic sclerosis at 1 year, 47.7% at 3 years, and 67.9% at 5 years. Considering puffy fingers and disease-specific antibodies together, 20% of 27 patients progressed at 1 year, 56.3% at 3 years, and 91.3% at 5 years. No patients with puffy fingers together and NVC abnormalities progressed to systemic sclerosis at 1 year, but 60.4% of 22 patients progressed at 3 years before plateauing at 5 years. For patients with NVC abnormalities alone, 7.1% progressed to systemic sclerosis from Raynaud’s phenomenon at 1 year, 39.4% at 3 years, and 52.7% at 5 years.
“Regarding capillaroscopy, we have to say that not all centers that participated were equally screened in capillaroscopy, and so we cannot assume the accuracy of this data,” she said.
Dr. Bellando-Randone noted that, apart from puffy fingers, disease-specific antibodies, and NVC abnormalities, patients were more likely to have a history of esophageal symptoms if they progressed to systemic sclerosis (37.3%), compared with patients who did not progress (23.6%; P = .003).
Puffy fingers alone were an independent predictor of systemic sclerosis (PPV, 78.9%; NPV, 45.1%) as well as in combination with disease-specific antibodies (PPV, 94.1%; NPV, 43.9%). The combination of disease-specific antibodies plus NVC abnormalities also independently predicted progression to systemic sclerosis (PPV, 82.2%; NPV, 50.4%). In a Cox multivariate analysis, disease-specific antibodies (relative risk, 5.4; 95% confidence interval, 3.7-7.9) and puffy fingers (RR, 3.0; 95% CI, 2.0-4.4) together were strongly predictive of progression from Raynaud’s phenomenon to systemic sclerosis (RR, 4.3; 95% CI, 2.6-7.3).
“This is really important for the risk stratification of patients [in] the very early stages of the disease, even if these data should be corroborated by larger data in larger studies in the future,” said Dr. Bellando-Randone.
The investigators reported having no conflicts of interest.
SOURCE: Bellando-Randone S et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 2914.
ATLANTA – , according to recent results from the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) study presented at the annual meeting of the American College of Rheumatology.
“Our data show that thanks [to a] combination of the signs that characterize the various phases of the disease, patients can be diagnosed [with systemic sclerosis] in the very early stages,” first author Silvia Bellando-Randone, MD, PhD, assistant professor in the division of rheumatology at the University of Florence (Italy), said in her presentation.
Dr. Bellando-Randone and colleagues performed a longitudinal, observational study of 742 patients (mean 45.7 years old) at 42 centers in a cohort of mostly women (90%), nearly all of whom had had Raynaud’s phenomenon for longer than 36 months (97.5%). Patients were excluded if they had systemic sclerosis based on ACR 1980 classification criteria and/or ACR–European League Against Rheumatism 2013 criteria, had systemic sclerosis together with other connective-tissue diseases, or were unlikely to be present for three consecutive annual exams. Data collection began in March 2012 with follow-up of 5 years.
The researchers determined the positive predictive values (PPV) and negative predictive values (NPV) of clinical features, systemic sclerosis–specific antibodies, and nailfold video capillaroscopy (NVC) abnormalities on progression from Raynaud’s phenomenon to systemic sclerosis. Laboratory data collected at baseline included presence of antinuclear antibodies (ANA), anticentromere antibodies (ACA), anti-DNA topoisomerase I antibodies (anti-Scl-70), anti-U1RNP antibodies, anti-RNA polymerase III antibodies (ARA), N-terminal pro b-type natriuretic peptides (NT-proBNP), and C-reactive protein/erythrocyte sedimentation rate. Dr. Bellando-Randone and colleagues also collected clinical, pulmonary function, lung high-resolution CT, echocardiographic, and ECG data at baseline.
Predictions were based on these factors alone and in combination. Overall, 65% of patients had positive ANA. Other baseline characteristics present in patients that predicted systemic sclerosis included positive ACA/anti-Scl-70/ARA (32%), NVC abnormalities such as giant capillaries (25%), and puffy fingers (17%).
Using Kaplan-Meier analysis, the researchers found 7.4% of 401 patients who were ANA positive progressed to meet ACR-EULAR 2013 criteria, and the percentage of these patients increased to 29.3% at 3 years and 44.1% at 5 years. When the researchers considered disease-specific antibodies alone, 10.6% of 90 patients progressed from Raynaud’s phenomenon to systemic sclerosis within 1 year, 39.6% within 3 years, and 50.3% within 5 years. When the researchers analyzed disease-specific antibodies and NVC abnormalities together, 16% of 72 patients progressed to systemic sclerosis within 1 year, 61.7% within 3 years, and 77.4% within 5 years.
Puffy fingers also were a predictor of progression, and 14.4% of 69 patients with puffy fingers alone progressed from Raynaud’s phenomenon to systemic sclerosis at 1 year, 47.7% at 3 years, and 67.9% at 5 years. Considering puffy fingers and disease-specific antibodies together, 20% of 27 patients progressed at 1 year, 56.3% at 3 years, and 91.3% at 5 years. No patients with puffy fingers together and NVC abnormalities progressed to systemic sclerosis at 1 year, but 60.4% of 22 patients progressed at 3 years before plateauing at 5 years. For patients with NVC abnormalities alone, 7.1% progressed to systemic sclerosis from Raynaud’s phenomenon at 1 year, 39.4% at 3 years, and 52.7% at 5 years.
“Regarding capillaroscopy, we have to say that not all centers that participated were equally screened in capillaroscopy, and so we cannot assume the accuracy of this data,” she said.
Dr. Bellando-Randone noted that, apart from puffy fingers, disease-specific antibodies, and NVC abnormalities, patients were more likely to have a history of esophageal symptoms if they progressed to systemic sclerosis (37.3%), compared with patients who did not progress (23.6%; P = .003).
Puffy fingers alone were an independent predictor of systemic sclerosis (PPV, 78.9%; NPV, 45.1%) as well as in combination with disease-specific antibodies (PPV, 94.1%; NPV, 43.9%). The combination of disease-specific antibodies plus NVC abnormalities also independently predicted progression to systemic sclerosis (PPV, 82.2%; NPV, 50.4%). In a Cox multivariate analysis, disease-specific antibodies (relative risk, 5.4; 95% confidence interval, 3.7-7.9) and puffy fingers (RR, 3.0; 95% CI, 2.0-4.4) together were strongly predictive of progression from Raynaud’s phenomenon to systemic sclerosis (RR, 4.3; 95% CI, 2.6-7.3).
