Lupus & Connective Tissue Diseases

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

Patients with thrombotic antiphospholipid syndrome (APS) may have a greater risk of recurrent thrombosis when taking rivaroxaban instead of a vitamin K antagonist, suggests a recent trial conducted in Spain.

Stroke was also more common among those taking rivaroxaban, while major bleeding was slightly less common, reported lead author Josep Ordi-Ros, MD, PhD, of Vall d’Hebrón University Hospital Research Institute in Barcelona, and colleagues in Annals of Internal Medicine.

“Two randomized, controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation but showed an increased thrombotic risk in those with triple-positive antiphospholipid antibodies,” the investigators wrote. However, they also noted that these findings required a cautious interpretation because of study limitations, such as premature termination caused by an excess of study events and the use of a laboratory surrogate marker as a primary outcome.

To learn more, the investigators performed an open-label, phase 3 trial involving 190 patients with thrombotic APS. Patients were randomized in a 1:1 ratio to receive either rivaroxaban (20 mg per day, or 15 mg per day for patients with a creatinine clearance of 30-49 mL/min per 1.73 m²) or an adjusted dosage of vitamin K antagonists (target international normalized ratio of 2.0-3.0, or 3.1-4.0 for those with a history of recurrent thrombosis).

Patients underwent evaluations every month for the first 3 months and then every 3 months thereafter, each of which involved a variety of laboratory diagnostics such as checks for antinuclear antibodies and lupus anticoagulant, among others. Statistical analyses aimed to determine if rivaroxaban was noninferior to therapy with vitamin K antagonists based on parameters drawn from previous meta-analyses, as no studies had compared the two types of treatment when the present study was designed.

After 3 years of follow-up, almost twice as many patients in the rivaroxaban group had experienced recurrent thrombosis (11.6% vs. 6.3%), although this finding lacked statistical significance for both noninferiority of rivaroxaban (P = .29) and superiority of vitamin K antagonists (P = .20). Still, supporting a similar trend toward differences in efficacy, stroke was more common in the rivaroxaban group, in which nine events occurred, compared with none in the vitamin K antagonist group. In contrast, major bleeding was slightly less common with rivaroxaban than vitamin K antagonists (6.3% vs. 7.4%).

“In conclusion, rivaroxaban did not demonstrate noninferiority to dose-adjusted vitamin K antagonists for secondary thromboprophylaxis in patients with thrombotic APS,” the investigators wrote. “Instead, our results indicate a recurrent thrombotic rate that is nearly double, albeit without statistical significance.”

The study was funded by Bayer Hispania. One coauthor reported additional relationships with Pfizer, Lilly, Janssen, and others.

SOURCE: Ordi-Ros J et al. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291.

Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.

Jake Remaly/MDedge News

The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.

Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”

Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
 

A poor relationship between pain and imaging

Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.

This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”

Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
 

Opioid responsiveness

To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.

Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.

Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).

Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
 

Diagnosed cases are the “tip of the iceberg”

Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.

Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”

Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”

Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.

Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.

Jake Remaly/MDedge News

The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.

Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”

Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
 

A poor relationship between pain and imaging

Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.

This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”

Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
 

Opioid responsiveness

To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.

Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.

Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).

Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
 

Diagnosed cases are the “tip of the iceberg”

Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.

Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”

Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”

Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.

Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.

Jake Remaly/MDedge News

The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.

Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”

Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
 

A poor relationship between pain and imaging

Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.

This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”

Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
 

Opioid responsiveness

To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.

Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.

Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).

Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
 

Diagnosed cases are the “tip of the iceberg”

Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.

Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”

Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”

Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.

Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

Age-adjusted mortality from antineutrophil cytoplasmic autoantibody–associated vasculitides (AAV) in the United States declined by nearly 2% each year between 1999 and 2017, based on data from the Centers for Disease Control and Prevention.

Significant morbidity and mortality are associated with untreated AAV, wrote Alexander W. Steinberg, MD, of Saint Joseph Hospital, Denver, Colo., and colleagues.

“Although population data from the United Kingdom have shown decreased AAV-related mortality during the past 20 years, it is unknown whether this pattern has occurred in the United States,” they wrote.

In a study published in Annals of Internal Medicine, the researchers identified 11,316 AAV-related deaths from 1999 to 2017 in the CDC data.

Overall, age-adjusted mortality was 1.86 per 1,000,000 persons, with highest rates among non-Hispanic whites, men, and residents of the Midwest. Mortality from AAV declined by an average of 1.6% in each year of the study period, and changes in subgroups stratified by gender, race, and geographic region were similar.

Mortality increased with age and was highest among individuals aged 75-84 years, but a significant decline in mortality occurred among individuals aged 65-74 years. “The decrease in overall mortality and mortality among persons aged 65 to 74 years may reflect increased longevity due to improved treatment of AAV and common comorbid conditions,” the researchers said.

“Surprisingly, the authors found much lower age-adjusted mortality rates for non-Hispanic black persons (0.77) and moderately lower mortality rates for Hispanic persons (1.57) than for non-Hispanic white persons (2.03),” wrote John R. Stone, MD, PhD, of Creighton University, Omaha, Neb., in an accompanying editorial.

“Suppose the mortality rate differences reported by Steinberg and colleagues are statistically significant, accurately represent death certificate diagnoses, and match people’s racial/ethnic self-identification. The data then show neither that the vasculitides actually have lower mortality rates in blacks or Hispanics compared with whites, nor that the diseases are indeed less frequent in blacks and Hispanics,” he said. “Rather, these differences probably signify how social inequities, social structural violence, and inferior health care access adversely influence diagnosis of rare diseases and promote health inequity,” Dr. Stone added. The findings suggest that clinicians should remain alert to AAV in some ethnic groups to improve diagnostic accuracy, he said.

“Moreover, improved AAV diagnosis in such groups is key to recruiting participants for research investigating whether therapies should differ among populations,” he emphasized.

The study findings were limited by possible under- or overreporting of AAV on death certificates, but they were strengthened by the large sample size, the researchers noted. “We hope that the mortality patterns presented here can be used to direct future research on the driving forces behind these trends,” they said.

Dr. Steinberg had no financial conflicts to disclose. Dr. Stone had no financial conflicts to disclose.

SOURCES: Steinberg AW et al. Ann Intern Med. 2019 Oct 8. doi: 10.7326/M19-1564; and Stone JR. Ann Intern Med. 2019 Oct 8. doi: 10.7326/M19-2755.