“This is really important for the risk stratification of patients [in] the very early stages of the disease, even if these data should be corroborated by larger data in larger studies in the future,” said Dr. Bellando-Randone.
The investigators reported having no conflicts of interest.
SOURCE: Bellando-Randone S et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 2914.
ATLANTA – , according to recent results from the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) study presented at the annual meeting of the American College of Rheumatology.
“Our data show that thanks [to a] combination of the signs that characterize the various phases of the disease, patients can be diagnosed [with systemic sclerosis] in the very early stages,” first author Silvia Bellando-Randone, MD, PhD, assistant professor in the division of rheumatology at the University of Florence (Italy), said in her presentation.
Dr. Bellando-Randone and colleagues performed a longitudinal, observational study of 742 patients (mean 45.7 years old) at 42 centers in a cohort of mostly women (90%), nearly all of whom had had Raynaud’s phenomenon for longer than 36 months (97.5%). Patients were excluded if they had systemic sclerosis based on ACR 1980 classification criteria and/or ACR–European League Against Rheumatism 2013 criteria, had systemic sclerosis together with other connective-tissue diseases, or were unlikely to be present for three consecutive annual exams. Data collection began in March 2012 with follow-up of 5 years.
The researchers determined the positive predictive values (PPV) and negative predictive values (NPV) of clinical features, systemic sclerosis–specific antibodies, and nailfold video capillaroscopy (NVC) abnormalities on progression from Raynaud’s phenomenon to systemic sclerosis. Laboratory data collected at baseline included presence of antinuclear antibodies (ANA), anticentromere antibodies (ACA), anti-DNA topoisomerase I antibodies (anti-Scl-70), anti-U1RNP antibodies, anti-RNA polymerase III antibodies (ARA), N-terminal pro b-type natriuretic peptides (NT-proBNP), and C-reactive protein/erythrocyte sedimentation rate. Dr. Bellando-Randone and colleagues also collected clinical, pulmonary function, lung high-resolution CT, echocardiographic, and ECG data at baseline.
Predictions were based on these factors alone and in combination. Overall, 65% of patients had positive ANA. Other baseline characteristics present in patients that predicted systemic sclerosis included positive ACA/anti-Scl-70/ARA (32%), NVC abnormalities such as giant capillaries (25%), and puffy fingers (17%).
Using Kaplan-Meier analysis, the researchers found 7.4% of 401 patients who were ANA positive progressed to meet ACR-EULAR 2013 criteria, and the percentage of these patients increased to 29.3% at 3 years and 44.1% at 5 years. When the researchers considered disease-specific antibodies alone, 10.6% of 90 patients progressed from Raynaud’s phenomenon to systemic sclerosis within 1 year, 39.6% within 3 years, and 50.3% within 5 years. When the researchers analyzed disease-specific antibodies and NVC abnormalities together, 16% of 72 patients progressed to systemic sclerosis within 1 year, 61.7% within 3 years, and 77.4% within 5 years.
Puffy fingers also were a predictor of progression, and 14.4% of 69 patients with puffy fingers alone progressed from Raynaud’s phenomenon to systemic sclerosis at 1 year, 47.7% at 3 years, and 67.9% at 5 years. Considering puffy fingers and disease-specific antibodies together, 20% of 27 patients progressed at 1 year, 56.3% at 3 years, and 91.3% at 5 years. No patients with puffy fingers together and NVC abnormalities progressed to systemic sclerosis at 1 year, but 60.4% of 22 patients progressed at 3 years before plateauing at 5 years. For patients with NVC abnormalities alone, 7.1% progressed to systemic sclerosis from Raynaud’s phenomenon at 1 year, 39.4% at 3 years, and 52.7% at 5 years.
“Regarding capillaroscopy, we have to say that not all centers that participated were equally screened in capillaroscopy, and so we cannot assume the accuracy of this data,” she said.
Dr. Bellando-Randone noted that, apart from puffy fingers, disease-specific antibodies, and NVC abnormalities, patients were more likely to have a history of esophageal symptoms if they progressed to systemic sclerosis (37.3%), compared with patients who did not progress (23.6%; P = .003).
Puffy fingers alone were an independent predictor of systemic sclerosis (PPV, 78.9%; NPV, 45.1%) as well as in combination with disease-specific antibodies (PPV, 94.1%; NPV, 43.9%). The combination of disease-specific antibodies plus NVC abnormalities also independently predicted progression to systemic sclerosis (PPV, 82.2%; NPV, 50.4%). In a Cox multivariate analysis, disease-specific antibodies (relative risk, 5.4; 95% confidence interval, 3.7-7.9) and puffy fingers (RR, 3.0; 95% CI, 2.0-4.4) together were strongly predictive of progression from Raynaud’s phenomenon to systemic sclerosis (RR, 4.3; 95% CI, 2.6-7.3).
“This is really important for the risk stratification of patients [in] the very early stages of the disease, even if these data should be corroborated by larger data in larger studies in the future,” said Dr. Bellando-Randone.
The investigators reported having no conflicts of interest.
SOURCE: Bellando-Randone S et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 2914.
REPORTING FROM ACR 2019
Repeat LTBI testing best in patients taking biologics with new risk factors
ATLANTA – Patients taking biologics who received latent tuberculosis testing on an annual basis were unlikely to convert from a negative QuantiFERON test to a positive result, which suggests that the test may be unnecessary for patients without new tuberculosis risk factors, according to research presented at the annual meeting of the American College of Rheumatology.
In addition, nearly all of the cost of repeat testing for latent tuberculosis infection (LTBI) went to patients who were not diagnosed with or treated for LTBI, noted Urmi Khanna, MD, a dermatologist with the Cleveland Clinic.
“All in all, about $1.4 million U.S. dollars was spent just on additional QuantiFERON testing, and only 1% of this additional cost was actually spent on testing patients who were diagnosed with and treated for latent tuberculosis,” Dr. Khanna said in her presentation at the meeting.
“Based on this study, we would like to propose that, in low incidence TB regions such as the United States, repeat LTBI testing in patients on biologic therapies should be focused on patients who have new risk factors for TB infection since their last screening,” she said.