Age-adjusted mortality from antineutrophil cytoplasmic autoantibody–associated vasculitides (AAV) in the United States declined by nearly 2% each year between 1999 and 2017, based on data from the Centers for Disease Control and Prevention.

Significant morbidity and mortality are associated with untreated AAV, wrote Alexander W. Steinberg, MD, of Saint Joseph Hospital, Denver, Colo., and colleagues.

“Although population data from the United Kingdom have shown decreased AAV-related mortality during the past 20 years, it is unknown whether this pattern has occurred in the United States,” they wrote.

In a study published in Annals of Internal Medicine, the researchers identified 11,316 AAV-related deaths from 1999 to 2017 in the CDC data.

Overall, age-adjusted mortality was 1.86 per 1,000,000 persons, with highest rates among non-Hispanic whites, men, and residents of the Midwest. Mortality from AAV declined by an average of 1.6% in each year of the study period, and changes in subgroups stratified by gender, race, and geographic region were similar.

Mortality increased with age and was highest among individuals aged 75-84 years, but a significant decline in mortality occurred among individuals aged 65-74 years. “The decrease in overall mortality and mortality among persons aged 65 to 74 years may reflect increased longevity due to improved treatment of AAV and common comorbid conditions,” the researchers said.

“Surprisingly, the authors found much lower age-adjusted mortality rates for non-Hispanic black persons (0.77) and moderately lower mortality rates for Hispanic persons (1.57) than for non-Hispanic white persons (2.03),” wrote John R. Stone, MD, PhD, of Creighton University, Omaha, Neb., in an accompanying editorial.

“Suppose the mortality rate differences reported by Steinberg and colleagues are statistically significant, accurately represent death certificate diagnoses, and match people’s racial/ethnic self-identification. The data then show neither that the vasculitides actually have lower mortality rates in blacks or Hispanics compared with whites, nor that the diseases are indeed less frequent in blacks and Hispanics,” he said. “Rather, these differences probably signify how social inequities, social structural violence, and inferior health care access adversely influence diagnosis of rare diseases and promote health inequity,” Dr. Stone added. The findings suggest that clinicians should remain alert to AAV in some ethnic groups to improve diagnostic accuracy, he said.

“Moreover, improved AAV diagnosis in such groups is key to recruiting participants for research investigating whether therapies should differ among populations,” he emphasized.

The study findings were limited by possible under- or overreporting of AAV on death certificates, but they were strengthened by the large sample size, the researchers noted. “We hope that the mortality patterns presented here can be used to direct future research on the driving forces behind these trends,” they said.

Dr. Steinberg had no financial conflicts to disclose. Dr. Stone had no financial conflicts to disclose.

SOURCES: Steinberg AW et al. Ann Intern Med. 2019 Oct 8. doi: 10.7326/M19-1564; and Stone JR. Ann Intern Med. 2019 Oct 8. doi: 10.7326/M19-2755.

Age-adjusted mortality from antineutrophil cytoplasmic autoantibody–associated vasculitides (AAV) in the United States declined by nearly 2% each year between 1999 and 2017, based on data from the Centers for Disease Control and Prevention.

Significant morbidity and mortality are associated with untreated AAV, wrote Alexander W. Steinberg, MD, of Saint Joseph Hospital, Denver, Colo., and colleagues.

“Although population data from the United Kingdom have shown decreased AAV-related mortality during the past 20 years, it is unknown whether this pattern has occurred in the United States,” they wrote.

In a study published in Annals of Internal Medicine, the researchers identified 11,316 AAV-related deaths from 1999 to 2017 in the CDC data.

Overall, age-adjusted mortality was 1.86 per 1,000,000 persons, with highest rates among non-Hispanic whites, men, and residents of the Midwest. Mortality from AAV declined by an average of 1.6% in each year of the study period, and changes in subgroups stratified by gender, race, and geographic region were similar.

Mortality increased with age and was highest among individuals aged 75-84 years, but a significant decline in mortality occurred among individuals aged 65-74 years. “The decrease in overall mortality and mortality among persons aged 65 to 74 years may reflect increased longevity due to improved treatment of AAV and common comorbid conditions,” the researchers said.

“Surprisingly, the authors found much lower age-adjusted mortality rates for non-Hispanic black persons (0.77) and moderately lower mortality rates for Hispanic persons (1.57) than for non-Hispanic white persons (2.03),” wrote John R. Stone, MD, PhD, of Creighton University, Omaha, Neb., in an accompanying editorial.

“Suppose the mortality rate differences reported by Steinberg and colleagues are statistically significant, accurately represent death certificate diagnoses, and match people’s racial/ethnic self-identification. The data then show neither that the vasculitides actually have lower mortality rates in blacks or Hispanics compared with whites, nor that the diseases are indeed less frequent in blacks and Hispanics,” he said. “Rather, these differences probably signify how social inequities, social structural violence, and inferior health care access adversely influence diagnosis of rare diseases and promote health inequity,” Dr. Stone added. The findings suggest that clinicians should remain alert to AAV in some ethnic groups to improve diagnostic accuracy, he said.

“Moreover, improved AAV diagnosis in such groups is key to recruiting participants for research investigating whether therapies should differ among populations,” he emphasized.

The study findings were limited by possible under- or overreporting of AAV on death certificates, but they were strengthened by the large sample size, the researchers noted. “We hope that the mortality patterns presented here can be used to direct future research on the driving forces behind these trends,” they said.

Dr. Steinberg had no financial conflicts to disclose. Dr. Stone had no financial conflicts to disclose.

SOURCES: Steinberg AW et al. Ann Intern Med. 2019 Oct 8. doi: 10.7326/M19-1564; and Stone JR. Ann Intern Med. 2019 Oct 8. doi: 10.7326/M19-2755.

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

MADRID – Pirfenidone was shown to be effective for slowing decline in lung function among patients with unclassifiable interstitial lung diseases (uILD), according to results of a late breaker, placebo-controlled, multinational trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

For preservation of lung function as monitored with forced vital capacity (FVC), pirfenidone provided a large and highly statistically significant advantage over placebo in a phase 2 trial that randomized 253 uILD patients to 2,403 mg pirfenidone or placebo, according to Toby M. Maher, MD, head of the Fibrosis Research Group for the National Heart and Lung Institute, Imperial College, London.

At 24 weeks, FVC lung function declined by just 17.8 mL in the pirfenidone group vs. 113 mL in the placebo group (P = .002). The results, published simultaneously with Dr. Maher’s ERS presentation in The Lancet Respiratory Medicine, are particularly encouraging because there are no currently approved treatments for uILD, according to Dr. Maher.

However, the data from this study, even though it was double blind and involved 70 participating centers in 14 countries, come with an asterisk. The significant FVC advantage was documented with in-hospital measurements, but this was a secondary, not the primary, endpoint. Measurements with hand-held spirometry, which was the primary endpoint, proved to be uninterpretable due to intra-individual variability.

“We had hoped that daily home spirometry would give us more information of the patient’s trajectory over time,” said Dr. Maher, who blames himself for selecting hand-held device measurements as the primary endpoint. In the end, the variability in the home hand-held spirometry data prevented the planned statistical testing.

“There were issues with the hand-held devices we had not anticipated,” Dr. Maher reported. However, hospital-based measurement, which has long been the “regulatory standard” in ILD trials “supports the conclusion that pirfenidone was effective.”

The conclusion is also supported by other secondary outcomes and analyses. For example, the categorical declines in FVC of greater than 5% (37.0% vs. 58.7%; P = .001) and greater than 10% (14.2% vs. 27.9%; P = .011) both favored pirfenidone. There were no between-group differences in progression-free survival at 24 weeks, but events were low in both study arms over this time period.

There was evidence of functional benefit for pirfenidone relative to placebo, such as a smaller decline in the 6-minute walk test (–2 vs. –26.7 M, P = .04). Treatment favoring pirfenidone over placebo was observed across subgroups defined by age, gender, baseline lung function, and presence or absence of interstitial pneumonia with autoimmune features.

Pirfenidone was generally well tolerated with side effects similar to those reported in other studies. The rate of treatment-related discontinuation was 12.6% on pirfenidone versus 0.8% on placebo. The most frequent adverse events, all of which were more common in the pirfenidone group, were gastrointestinal complaints (47.2% vs. 25.8%), rash (10.2% vs. 7.3%), and dizziness (7.9% vs. 0.8%). Rates of photosensitivity were higher in the experimental arm (7.9% vs. 1.8%), but low relative to previous studies, potentially because of greater emphasis on sun protection, Dr. Maher reported.

About 10%-15% of patients with ILD have an unclassifiable type, he noted. Although it is possible for uILD to be a missed diagnosis of an established ILD type, Dr. Maher reported that participating centers for this study were specifically selected for their expertise in ILD. He noted that more than 45% of patients were deemed uILD on the basis of biopsy.

The ERS-invited discussant of this trial, Martin Kolb, MD, professor of respirology, McMaster University, Hamilton, Ont., called the data “strong.” He suggested the data are particularly encouraging in the context of the lack of approved therapies for uILD.

Despite the fact that benefit of pirfenidone was not established on the primary endpoint, Dr. Maher contended that this is a positive study that can be used to design future investigations. “When we use the normal standard endpoint for the study, we see a clear benefit of pirfenidone over placebo.”

Dr. Maher reported no potential conflicts of interest.

SOURCE: Maher TM et al. Lancet Respir Med. 2019 Sep 29. doi: 10.1016/S2213-2600(19)30341-8.

MADRID – Pirfenidone was shown to be effective for slowing decline in lung function among patients with unclassifiable interstitial lung diseases (uILD), according to results of a late breaker, placebo-controlled, multinational trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

For preservation of lung function as monitored with forced vital capacity (FVC), pirfenidone provided a large and highly statistically significant advantage over placebo in a phase 2 trial that randomized 253 uILD patients to 2,403 mg pirfenidone or placebo, according to Toby M. Maher, MD, head of the Fibrosis Research Group for the National Heart and Lung Institute, Imperial College, London.

At 24 weeks, FVC lung function declined by just 17.8 mL in the pirfenidone group vs. 113 mL in the placebo group (P = .002). The results, published simultaneously with Dr. Maher’s ERS presentation in The Lancet Respiratory Medicine, are particularly encouraging because there are no currently approved treatments for uILD, according to Dr. Maher.

However, the data from this study, even though it was double blind and involved 70 participating centers in 14 countries, come with an asterisk. The significant FVC advantage was documented with in-hospital measurements, but this was a secondary, not the primary, endpoint. Measurements with hand-held spirometry, which was the primary endpoint, proved to be uninterpretable due to intra-individual variability.

“We had hoped that daily home spirometry would give us more information of the patient’s trajectory over time,” said Dr. Maher, who blames himself for selecting hand-held device measurements as the primary endpoint. In the end, the variability in the home hand-held spirometry data prevented the planned statistical testing.

“There were issues with the hand-held devices we had not anticipated,” Dr. Maher reported. However, hospital-based measurement, which has long been the “regulatory standard” in ILD trials “supports the conclusion that pirfenidone was effective.”

The conclusion is also supported by other secondary outcomes and analyses. For example, the categorical declines in FVC of greater than 5% (37.0% vs. 58.7%; P = .001) and greater than 10% (14.2% vs. 27.9%; P = .011) both favored pirfenidone. There were no between-group differences in progression-free survival at 24 weeks, but events were low in both study arms over this time period.

There was evidence of functional benefit for pirfenidone relative to placebo, such as a smaller decline in the 6-minute walk test (–2 vs. –26.7 M, P = .04). Treatment favoring pirfenidone over placebo was observed across subgroups defined by age, gender, baseline lung function, and presence or absence of interstitial pneumonia with autoimmune features.

Pirfenidone was generally well tolerated with side effects similar to those reported in other studies. The rate of treatment-related discontinuation was 12.6% on pirfenidone versus 0.8% on placebo. The most frequent adverse events, all of which were more common in the pirfenidone group, were gastrointestinal complaints (47.2% vs. 25.8%), rash (10.2% vs. 7.3%), and dizziness (7.9% vs. 0.8%). Rates of photosensitivity were higher in the experimental arm (7.9% vs. 1.8%), but low relative to previous studies, potentially because of greater emphasis on sun protection, Dr. Maher reported.

About 10%-15% of patients with ILD have an unclassifiable type, he noted. Although it is possible for uILD to be a missed diagnosis of an established ILD type, Dr. Maher reported that participating centers for this study were specifically selected for their expertise in ILD. He noted that more than 45% of patients were deemed uILD on the basis of biopsy.