The National Psoriasis Foundation has recommended patients be screened annually for LTBI, and the Centers for Disease Control and Prevention and the ACR have recommended patients taking biologics be screened annually for LTBI if they have new risk factors for TB, such as coming into contact with immigrants, a person infected with TB, immunosuppressed individuals, or persons working in areas where TB might be present. Annual screening was also recently added to the Medicare Merit-Based Incentive Payment System (MIPS), which will affect physician reimbursement. “Based on [the addition of this quality outcome measure], we expect that more and more physicians will adopt this practice of annual LTBI screening in all patients on biologics,” Dr. Khanna said.
She and her colleagues examined QuantiFERON tuberculosis test (QFT) results of 10,914 patients from the Cleveland Clinic Foundation between August 2007 and March 2019 where patients were receiving systemic biologic therapy for inflammatory or autoimmune conditions, including nearly 32% with inflammatory bowel disease, 29% with rheumatoid arthritis, and 25% with psoriatic disease. Overall, 5,212 patients were included in the final analysis, and patients had a median of three QFT results. Patients had a median age of 41 years, had taken an average of 1.80 biologics during follow-up, and had a median biologic therapy duration of about 49 months. The most common biologics used were adalimumab (33%), etanercept (17%), and infliximab (17%).
Of these patients, 4,561 patients had negative QFTs (88%), 172 patients had one or more positive QFTs (3%), and 479 patients had one or more indeterminate QFTs (9%). For patients who converted from a negative QFT to a positive QFT, the most common risk factors were exposure to someone with TB (26%), immigrating or traveling to an endemic area (26%), and occupational exposure (16%).
Within the group with one or more positive QFTs, there were 108 patients with baseline positive QFTs prior to starting biologic therapy (2.1%), 61 patients who converted from a baseline negative QFT to a positive QFT (1.2%), and 3 patients where a positive result overlapped with a negative result (0.1%). The majority of patients who converted to a positive QFT result had borderline positive results (70.5%), defined as 0.35 to 1 IU/mL, compared with 29.5% of converters who had a positive QFT result of more than 1.0 IU/mL.
Among the 61 patients who converted to a positive QFT result, 28 patients with LTBI (46%) and 1 patient with an active case of TB (2%) were diagnosed and treated. The active TB case was a 29-year-old patient with inflammatory bowel disease and ankylosing spondylitis receiving adalimumab who had recently traveled to India.
The researchers also examined the cost of additional QFTs in each group. Among negative QFTs, the cost of an additional 9,611 tests was $1,201,375. The cost of additional tests for indeterminate QFTs was $136,200, but Dr. Khanna noted that 99.99% of additional tests in this group were for patients never diagnosed with or treated for LTBI. Additional tests for positive QFTs cost another $47,700, and 26.1% of patients in this group were diagnosed and received treatment for LTBI, compared with 73.9% who did not receive an LTBI diagnosis or treatment.
In the discussion session following the presentation, Dr. Khanna emphasized that discontinuing annual screening in low-risk patients was not standard of care at the Cleveland Clinic, and this study was conducted to raise awareness of focusing testing on patients with new TB risk factors.
Dr. Khanna reported no relevant financial disclosures. A few of her coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Khanna U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1802.
ATLANTA – Patients taking biologics who received latent tuberculosis testing on an annual basis were unlikely to convert from a negative QuantiFERON test to a positive result, which suggests that the test may be unnecessary for patients without new tuberculosis risk factors, according to research presented at the annual meeting of the American College of Rheumatology.
In addition, nearly all of the cost of repeat testing for latent tuberculosis infection (LTBI) went to patients who were not diagnosed with or treated for LTBI, noted Urmi Khanna, MD, a dermatologist with the Cleveland Clinic.
“All in all, about $1.4 million U.S. dollars was spent just on additional QuantiFERON testing, and only 1% of this additional cost was actually spent on testing patients who were diagnosed with and treated for latent tuberculosis,” Dr. Khanna said in her presentation at the meeting.
“Based on this study, we would like to propose that, in low incidence TB regions such as the United States, repeat LTBI testing in patients on biologic therapies should be focused on patients who have new risk factors for TB infection since their last screening,” she said.
The National Psoriasis Foundation has recommended patients be screened annually for LTBI, and the Centers for Disease Control and Prevention and the ACR have recommended patients taking biologics be screened annually for LTBI if they have new risk factors for TB, such as coming into contact with immigrants, a person infected with TB, immunosuppressed individuals, or persons working in areas where TB might be present. Annual screening was also recently added to the Medicare Merit-Based Incentive Payment System (MIPS), which will affect physician reimbursement. “Based on [the addition of this quality outcome measure], we expect that more and more physicians will adopt this practice of annual LTBI screening in all patients on biologics,” Dr. Khanna said.
She and her colleagues examined QuantiFERON tuberculosis test (QFT) results of 10,914 patients from the Cleveland Clinic Foundation between August 2007 and March 2019 where patients were receiving systemic biologic therapy for inflammatory or autoimmune conditions, including nearly 32% with inflammatory bowel disease, 29% with rheumatoid arthritis, and 25% with psoriatic disease. Overall, 5,212 patients were included in the final analysis, and patients had a median of three QFT results. Patients had a median age of 41 years, had taken an average of 1.80 biologics during follow-up, and had a median biologic therapy duration of about 49 months. The most common biologics used were adalimumab (33%), etanercept (17%), and infliximab (17%).
Of these patients, 4,561 patients had negative QFTs (88%), 172 patients had one or more positive QFTs (3%), and 479 patients had one or more indeterminate QFTs (9%). For patients who converted from a negative QFT to a positive QFT, the most common risk factors were exposure to someone with TB (26%), immigrating or traveling to an endemic area (26%), and occupational exposure (16%).
Within the group with one or more positive QFTs, there were 108 patients with baseline positive QFTs prior to starting biologic therapy (2.1%), 61 patients who converted from a baseline negative QFT to a positive QFT (1.2%), and 3 patients where a positive result overlapped with a negative result (0.1%). The majority of patients who converted to a positive QFT result had borderline positive results (70.5%), defined as 0.35 to 1 IU/mL, compared with 29.5% of converters who had a positive QFT result of more than 1.0 IU/mL.
Among the 61 patients who converted to a positive QFT result, 28 patients with LTBI (46%) and 1 patient with an active case of TB (2%) were diagnosed and treated. The active TB case was a 29-year-old patient with inflammatory bowel disease and ankylosing spondylitis receiving adalimumab who had recently traveled to India.