The ERS-invited discussant of this trial, Martin Kolb, MD, professor of respirology, McMaster University, Hamilton, Ont., called the data “strong.” He suggested the data are particularly encouraging in the context of the lack of approved therapies for uILD.

Despite the fact that benefit of pirfenidone was not established on the primary endpoint, Dr. Maher contended that this is a positive study that can be used to design future investigations. “When we use the normal standard endpoint for the study, we see a clear benefit of pirfenidone over placebo.”

Dr. Maher reported no potential conflicts of interest.

SOURCE: Maher TM et al. Lancet Respir Med. 2019 Sep 29. doi: 10.1016/S2213-2600(19)30341-8.

MADRID – Pirfenidone was shown to be effective for slowing decline in lung function among patients with unclassifiable interstitial lung diseases (uILD), according to results of a late breaker, placebo-controlled, multinational trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

For preservation of lung function as monitored with forced vital capacity (FVC), pirfenidone provided a large and highly statistically significant advantage over placebo in a phase 2 trial that randomized 253 uILD patients to 2,403 mg pirfenidone or placebo, according to Toby M. Maher, MD, head of the Fibrosis Research Group for the National Heart and Lung Institute, Imperial College, London.

At 24 weeks, FVC lung function declined by just 17.8 mL in the pirfenidone group vs. 113 mL in the placebo group (P = .002). The results, published simultaneously with Dr. Maher’s ERS presentation in The Lancet Respiratory Medicine, are particularly encouraging because there are no currently approved treatments for uILD, according to Dr. Maher.

However, the data from this study, even though it was double blind and involved 70 participating centers in 14 countries, come with an asterisk. The significant FVC advantage was documented with in-hospital measurements, but this was a secondary, not the primary, endpoint. Measurements with hand-held spirometry, which was the primary endpoint, proved to be uninterpretable due to intra-individual variability.

“We had hoped that daily home spirometry would give us more information of the patient’s trajectory over time,” said Dr. Maher, who blames himself for selecting hand-held device measurements as the primary endpoint. In the end, the variability in the home hand-held spirometry data prevented the planned statistical testing.

“There were issues with the hand-held devices we had not anticipated,” Dr. Maher reported. However, hospital-based measurement, which has long been the “regulatory standard” in ILD trials “supports the conclusion that pirfenidone was effective.”

The conclusion is also supported by other secondary outcomes and analyses. For example, the categorical declines in FVC of greater than 5% (37.0% vs. 58.7%; P = .001) and greater than 10% (14.2% vs. 27.9%; P = .011) both favored pirfenidone. There were no between-group differences in progression-free survival at 24 weeks, but events were low in both study arms over this time period.

There was evidence of functional benefit for pirfenidone relative to placebo, such as a smaller decline in the 6-minute walk test (–2 vs. –26.7 M, P = .04). Treatment favoring pirfenidone over placebo was observed across subgroups defined by age, gender, baseline lung function, and presence or absence of interstitial pneumonia with autoimmune features.

Pirfenidone was generally well tolerated with side effects similar to those reported in other studies. The rate of treatment-related discontinuation was 12.6% on pirfenidone versus 0.8% on placebo. The most frequent adverse events, all of which were more common in the pirfenidone group, were gastrointestinal complaints (47.2% vs. 25.8%), rash (10.2% vs. 7.3%), and dizziness (7.9% vs. 0.8%). Rates of photosensitivity were higher in the experimental arm (7.9% vs. 1.8%), but low relative to previous studies, potentially because of greater emphasis on sun protection, Dr. Maher reported.

About 10%-15% of patients with ILD have an unclassifiable type, he noted. Although it is possible for uILD to be a missed diagnosis of an established ILD type, Dr. Maher reported that participating centers for this study were specifically selected for their expertise in ILD. He noted that more than 45% of patients were deemed uILD on the basis of biopsy.

The ERS-invited discussant of this trial, Martin Kolb, MD, professor of respirology, McMaster University, Hamilton, Ont., called the data “strong.” He suggested the data are particularly encouraging in the context of the lack of approved therapies for uILD.

Despite the fact that benefit of pirfenidone was not established on the primary endpoint, Dr. Maher contended that this is a positive study that can be used to design future investigations. “When we use the normal standard endpoint for the study, we see a clear benefit of pirfenidone over placebo.”

Dr. Maher reported no potential conflicts of interest.

SOURCE: Maher TM et al. Lancet Respir Med. 2019 Sep 29. doi: 10.1016/S2213-2600(19)30341-8.

Immune checkpoint inhibitor (ICI)–induced inflammatory arthritis (IA) can remain active months and even years after ending ICI therapy, according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.

“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”

Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.

To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.

Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.

According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).

The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.

The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.

SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.

Immune checkpoint inhibitor (ICI)–induced inflammatory arthritis (IA) can remain active months and even years after ending ICI therapy, according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.

“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”

Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.

To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.

Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.

According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).

The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.

The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.

SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.

Immune checkpoint inhibitor (ICI)–induced inflammatory arthritis (IA) can remain active months and even years after ending ICI therapy, according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.

“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”

Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.

To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.

Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.

According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).

The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.

The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.

SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.

MADRID – In patients with fibrosing lung diseases other than idiopathic pulmonary fibrosis (IPF), nintedanib, a tyrosine kinase inhibitor, substantially reduced the rate of decline in lung function, according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).

Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.

On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).

In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.

“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).

The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”

However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.

The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.

A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.

In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.

More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.

The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”

Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.

SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.

MADRID – In patients with fibrosing lung diseases other than idiopathic pulmonary fibrosis (IPF), nintedanib, a tyrosine kinase inhibitor, substantially reduced the rate of decline in lung function, according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).

Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.

On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).

In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.

“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).

The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”

However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.

The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.

A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.

In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.

More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.

The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”

Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.

SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.

MADRID – In patients with fibrosing lung diseases other than idiopathic pulmonary fibrosis (IPF), nintedanib, a tyrosine kinase inhibitor, substantially reduced the rate of decline in lung function, according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).

Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.

On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).

In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.

“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).

The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”

However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.

The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.

A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.

In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.

More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.

The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”

Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.

SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.

The Food and Drug Administration approved rituximab (Rituxan) by injection to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in children 2 years of age and older in combination with glucocorticoid treatment, according to an FDA news release.

Olivier Le Moal/Getty Images

These rare forms of vasculitis damage small blood vessels through inflammation and can lead to serious organ failure, including lungs and kidneys.

The Genentech drug received priority review and an orphan drug designation based on the results of a pediatric clinical trial of 25 patients aged 6-17 years with active GPA or MPA who were treated with rituximab in an international multicenter, open-label, uncontrolled study. Patients in the trial were also given methylprednisolone prior to starting treatment.

The trial consisted of a 6-month remission induction phase where patients were treated only with rituximab and glucocorticoids. In addition, patients who had not achieved remission could receive additional treatment, including other therapies, at the discretion of the investigator, according to the FDA. By 6 months, 14 of the patients were in remission, and after 18 months, all 25 patients were in remission.

Rituximab contains a boxed warning regarding increased risks of fatal infusion reactions, potentially fatal severe skin and mouth reactions, hepatitis B virus reactivation that may cause serious or lethal liver problems, and progressive multifocal leukoencephalopathy, a rare, potentially lethal brain infection.

The trial was conducted and sponsored by F. Hoffmann-La Roche, which owns Genentech.

[email protected]

The Food and Drug Administration approved rituximab (Rituxan) by injection to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in children 2 years of age and older in combination with glucocorticoid treatment, according to an FDA news release.

Olivier Le Moal/Getty Images

These rare forms of vasculitis damage small blood vessels through inflammation and can lead to serious organ failure, including lungs and kidneys.

The Genentech drug received priority review and an orphan drug designation based on the results of a pediatric clinical trial of 25 patients aged 6-17 years with active GPA or MPA who were treated with rituximab in an international multicenter, open-label, uncontrolled study. Patients in the trial were also given methylprednisolone prior to starting treatment.

The trial consisted of a 6-month remission induction phase where patients were treated only with rituximab and glucocorticoids. In addition, patients who had not achieved remission could receive additional treatment, including other therapies, at the discretion of the investigator, according to the FDA. By 6 months, 14 of the patients were in remission, and after 18 months, all 25 patients were in remission.

Rituximab contains a boxed warning regarding increased risks of fatal infusion reactions, potentially fatal severe skin and mouth reactions, hepatitis B virus reactivation that may cause serious or lethal liver problems, and progressive multifocal leukoencephalopathy, a rare, potentially lethal brain infection.

The trial was conducted and sponsored by F. Hoffmann-La Roche, which owns Genentech.

[email protected]

The Food and Drug Administration approved rituximab (Rituxan) by injection to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in children 2 years of age and older in combination with glucocorticoid treatment, according to an FDA news release.

Olivier Le Moal/Getty Images

These rare forms of vasculitis damage small blood vessels through inflammation and can lead to serious organ failure, including lungs and kidneys.

The Genentech drug received priority review and an orphan drug designation based on the results of a pediatric clinical trial of 25 patients aged 6-17 years with active GPA or MPA who were treated with rituximab in an international multicenter, open-label, uncontrolled study. Patients in the trial were also given methylprednisolone prior to starting treatment.

The trial consisted of a 6-month remission induction phase where patients were treated only with rituximab and glucocorticoids. In addition, patients who had not achieved remission could receive additional treatment, including other therapies, at the discretion of the investigator, according to the FDA. By 6 months, 14 of the patients were in remission, and after 18 months, all 25 patients were in remission.

Rituximab contains a boxed warning regarding increased risks of fatal infusion reactions, potentially fatal severe skin and mouth reactions, hepatitis B virus reactivation that may cause serious or lethal liver problems, and progressive multifocal leukoencephalopathy, a rare, potentially lethal brain infection.

The trial was conducted and sponsored by F. Hoffmann-La Roche, which owns Genentech.

[email protected]

A live-attenuated herpes zoster vaccine can be used in individuals with systemic lupus erythematosus (SLE) if they are not intensively immunosuppressed and their condition is dormant, research suggests.

A paper published in Annals of the Rheumatic Diseases reported the outcomes of a randomized, placebo-controlled trial of the Zostavax herpes zoster vaccine in 90 adults with clinically stable SLE. Participants had to have been on a stable dose of immunosuppressive agents for at least 6 months and have a history of chicken pox or herpes zoster infection.

Chi Chiu Mok, MD, of the Tuen Mun Hospital in Hong Kong and coauthors wrote that herpes zoster reactivation has been reported to occur in 6.4 to 91.4 individuals with SLE per 1,000 patient-years, with consequences including postherpetic neuralgia and even death from disseminated infection. But because Zostavax is live-attenuated, it has not been widely used in immunocompromised people.

After a single subcutaneous dose of either the vaccine or placebo, researchers saw a significant increase in anti–varicella zoster virus (VZV) IgG antibodies in vaccinated individuals over 6 weeks. The magnitude of the increase in anti-VZV IgG seen in vaccinated individuals was on par with that previously seen in vaccinated healthy controls, although the authors noted that the absolute increase in values was lower.

“While the reason is not apparent, one contributing factor is the high rate of previous exposure to VZV infection in most participants, which could have led to a higher baseline anti-IgG anti-VZV value that limited its rise after vaccination,” the authors wrote.

In contrast, IgG reactivity declined in those who received the placebo injection, and the difference between the two groups was statistically significant after adjustment for baseline antibody titers.

The study also looked at the cell-mediated immune response to the vaccine and found the number of interferon-gamma secreting CD4+ T-cell spots increased in the vaccinated patients but decreased in the placebo arm, and by week 6 it was significantly higher in the treated group. The increase in the vaccine-treated patients was again similar to that previously seen in healthy controls.

However, prednisolone use at baseline may have attenuated the vaccine response. Vaccinated patients who were treated with prednisolone at baseline had a lower increase in T-cell spots and lower anti-VZV IgG reactivity after the vaccination than did those not taking prednisolone, although the difference between the two groups was not statistically significant. The study did not see any effect of age, sex, baseline lymphocyte count, disease activity scores, and other factors on response to the vaccine.

None of the patients who received the vaccine withdrew from the study because of serious adverse events. The most common adverse events reported were injection-site redness and pain, which were more common in the vaccine-treated group than in the placebo group. However these symptoms were mild and resolved by themselves after a few days. Two patients in the vaccine group and one in the placebo group experienced mild or moderate SLE flares.

The authors commented that this was the first randomized, controlled trial examining the safety and immune response of a live-attenuated herpes zoster vaccine in individuals with SLE and this trial showed it was safe and well tolerated in those with stable disease who were not on intensive immunosuppressive therapy.