The researchers also examined the cost of additional QFTs in each group. Among negative QFTs, the cost of an additional 9,611 tests was $1,201,375. The cost of additional tests for indeterminate QFTs was $136,200, but Dr. Khanna noted that 99.99% of additional tests in this group were for patients never diagnosed with or treated for LTBI. Additional tests for positive QFTs cost another $47,700, and 26.1% of patients in this group were diagnosed and received treatment for LTBI, compared with 73.9% who did not receive an LTBI diagnosis or treatment.
In the discussion session following the presentation, Dr. Khanna emphasized that discontinuing annual screening in low-risk patients was not standard of care at the Cleveland Clinic, and this study was conducted to raise awareness of focusing testing on patients with new TB risk factors.
Dr. Khanna reported no relevant financial disclosures. A few of her coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Khanna U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1802.
ATLANTA – Patients taking biologics who received latent tuberculosis testing on an annual basis were unlikely to convert from a negative QuantiFERON test to a positive result, which suggests that the test may be unnecessary for patients without new tuberculosis risk factors, according to research presented at the annual meeting of the American College of Rheumatology.
In addition, nearly all of the cost of repeat testing for latent tuberculosis infection (LTBI) went to patients who were not diagnosed with or treated for LTBI, noted Urmi Khanna, MD, a dermatologist with the Cleveland Clinic.
“All in all, about $1.4 million U.S. dollars was spent just on additional QuantiFERON testing, and only 1% of this additional cost was actually spent on testing patients who were diagnosed with and treated for latent tuberculosis,” Dr. Khanna said in her presentation at the meeting.
“Based on this study, we would like to propose that, in low incidence TB regions such as the United States, repeat LTBI testing in patients on biologic therapies should be focused on patients who have new risk factors for TB infection since their last screening,” she said.
The National Psoriasis Foundation has recommended patients be screened annually for LTBI, and the Centers for Disease Control and Prevention and the ACR have recommended patients taking biologics be screened annually for LTBI if they have new risk factors for TB, such as coming into contact with immigrants, a person infected with TB, immunosuppressed individuals, or persons working in areas where TB might be present. Annual screening was also recently added to the Medicare Merit-Based Incentive Payment System (MIPS), which will affect physician reimbursement. “Based on [the addition of this quality outcome measure], we expect that more and more physicians will adopt this practice of annual LTBI screening in all patients on biologics,” Dr. Khanna said.
She and her colleagues examined QuantiFERON tuberculosis test (QFT) results of 10,914 patients from the Cleveland Clinic Foundation between August 2007 and March 2019 where patients were receiving systemic biologic therapy for inflammatory or autoimmune conditions, including nearly 32% with inflammatory bowel disease, 29% with rheumatoid arthritis, and 25% with psoriatic disease. Overall, 5,212 patients were included in the final analysis, and patients had a median of three QFT results. Patients had a median age of 41 years, had taken an average of 1.80 biologics during follow-up, and had a median biologic therapy duration of about 49 months. The most common biologics used were adalimumab (33%), etanercept (17%), and infliximab (17%).
Of these patients, 4,561 patients had negative QFTs (88%), 172 patients had one or more positive QFTs (3%), and 479 patients had one or more indeterminate QFTs (9%). For patients who converted from a negative QFT to a positive QFT, the most common risk factors were exposure to someone with TB (26%), immigrating or traveling to an endemic area (26%), and occupational exposure (16%).
Within the group with one or more positive QFTs, there were 108 patients with baseline positive QFTs prior to starting biologic therapy (2.1%), 61 patients who converted from a baseline negative QFT to a positive QFT (1.2%), and 3 patients where a positive result overlapped with a negative result (0.1%). The majority of patients who converted to a positive QFT result had borderline positive results (70.5%), defined as 0.35 to 1 IU/mL, compared with 29.5% of converters who had a positive QFT result of more than 1.0 IU/mL.
Among the 61 patients who converted to a positive QFT result, 28 patients with LTBI (46%) and 1 patient with an active case of TB (2%) were diagnosed and treated. The active TB case was a 29-year-old patient with inflammatory bowel disease and ankylosing spondylitis receiving adalimumab who had recently traveled to India.
The researchers also examined the cost of additional QFTs in each group. Among negative QFTs, the cost of an additional 9,611 tests was $1,201,375. The cost of additional tests for indeterminate QFTs was $136,200, but Dr. Khanna noted that 99.99% of additional tests in this group were for patients never diagnosed with or treated for LTBI. Additional tests for positive QFTs cost another $47,700, and 26.1% of patients in this group were diagnosed and received treatment for LTBI, compared with 73.9% who did not receive an LTBI diagnosis or treatment.
In the discussion session following the presentation, Dr. Khanna emphasized that discontinuing annual screening in low-risk patients was not standard of care at the Cleveland Clinic, and this study was conducted to raise awareness of focusing testing on patients with new TB risk factors.
Dr. Khanna reported no relevant financial disclosures. A few of her coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Khanna U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1802.
REPORTING FROM ACR 2019
TULIP trials show clinical benefit of anifrolumab for SLE
ATLANTA –
In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.
The findings were published online Nov. 11 in Lancet Rheumatology.
TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.
The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.
The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.
“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”
Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.
In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.
TULIP-1
The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.
The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.
Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.
BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.
The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.
“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”
The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.
“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.
The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.
However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).
“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.
Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.
The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.
Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).
“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.
The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”
Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.
“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”
TULIP-2
BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.
“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”
Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).
“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).
Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.
Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.
Serum anti–double stranded DNA also trended toward normalization with anifrolumab.
The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”
Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.
No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”
“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.
The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.
SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
ATLANTA –
In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.
The findings were published online Nov. 11 in Lancet Rheumatology.
TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.
The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.
The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.
“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”
Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.
In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.
TULIP-1
The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.
The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.
Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.
BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.
The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.
“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”
The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.
“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.
The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.
However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).
“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.
Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.
The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.
Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).
“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.
The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”
Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.
“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”
TULIP-2
BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.
“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”
Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).
“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).
Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.
Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.
Serum anti–double stranded DNA also trended toward normalization with anifrolumab.
The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”
Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.
No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”
“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.
The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.
SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
ATLANTA –
In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.
The findings were published online Nov. 11 in Lancet Rheumatology.
TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.
The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.
The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.
“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”
Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.
In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.
TULIP-1
The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.
The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.
Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.
BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.
The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.
“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”
The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.
“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.