“Despite the increased risk of HZ [herpes zoster] infection, SLE had the lowest HZ vaccination rates among age-eligible subjects, probably because of the concern of vaccine safety, the principle of contraindication to live-attenuated vaccines in immunocompromised hosts, as well as the current ambiguous guidelines for HZ vaccination in SLE,” they wrote.

But they also stressed that their results did not apply to patients with active disease or on more intensive immunosuppression and that longer-term data on the persistence of vaccine immunogenicity was still being collected.

The study was funded by the Hong Kong Research Fund Secretariat. No conflicts of interest were declared.

SOURCE: Mok CC et al. Ann Rheum Dis. 2019 Sep 17. doi: 10.1136/annrheumdis-2019-215925

A live-attenuated herpes zoster vaccine can be used in individuals with systemic lupus erythematosus (SLE) if they are not intensively immunosuppressed and their condition is dormant, research suggests.

A paper published in Annals of the Rheumatic Diseases reported the outcomes of a randomized, placebo-controlled trial of the Zostavax herpes zoster vaccine in 90 adults with clinically stable SLE. Participants had to have been on a stable dose of immunosuppressive agents for at least 6 months and have a history of chicken pox or herpes zoster infection.

Chi Chiu Mok, MD, of the Tuen Mun Hospital in Hong Kong and coauthors wrote that herpes zoster reactivation has been reported to occur in 6.4 to 91.4 individuals with SLE per 1,000 patient-years, with consequences including postherpetic neuralgia and even death from disseminated infection. But because Zostavax is live-attenuated, it has not been widely used in immunocompromised people.

After a single subcutaneous dose of either the vaccine or placebo, researchers saw a significant increase in anti–varicella zoster virus (VZV) IgG antibodies in vaccinated individuals over 6 weeks. The magnitude of the increase in anti-VZV IgG seen in vaccinated individuals was on par with that previously seen in vaccinated healthy controls, although the authors noted that the absolute increase in values was lower.

“While the reason is not apparent, one contributing factor is the high rate of previous exposure to VZV infection in most participants, which could have led to a higher baseline anti-IgG anti-VZV value that limited its rise after vaccination,” the authors wrote.

In contrast, IgG reactivity declined in those who received the placebo injection, and the difference between the two groups was statistically significant after adjustment for baseline antibody titers.

The study also looked at the cell-mediated immune response to the vaccine and found the number of interferon-gamma secreting CD4+ T-cell spots increased in the vaccinated patients but decreased in the placebo arm, and by week 6 it was significantly higher in the treated group. The increase in the vaccine-treated patients was again similar to that previously seen in healthy controls.

However, prednisolone use at baseline may have attenuated the vaccine response. Vaccinated patients who were treated with prednisolone at baseline had a lower increase in T-cell spots and lower anti-VZV IgG reactivity after the vaccination than did those not taking prednisolone, although the difference between the two groups was not statistically significant. The study did not see any effect of age, sex, baseline lymphocyte count, disease activity scores, and other factors on response to the vaccine.

None of the patients who received the vaccine withdrew from the study because of serious adverse events. The most common adverse events reported were injection-site redness and pain, which were more common in the vaccine-treated group than in the placebo group. However these symptoms were mild and resolved by themselves after a few days. Two patients in the vaccine group and one in the placebo group experienced mild or moderate SLE flares.

The authors commented that this was the first randomized, controlled trial examining the safety and immune response of a live-attenuated herpes zoster vaccine in individuals with SLE and this trial showed it was safe and well tolerated in those with stable disease who were not on intensive immunosuppressive therapy.

“Despite the increased risk of HZ [herpes zoster] infection, SLE had the lowest HZ vaccination rates among age-eligible subjects, probably because of the concern of vaccine safety, the principle of contraindication to live-attenuated vaccines in immunocompromised hosts, as well as the current ambiguous guidelines for HZ vaccination in SLE,” they wrote.

But they also stressed that their results did not apply to patients with active disease or on more intensive immunosuppression and that longer-term data on the persistence of vaccine immunogenicity was still being collected.

The study was funded by the Hong Kong Research Fund Secretariat. No conflicts of interest were declared.

SOURCE: Mok CC et al. Ann Rheum Dis. 2019 Sep 17. doi: 10.1136/annrheumdis-2019-215925

A live-attenuated herpes zoster vaccine can be used in individuals with systemic lupus erythematosus (SLE) if they are not intensively immunosuppressed and their condition is dormant, research suggests.

A paper published in Annals of the Rheumatic Diseases reported the outcomes of a randomized, placebo-controlled trial of the Zostavax herpes zoster vaccine in 90 adults with clinically stable SLE. Participants had to have been on a stable dose of immunosuppressive agents for at least 6 months and have a history of chicken pox or herpes zoster infection.

Chi Chiu Mok, MD, of the Tuen Mun Hospital in Hong Kong and coauthors wrote that herpes zoster reactivation has been reported to occur in 6.4 to 91.4 individuals with SLE per 1,000 patient-years, with consequences including postherpetic neuralgia and even death from disseminated infection. But because Zostavax is live-attenuated, it has not been widely used in immunocompromised people.

After a single subcutaneous dose of either the vaccine or placebo, researchers saw a significant increase in anti–varicella zoster virus (VZV) IgG antibodies in vaccinated individuals over 6 weeks. The magnitude of the increase in anti-VZV IgG seen in vaccinated individuals was on par with that previously seen in vaccinated healthy controls, although the authors noted that the absolute increase in values was lower.

“While the reason is not apparent, one contributing factor is the high rate of previous exposure to VZV infection in most participants, which could have led to a higher baseline anti-IgG anti-VZV value that limited its rise after vaccination,” the authors wrote.

In contrast, IgG reactivity declined in those who received the placebo injection, and the difference between the two groups was statistically significant after adjustment for baseline antibody titers.

The study also looked at the cell-mediated immune response to the vaccine and found the number of interferon-gamma secreting CD4+ T-cell spots increased in the vaccinated patients but decreased in the placebo arm, and by week 6 it was significantly higher in the treated group. The increase in the vaccine-treated patients was again similar to that previously seen in healthy controls.

However, prednisolone use at baseline may have attenuated the vaccine response. Vaccinated patients who were treated with prednisolone at baseline had a lower increase in T-cell spots and lower anti-VZV IgG reactivity after the vaccination than did those not taking prednisolone, although the difference between the two groups was not statistically significant. The study did not see any effect of age, sex, baseline lymphocyte count, disease activity scores, and other factors on response to the vaccine.

None of the patients who received the vaccine withdrew from the study because of serious adverse events. The most common adverse events reported were injection-site redness and pain, which were more common in the vaccine-treated group than in the placebo group. However these symptoms were mild and resolved by themselves after a few days. Two patients in the vaccine group and one in the placebo group experienced mild or moderate SLE flares.

The authors commented that this was the first randomized, controlled trial examining the safety and immune response of a live-attenuated herpes zoster vaccine in individuals with SLE and this trial showed it was safe and well tolerated in those with stable disease who were not on intensive immunosuppressive therapy.

“Despite the increased risk of HZ [herpes zoster] infection, SLE had the lowest HZ vaccination rates among age-eligible subjects, probably because of the concern of vaccine safety, the principle of contraindication to live-attenuated vaccines in immunocompromised hosts, as well as the current ambiguous guidelines for HZ vaccination in SLE,” they wrote.

But they also stressed that their results did not apply to patients with active disease or on more intensive immunosuppression and that longer-term data on the persistence of vaccine immunogenicity was still being collected.

The study was funded by the Hong Kong Research Fund Secretariat. No conflicts of interest were declared.

SOURCE: Mok CC et al. Ann Rheum Dis. 2019 Sep 17. doi: 10.1136/annrheumdis-2019-215925

Rheumatologist Zachary S. Wallace, MD, knew just how prior authorization requirements were impacting his staff time and work flow when he embarked on a study several years ago. Managing authorizations for infusible medications alone was about to become a full-time job for one of the administrative assistants in the rheumatology unit at Massachusetts General Hospital in Boston.

His research questions concerned patients. “There’s a lot of talk about how much onus prior authorization requirements put on providers and the practice,” Dr. Wallace said. ”I was interested in understanding what impact [these requirements] have on patients themselves.”

Dr. Wallace led a review of the EHRs of 225 patients for whom an infusible medication such as rituximab and infliximab was ordered by 1 of the 16 physicians in the rheumatology unit between July 2016 and June 2018. The findings – that patients who needed prior authorizations for infusible medications had a significantly longer time to treatment initiation and higher prednisone-equivalent glucocorticoid exposure – were reported online in Arthritis Care & Research.

Among patients whose authorizations were initially denied, these differences were “pretty drastic,” Dr. Wallace said. The median time to receiving a first infusion was 50 days, compared with 27 days when permission was not required, and glucocorticoid exposure during the 3 months following the request was 605 mg versus 160 mg.

Among patients whose authorizations were not denied, the median time to first infusion was 31 days, compared with 27 days when authorization was not required, and the mean glucocorticoid exposure over 3 months was 364 mg versus 160 mg.

“I hope that our findings will help facilitate discussions with insurance providers, pharmacy benefit managers, and state and federal legislators about the need to address the impact that prior authorization requirements have on patients and providers,” said Dr. Wallace, also of the clinical epidemiology program in the division of rheumatology, allergy and immunology at Massachusetts General, and an assistant professor of medicine at Harvard Medical School, Boston.

Of the 225 patients for whom an infusible medication was ordered, 71% required preauthorization. Of these, 79% were approved and 21% were denied after the first request. And in a finding that Dr. Wallace called “somewhat surprising,” 82% of the authorizations originally denied were approved after appeal.

All told, prior authorizations for infusible medications were eventually approved in all but a small number of cases. “We go through all this effort to get these prior authorizations approved, and 96% of the time, they were ultimately approved,” he said in an interview.

Christopher Phillips, MD, a community rheumatologist in Paducah, Ky., who serves as chair of the insurance subcommittee of the American College of Rheumatology’s committee on rheumatologic care, said the findings “give further credence” to rheumatologists’ concerns. “We know [from our own experiences] that prior authorizations delay care, and we know that delays can cause harm to patients. We now have hard data backing up this assertion.”

Regarding the high number of authorization approvals, “there’s an argument to be made that for certain treatments and certain conditions where the success rate of appeals is high enough, you shouldn’t be subjecting these treatments to these [preauthorization] policies,” he said.

Calls for prior authorization reform

Most patients in the study (71%) had private insurance. But the findings also have implications for Medicare, Dr. Wallace said, as recent federal policies have expanded Medicare Advantage plans’ authority to use prior authorization in conjunction with step therapy for medications administered under Part B. Step therapy favors primary use of what insurers deem the most cost-effective therapies.

The ACR is one of almost 370 physician, patient, and health care organizations that are urging Congress to pass a bipartisan bill aimed at streamlining and standardizing prior authorization under the Medicare Advantage program. The legislation – Improving Seniors’ Timely Access to Care Act of 2019 (H.R. 3107) – was introduced by Reps. Suzan DelBene (D-Wash.), Mike Kelly (R-Pa.), Roger Marshall, MD (R-Kan.), and Ami Bera, MD (D-Calif.).

The bill calls for the creation of an electronic prior authorization program and a “real-time process for items and services that are routinely approved,” as well as greater Centers for Medicare & Medicaid Services oversight on how Medicare Advantage plans use prior authorization. Plans would be required to report to the CMS on the extent of their use of prior authorization and the rate of approvals or denials. They would also be held accountable for making timely prior authorization determinations and providing rationales for denials, according to a letter to Congress cosigned by the ACR.

In a press release about the legislation, Paula Marchetta, MD, president of the ACR, said that “the unregulated use of prior authorization has devolved into a time-consuming and obstructive process that often stalls or outright revokes patient access to medically necessary therapies.” She added that “many health care plans now use prior authorization indiscriminately.”

Cathryn Donaldson, director of communications for America’s Health Insurance Plans (AHIP), said in an email that prior authorization is used for less than 15% of covered services, and that, along with step therapy, it “helps ensure that patients receive care that is safe, effective, and necessary.” AHIP “knows that prior authorization can be improved,” she said, and is committed to streamlining the process.

A demonstration project on the automation of various parts of prior authorization is being coordinated with health information technology companies, plans, and providers, she noted.

The federal legislation is based at least partly on a consensus statement drafted by AHIP, the American Medical Association, and four other organizations representing hospitals, medical groups, and health plans on ways to improve the prior authorization process. Among the items mentioned in the statement is that “regular review” of services subject to prior authorization could help identify therapies that “no longer warrant” prior authorization because of low denial rates.