The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.
However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).
“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.
Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.
The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.
Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).
“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.
The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”
Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.
“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”
TULIP-2
BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.
“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”
Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).
“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).
Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.
Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.
Serum anti–double stranded DNA also trended toward normalization with anifrolumab.
The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”
Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.
No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”
“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.
The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.
SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
REPORTING FROM ACR 2019
Glucocorticoids linked to damage accrual in SLE regardless of disease activity
, according to recent findings published in The Lancet Rheumatology.
“Disentangling the potential contribution of glucocorticoid use to organ damage in SLE is confounded, in most studies, by the fact that glucocorticoid use is usually associated with active disease. Our study showed that organ damage accrual occurred in a similar proportion of patients without disease activity as in the overall cohort, and that glucocorticoid use was a significant risk factor for damage,” wrote Diane Apostolopoulos, MBBS, of Monash University, Melbourne, and colleagues.
The longitudinal cohort study prospectively enrolled 1,707 patients with SLE from May 2013 to December 2016. Study participants were recruited from 13 institutions throughout Australia and Asia. The researchers defined glucocorticoid use as any exposure and cumulative exposure to prednisolone, in addition to mean time-adjusted daily prednisolone dose. Follow-up assessment occurred at least once every 6 months and varied depending on clinical necessity. At baseline, the researchers collected various demographic information, including smoking status, age, and education level, among others. The primary endpoint measured was organ damage accrual, which was assessed at baseline and annually thereafter. In addition, disease activity was evaluated in two multivariable models using Physician Global Assessment (PGA) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores.
After a median duration of 2.2 years, the researchers found that 82.3% of patients were exposed to prednisolone, and 14.9% of patients had experienced a damage accrual event. In the PGA model, mean time-adjusted PGA score (based on a 0- to 1-unit increase) was associated with damage accrual independent of clinical or serologic disease activity (hazard ratio, 1.05; P = .0012).
In the SLEDAI-2K model, baseline damage scores were independently associated with damage accrual (hazard ratio, 1.32; P = .0427).
In both models, ethnicity (Asian vs. non-Asian), age at study enrollment, and mean time-adjusted prednisolone dose were parameters independently associated with damage accrual.
“Novel findings from this study were that Asian ethnicity was protective when compared with any non-Asian ethnicity, and that antimalarial usage was not protective for damage accrual,” the researchers wrote.
Despite the novel results, the researchers acknowledged that the protective effects of antimalarials could have gone undetected because of the short duration of follow-up.
In a related editorial, Guillermo Ruiz-Irastorza, MD, PhD, of University of the Basque Country in Bizkaia, Spain, said that the study provides novel data highlighting that glucocorticoid use has the potential to negatively affect the clinical progression of patients with SLE (Lancet Rheumatol. 2019 Nov 25. doi: 10.1016/S2665-9913(19)30132-8).
One question that remains from the current study is how to effectively reduce glucocorticoid-related adverse events, while still managing the disease, he further explained.
“These findings suggest that unnecessary use of glucocorticoids should be avoided in the management of the disease where possible,” the investigators concluded.
The study was funded by UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca. The authors reported financial affiliations with Abbott, AbbVie, Astellas, Ayumi Pharmaceutical, Bristol-Myers Squibb, Novartis, Pfizer, and several others.
SOURCE: Apostolopoulos D et al. Lancet Rheumatol. 2019 Nov 25. doi: 10.1016/S2665-9913(19)30105-5.
, according to recent findings published in The Lancet Rheumatology.
“Disentangling the potential contribution of glucocorticoid use to organ damage in SLE is confounded, in most studies, by the fact that glucocorticoid use is usually associated with active disease. Our study showed that organ damage accrual occurred in a similar proportion of patients without disease activity as in the overall cohort, and that glucocorticoid use was a significant risk factor for damage,” wrote Diane Apostolopoulos, MBBS, of Monash University, Melbourne, and colleagues.
The longitudinal cohort study prospectively enrolled 1,707 patients with SLE from May 2013 to December 2016. Study participants were recruited from 13 institutions throughout Australia and Asia. The researchers defined glucocorticoid use as any exposure and cumulative exposure to prednisolone, in addition to mean time-adjusted daily prednisolone dose. Follow-up assessment occurred at least once every 6 months and varied depending on clinical necessity. At baseline, the researchers collected various demographic information, including smoking status, age, and education level, among others. The primary endpoint measured was organ damage accrual, which was assessed at baseline and annually thereafter. In addition, disease activity was evaluated in two multivariable models using Physician Global Assessment (PGA) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores.
After a median duration of 2.2 years, the researchers found that 82.3% of patients were exposed to prednisolone, and 14.9% of patients had experienced a damage accrual event. In the PGA model, mean time-adjusted PGA score (based on a 0- to 1-unit increase) was associated with damage accrual independent of clinical or serologic disease activity (hazard ratio, 1.05; P = .0012).
In the SLEDAI-2K model, baseline damage scores were independently associated with damage accrual (hazard ratio, 1.32; P = .0427).
In both models, ethnicity (Asian vs. non-Asian), age at study enrollment, and mean time-adjusted prednisolone dose were parameters independently associated with damage accrual.
“Novel findings from this study were that Asian ethnicity was protective when compared with any non-Asian ethnicity, and that antimalarial usage was not protective for damage accrual,” the researchers wrote.
Despite the novel results, the researchers acknowledged that the protective effects of antimalarials could have gone undetected because of the short duration of follow-up.
In a related editorial, Guillermo Ruiz-Irastorza, MD, PhD, of University of the Basque Country in Bizkaia, Spain, said that the study provides novel data highlighting that glucocorticoid use has the potential to negatively affect the clinical progression of patients with SLE (Lancet Rheumatol. 2019 Nov 25. doi: 10.1016/S2665-9913(19)30132-8).
One question that remains from the current study is how to effectively reduce glucocorticoid-related adverse events, while still managing the disease, he further explained.
“These findings suggest that unnecessary use of glucocorticoids should be avoided in the management of the disease where possible,” the investigators concluded.
The study was funded by UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca. The authors reported financial affiliations with Abbott, AbbVie, Astellas, Ayumi Pharmaceutical, Bristol-Myers Squibb, Novartis, Pfizer, and several others.
SOURCE: Apostolopoulos D et al. Lancet Rheumatol. 2019 Nov 25. doi: 10.1016/S2665-9913(19)30105-5.
, according to recent findings published in The Lancet Rheumatology.
“Disentangling the potential contribution of glucocorticoid use to organ damage in SLE is confounded, in most studies, by the fact that glucocorticoid use is usually associated with active disease. Our study showed that organ damage accrual occurred in a similar proportion of patients without disease activity as in the overall cohort, and that glucocorticoid use was a significant risk factor for damage,” wrote Diane Apostolopoulos, MBBS, of Monash University, Melbourne, and colleagues.
The longitudinal cohort study prospectively enrolled 1,707 patients with SLE from May 2013 to December 2016. Study participants were recruited from 13 institutions throughout Australia and Asia. The researchers defined glucocorticoid use as any exposure and cumulative exposure to prednisolone, in addition to mean time-adjusted daily prednisolone dose. Follow-up assessment occurred at least once every 6 months and varied depending on clinical necessity. At baseline, the researchers collected various demographic information, including smoking status, age, and education level, among others. The primary endpoint measured was organ damage accrual, which was assessed at baseline and annually thereafter. In addition, disease activity was evaluated in two multivariable models using Physician Global Assessment (PGA) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores.
After a median duration of 2.2 years, the researchers found that 82.3% of patients were exposed to prednisolone, and 14.9% of patients had experienced a damage accrual event. In the PGA model, mean time-adjusted PGA score (based on a 0- to 1-unit increase) was associated with damage accrual independent of clinical or serologic disease activity (hazard ratio, 1.05; P = .0012).
In the SLEDAI-2K model, baseline damage scores were independently associated with damage accrual (hazard ratio, 1.32; P = .0427).
In both models, ethnicity (Asian vs. non-Asian), age at study enrollment, and mean time-adjusted prednisolone dose were parameters independently associated with damage accrual.
“Novel findings from this study were that Asian ethnicity was protective when compared with any non-Asian ethnicity, and that antimalarial usage was not protective for damage accrual,” the researchers wrote.
Despite the novel results, the researchers acknowledged that the protective effects of antimalarials could have gone undetected because of the short duration of follow-up.
In a related editorial, Guillermo Ruiz-Irastorza, MD, PhD, of University of the Basque Country in Bizkaia, Spain, said that the study provides novel data highlighting that glucocorticoid use has the potential to negatively affect the clinical progression of patients with SLE (Lancet Rheumatol. 2019 Nov 25. doi: 10.1016/S2665-9913(19)30132-8).
One question that remains from the current study is how to effectively reduce glucocorticoid-related adverse events, while still managing the disease, he further explained.
“These findings suggest that unnecessary use of glucocorticoids should be avoided in the management of the disease where possible,” the investigators concluded.
The study was funded by UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca. The authors reported financial affiliations with Abbott, AbbVie, Astellas, Ayumi Pharmaceutical, Bristol-Myers Squibb, Novartis, Pfizer, and several others.
SOURCE: Apostolopoulos D et al. Lancet Rheumatol. 2019 Nov 25. doi: 10.1016/S2665-9913(19)30105-5.
FROM THE LANCET RHEUMATOLOGY
Have earlier diagnosis and treatment advances cut deaths from systemic sclerosis?
This abstract highlights a promising result for our younger patients diagnosed with systemic sclerosis. The fact that patients aged 44 years and younger with systemic sclerosis now have a death rate similar to that of the general population should be celebrated. Practicing clinicians can speculate why this trend has occurred. It is well known that these patients many times suffer from cardiopulmonary involvement.
Thus, the advances in the treatment of interstitial lung disease and pulmonary hypertension may account for the decreased mortality in this population.
Earlier detection has certainly helped this group. In addition, using immune modulators earlier at disease onset is likely another contributor to this positive trend. We are entering a decade and beyond filled with hope to change the course of this particular autoimmune disease.
Dr. Oberstein is a practicing rheumatologist at the University of Miami Health System and is senior medical director of musculoskeletal at Modernizing Medicine in Boca Raton, Fla. She has no relevant disclosures to report.
This abstract highlights a promising result for our younger patients diagnosed with systemic sclerosis. The fact that patients aged 44 years and younger with systemic sclerosis now have a death rate similar to that of the general population should be celebrated. Practicing clinicians can speculate why this trend has occurred. It is well known that these patients many times suffer from cardiopulmonary involvement.
Thus, the advances in the treatment of interstitial lung disease and pulmonary hypertension may account for the decreased mortality in this population.
Earlier detection has certainly helped this group. In addition, using immune modulators earlier at disease onset is likely another contributor to this positive trend. We are entering a decade and beyond filled with hope to change the course of this particular autoimmune disease.
Dr. Oberstein is a practicing rheumatologist at the University of Miami Health System and is senior medical director of musculoskeletal at Modernizing Medicine in Boca Raton, Fla. She has no relevant disclosures to report.
This abstract highlights a promising result for our younger patients diagnosed with systemic sclerosis. The fact that patients aged 44 years and younger with systemic sclerosis now have a death rate similar to that of the general population should be celebrated. Practicing clinicians can speculate why this trend has occurred. It is well known that these patients many times suffer from cardiopulmonary involvement.
Thus, the advances in the treatment of interstitial lung disease and pulmonary hypertension may account for the decreased mortality in this population.
Earlier detection has certainly helped this group. In addition, using immune modulators earlier at disease onset is likely another contributor to this positive trend. We are entering a decade and beyond filled with hope to change the course of this particular autoimmune disease.
Dr. Oberstein is a practicing rheumatologist at the University of Miami Health System and is senior medical director of musculoskeletal at Modernizing Medicine in Boca Raton, Fla. She has no relevant disclosures to report.
Fewer people are dying from systemic sclerosis at younger ages
ATLANTA – Patients with systemic sclerosis aged 44 years and younger in the United States now have mortality comparable to that of the general population in that age group, according to recent results presented at the annual meeting of the American College of Rheumatology.
“Mortality for scleroderma has steadily decreased in younger ages for the last 5 decades,” Ram R. Singh, MD, professor of medicine, pathology, and laboratory medicine at the University of California, Los Angeles, said in his presentation.
Using the Centers for Disease Control and Prevention’s National Vital Statistics System database, Dr. Singh and colleagues analyzed data of adults with systemic sclerosis (SSc) and identified 46,798 adults who died between 1968 and 2015. They divided the adults with and without SSc into three different age groups: 44 and younger, 45-64, and 65 and older. The researchers performed a joinpoint trend analysis, calculating the annual percent change (APC) and average APC as well as the age-standardized mortality rate (ASMR) in each age group.
In 1968, 466 deaths were attributed to SSc, compared with 1,195 deaths in 2015. Between 1968 and 2015, there was a 19% cumulative percentage increase in SSc-related deaths, compared with a 44% decrease in mortality not attributed to SSc; when the researchers analyzed the ratio of SSc-related ASMR to non-SSc-related ASMR, there was an increase of 112%, Dr. Singh said.
When analyzing the mortality of adults with SSc by age group during 1968-2015 using the CDC’s database, Dr. Singh and colleagues found 5,457 deaths in adults 44 and younger (11.7%), 18,395 deaths in adults aged 45-64 (39.3%), and 22,946 deaths in adults aged 65 and older (49.0%), compared with totals for the general population of 10.3 million deaths in adults aged 44 and younger (9.7%), 20.8 million deaths in adults 45-64 years (19.6%), and 74.8 million deaths in adults aged 65 and older (70.6%).
Over the 48-year period, there were three major trends in SSc-related ASMR, Dr. Singh noted. In the first trend period between 1968 and 1988, there was a 1.0% increase per year (95% confidence interval, 0.6%-1.4%). The second trend period, lasting until 2000, saw a 2.2% increase per year (95% CI, 1.6%-2.7%), while the SSc-related ASMR declined by 2.6% per year in the third trend period from 2001 to 2015 (95% CI, –3.1% to –2.2%).
The percentage of annual deaths for adults with SSc decreased between 1968 and 2015, from 23.4% to 5.7%, and the average APC was greater among adults aged 44 and younger with SSc (–2.2%; 95% CI, –2.4% to –2.0%) than for adults without SSc in the same age group (–1.5%; 95% CI, –1.9% to –1.1%).
There was a cumulative 60% decrease in the ASMR of adults with SSc aged 44 and younger between 1968 and 2015 from an ASMR of 1.0 per million (95% CI, 0.8%-1.2%) to an ASMR of 0.4 per million (0.3-0.5). Adults aged 45-64 years with SSc had a cumulative 20.3% decrease in ASMR over the same time period, with an ASMR of 5.9 per million in 1968 (95% CI, 5.2-6.7) and an ASMR of 4.7 per million in 2015 (95% CI, 4.2-5.2). However, adults aged 65 and older with SSc had a 187% cumulative increase in ASMR, with an ASMR of 5.4 per million in 1968 (95% CI, 4.4-6.5) and an ASMR of 15.5 per million in 2015 (95% CI, 14.3-16.6). Adults with non-SSc-related deaths between 1968 and 2015 had a 50.0% cumulative decrease in ASMR in the group aged 44 and under, a 48.0% cumulative decrease in the 45-year to 64-year-old group, and a 42.1% decrease in the 65-year-old or older group.
The ratio of SSc to non-SSc ASMRs between 1968 and 2015 in the group aged 44 and younger declined 20.0%, whereas there was a 53.1% cumulative increase in the 45- to 64-year-old group and a 395.4% cumulative increase in the 65-year-old and older group. In the oldest group, the APC increased by 3.9% each year for 33 years (95% CI, 3.7%-4.1%) before declining by 1.6% until 2015 (95% CI, –2.0 to –1.3). In contrast, the APC for adults 44 and younger never significantly increased over the 48 years, Dr. Singh noted.
“Increasing scleroderma mortality in older age could be due to improving survival and/or increasing age of onset of scleroderma,” he said.
Dr. Singh reported no conflicts of interest.
SOURCE: Yen E et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 825.
ATLANTA – Patients with systemic sclerosis aged 44 years and younger in the United States now have mortality comparable to that of the general population in that age group, according to recent results presented at the annual meeting of the American College of Rheumatology.
“Mortality for scleroderma has steadily decreased in younger ages for the last 5 decades,” Ram R. Singh, MD, professor of medicine, pathology, and laboratory medicine at the University of California, Los Angeles, said in his presentation.
Using the Centers for Disease Control and Prevention’s National Vital Statistics System database, Dr. Singh and colleagues analyzed data of adults with systemic sclerosis (SSc) and identified 46,798 adults who died between 1968 and 2015. They divided the adults with and without SSc into three different age groups: 44 and younger, 45-64, and 65 and older. The researchers performed a joinpoint trend analysis, calculating the annual percent change (APC) and average APC as well as the age-standardized mortality rate (ASMR) in each age group.
In 1968, 466 deaths were attributed to SSc, compared with 1,195 deaths in 2015. Between 1968 and 2015, there was a 19% cumulative percentage increase in SSc-related deaths, compared with a 44% decrease in mortality not attributed to SSc; when the researchers analyzed the ratio of SSc-related ASMR to non-SSc-related ASMR, there was an increase of 112%, Dr. Singh said.
When analyzing the mortality of adults with SSc by age group during 1968-2015 using the CDC’s database, Dr. Singh and colleagues found 5,457 deaths in adults 44 and younger (11.7%), 18,395 deaths in adults aged 45-64 (39.3%), and 22,946 deaths in adults aged 65 and older (49.0%), compared with totals for the general population of 10.3 million deaths in adults aged 44 and younger (9.7%), 20.8 million deaths in adults 45-64 years (19.6%), and 74.8 million deaths in adults aged 65 and older (70.6%).
Over the 48-year period, there were three major trends in SSc-related ASMR, Dr. Singh noted. In the first trend period between 1968 and 1988, there was a 1.0% increase per year (95% confidence interval, 0.6%-1.4%). The second trend period, lasting until 2000, saw a 2.2% increase per year (95% CI, 1.6%-2.7%), while the SSc-related ASMR declined by 2.6% per year in the third trend period from 2001 to 2015 (95% CI, –3.1% to –2.2%).
The percentage of annual deaths for adults with SSc decreased between 1968 and 2015, from 23.4% to 5.7%, and the average APC was greater among adults aged 44 and younger with SSc (–2.2%; 95% CI, –2.4% to –2.0%) than for adults without SSc in the same age group (–1.5%; 95% CI, –1.9% to –1.1%).
There was a cumulative 60% decrease in the ASMR of adults with SSc aged 44 and younger between 1968 and 2015 from an ASMR of 1.0 per million (95% CI, 0.8%-1.2%) to an ASMR of 0.4 per million (0.3-0.5). Adults aged 45-64 years with SSc had a cumulative 20.3% decrease in ASMR over the same time period, with an ASMR of 5.9 per million in 1968 (95% CI, 5.2-6.7) and an ASMR of 4.7 per million in 2015 (95% CI, 4.2-5.2). However, adults aged 65 and older with SSc had a 187% cumulative increase in ASMR, with an ASMR of 5.4 per million in 1968 (95% CI, 4.4-6.5) and an ASMR of 15.5 per million in 2015 (95% CI, 14.3-16.6). Adults with non-SSc-related deaths between 1968 and 2015 had a 50.0% cumulative decrease in ASMR in the group aged 44 and under, a 48.0% cumulative decrease in the 45-year to 64-year-old group, and a 42.1% decrease in the 65-year-old or older group.
The ratio of SSc to non-SSc ASMRs between 1968 and 2015 in the group aged 44 and younger declined 20.0%, whereas there was a 53.1% cumulative increase in the 45- to 64-year-old group and a 395.4% cumulative increase in the 65-year-old and older group. In the oldest group, the APC increased by 3.9% each year for 33 years (95% CI, 3.7%-4.1%) before declining by 1.6% until 2015 (95% CI, –2.0 to –1.3). In contrast, the APC for adults 44 and younger never significantly increased over the 48 years, Dr. Singh noted.
“Increasing scleroderma mortality in older age could be due to improving survival and/or increasing age of onset of scleroderma,” he said.
Dr. Singh reported no conflicts of interest.
SOURCE: Yen E et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 825.
ATLANTA – Patients with systemic sclerosis aged 44 years and younger in the United States now have mortality comparable to that of the general population in that age group, according to recent results presented at the annual meeting of the American College of Rheumatology.
“Mortality for scleroderma has steadily decreased in younger ages for the last 5 decades,” Ram R. Singh, MD, professor of medicine, pathology, and laboratory medicine at the University of California, Los Angeles, said in his presentation.
Using the Centers for Disease Control and Prevention’s National Vital Statistics System database, Dr. Singh and colleagues analyzed data of adults with systemic sclerosis (SSc) and identified 46,798 adults who died between 1968 and 2015. They divided the adults with and without SSc into three different age groups: 44 and younger, 45-64, and 65 and older. The researchers performed a joinpoint trend analysis, calculating the annual percent change (APC) and average APC as well as the age-standardized mortality rate (ASMR) in each age group.
In 1968, 466 deaths were attributed to SSc, compared with 1,195 deaths in 2015. Between 1968 and 2015, there was a 19% cumulative percentage increase in SSc-related deaths, compared with a 44% decrease in mortality not attributed to SSc; when the researchers analyzed the ratio of SSc-related ASMR to non-SSc-related ASMR, there was an increase of 112%, Dr. Singh said.
When analyzing the mortality of adults with SSc by age group during 1968-2015 using the CDC’s database, Dr. Singh and colleagues found 5,457 deaths in adults 44 and younger (11.7%), 18,395 deaths in adults aged 45-64 (39.3%), and 22,946 deaths in adults aged 65 and older (49.0%), compared with totals for the general population of 10.3 million deaths in adults aged 44 and younger (9.7%), 20.8 million deaths in adults 45-64 years (19.6%), and 74.8 million deaths in adults aged 65 and older (70.6%).
Over the 48-year period, there were three major trends in SSc-related ASMR, Dr. Singh noted. In the first trend period between 1968 and 1988, there was a 1.0% increase per year (95% confidence interval, 0.6%-1.4%). The second trend period, lasting until 2000, saw a 2.2% increase per year (95% CI, 1.6%-2.7%), while the SSc-related ASMR declined by 2.6% per year in the third trend period from 2001 to 2015 (95% CI, –3.1% to –2.2%).
The percentage of annual deaths for adults with SSc decreased between 1968 and 2015, from 23.4% to 5.7%, and the average APC was greater among adults aged 44 and younger with SSc (–2.2%; 95% CI, –2.4% to –2.0%) than for adults without SSc in the same age group (–1.5%; 95% CI, –1.9% to –1.1%).
There was a cumulative 60% decrease in the ASMR of adults with SSc aged 44 and younger between 1968 and 2015 from an ASMR of 1.0 per million (95% CI, 0.8%-1.2%) to an ASMR of 0.4 per million (0.3-0.5). Adults aged 45-64 years with SSc had a cumulative 20.3% decrease in ASMR over the same time period, with an ASMR of 5.9 per million in 1968 (95% CI, 5.2-6.7) and an ASMR of 4.7 per million in 2015 (95% CI, 4.2-5.2). However, adults aged 65 and older with SSc had a 187% cumulative increase in ASMR, with an ASMR of 5.4 per million in 1968 (95% CI, 4.4-6.5) and an ASMR of 15.5 per million in 2015 (95% CI, 14.3-16.6). Adults with non-SSc-related deaths between 1968 and 2015 had a 50.0% cumulative decrease in ASMR in the group aged 44 and under, a 48.0% cumulative decrease in the 45-year to 64-year-old group, and a 42.1% decrease in the 65-year-old or older group.
The ratio of SSc to non-SSc ASMRs between 1968 and 2015 in the group aged 44 and younger declined 20.0%, whereas there was a 53.1% cumulative increase in the 45- to 64-year-old group and a 395.4% cumulative increase in the 65-year-old and older group. In the oldest group, the APC increased by 3.9% each year for 33 years (95% CI, 3.7%-4.1%) before declining by 1.6% until 2015 (95% CI, –2.0 to –1.3). In contrast, the APC for adults 44 and younger never significantly increased over the 48 years, Dr. Singh noted.
“Increasing scleroderma mortality in older age could be due to improving survival and/or increasing age of onset of scleroderma,” he said.
Dr. Singh reported no conflicts of interest.
SOURCE: Yen E et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 825.
REPORTING FROM ACR 2019
Rituximab tops azathioprine for relapsing ANCA-associated vasculitis remission maintenance
ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.
Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.
Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m2 per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.
After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.
Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.
Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.
Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.
Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.
There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.
There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.
The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.
The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.
SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.
ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.
Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.
Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m2 per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.
After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.
Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.
Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.
Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.
Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.
There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.
There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.
The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.
The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.
SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.
ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.
Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.
Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m2 per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.
After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.
Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.
Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.
Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.
Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.
There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.
There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.
The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.
The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.
SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.
REPORTING FROM ACR 2019