Outside of Medicare Advantage, the AMA is aware of at least 85 bills being introduced in states this year that address utilization management in commercial plans. Nearly all these bills attempt to reform prior authorization programs in some way, according to R. J. Mills, media relations coordinator for the AMA.

Rheumatologic patients hard hit

Off-label medication use was the most common reason (82%) for a prior authorization denial in the Massachusetts General study, even though 78% of the patients for whom infusible medications were prescribed had a condition with no Food and Drug Administration–approved treatment. Having such a condition was associated with 120% or 190% higher odds of having a denial in unadjusted and adjusted (for age and sex) analyses, Dr. Wallace and colleagues reported.

Moreover, nearly half (48%) of the patients with denials had already tried or were currently taking an oral disease-modifying antirheumatic drug, such as methotrexate.

The majority of denials were for the use of rituximab (70%), followed by infliximab (12%) and tocilizumab (12%). Most of the denials (79%) were appealed successfully through a peer-to-peer discussion. In five cases, the insurer’s preferred drug (for example, adalimumab) had to be used rather than the requested infusion (for example, infliximab).

Infused medications, many of which are biologics, are among the most expensive drugs prescribed for patients with rheumatic diseases. They were easiest for Dr. Wallace to study because of the way prior authorizations are handled in his unit, but prior authorization requirements are “widespread” in rheumatology practices across treatment types, he and Dr. Phillips said.

“Some of our relatively inexpensive treatments are subject to prior authorization requirements,” Dr. Phillips said. “We hear stories about prednisone needing a prior authorization sometimes.”

With respect to infusible medications, the insurance subcommittee is hearing from ACR members about seemingly increasing numbers of both clinical coverage reviews – for example, reviews of prior treatments – and site-of-care restrictions, Dr. Phillips noted. “Some carriers are insisting on infusions in non-hospital-based settings, for cost savings, or on home infusions, which are concerning because of [possible] infusion reactions and medical service availability.”

The application of step therapy to rheumatologic patients is troubling because of the “often unique medical circumstances of the patient,” Dr. Phillips said. “There are enough differences among the [tumor necrosis factor] antagonists, for instance, that make one more appropriate for a certain patient than another. Those differences are not brought into consideration with these policies.”

There are other ways in which prior authorization processes “are not well informed medically,” he said, recalling a case brought to the attention of the subcommittee in which a patient prescribed a biologic drug for psoriatic arthritis was denied authorization because “the documentation did not include a [disease activity measure] that is specific to RA and not used for psoriatic arthritis.”

It is not uncommon for authorizations for infusible medications to take 2 weeks or longer to secure – even when initially approved. In the AMA’s 2018 Prior Authorization Physician Survey, 65% reported waiting at least 1 business day for a decision and 26% reported waiting at least 3 business days for responses. “With infusibles, we’re absolutely dealing with a much longer time,” Dr. Phillips said.

In Dr. Wallace’s study, the finding that prior authorizations facilitated greater prednisone-equivalent glucocorticoid exposure is important, he and his colleagues wrote, because these medications may put patients at higher risk of infection, cardiovascular disease, and diabetes – even in low doses and with short-term use. Notably, the median delay to the initiation of treatment was 29 days, regardless of prior authorization requirements. Dr. Wallace said the delays “likely reflect a combination of factors” – including infusion center waiting lists and patient-level factors – and that his team is “thinking about how to facilitate better access [to their practice’s infusion center] for those who are approved for treatment.”

The most common conditions for which infused medication was ordered were inflammatory arthritis (32%), vasculitis (23%), and IgG4-related disease (17%). The 225 patients in the study had an average age of 53 years.

Dr. Wallace reported that he has no relevant financial disclosures.

SOURCE: Wallace ZS et al. Arthritis Care Res. 2019 Sep 10. doi: 10.1002/acr.24062.

Rheumatologist Zachary S. Wallace, MD, knew just how prior authorization requirements were impacting his staff time and work flow when he embarked on a study several years ago. Managing authorizations for infusible medications alone was about to become a full-time job for one of the administrative assistants in the rheumatology unit at Massachusetts General Hospital in Boston.

His research questions concerned patients. “There’s a lot of talk about how much onus prior authorization requirements put on providers and the practice,” Dr. Wallace said. ”I was interested in understanding what impact [these requirements] have on patients themselves.”

Dr. Wallace led a review of the EHRs of 225 patients for whom an infusible medication such as rituximab and infliximab was ordered by 1 of the 16 physicians in the rheumatology unit between July 2016 and June 2018. The findings – that patients who needed prior authorizations for infusible medications had a significantly longer time to treatment initiation and higher prednisone-equivalent glucocorticoid exposure – were reported online in Arthritis Care & Research.

Among patients whose authorizations were initially denied, these differences were “pretty drastic,” Dr. Wallace said. The median time to receiving a first infusion was 50 days, compared with 27 days when permission was not required, and glucocorticoid exposure during the 3 months following the request was 605 mg versus 160 mg.

Among patients whose authorizations were not denied, the median time to first infusion was 31 days, compared with 27 days when authorization was not required, and the mean glucocorticoid exposure over 3 months was 364 mg versus 160 mg.

“I hope that our findings will help facilitate discussions with insurance providers, pharmacy benefit managers, and state and federal legislators about the need to address the impact that prior authorization requirements have on patients and providers,” said Dr. Wallace, also of the clinical epidemiology program in the division of rheumatology, allergy and immunology at Massachusetts General, and an assistant professor of medicine at Harvard Medical School, Boston.

Of the 225 patients for whom an infusible medication was ordered, 71% required preauthorization. Of these, 79% were approved and 21% were denied after the first request. And in a finding that Dr. Wallace called “somewhat surprising,” 82% of the authorizations originally denied were approved after appeal.

All told, prior authorizations for infusible medications were eventually approved in all but a small number of cases. “We go through all this effort to get these prior authorizations approved, and 96% of the time, they were ultimately approved,” he said in an interview.

Christopher Phillips, MD, a community rheumatologist in Paducah, Ky., who serves as chair of the insurance subcommittee of the American College of Rheumatology’s committee on rheumatologic care, said the findings “give further credence” to rheumatologists’ concerns. “We know [from our own experiences] that prior authorizations delay care, and we know that delays can cause harm to patients. We now have hard data backing up this assertion.”

Regarding the high number of authorization approvals, “there’s an argument to be made that for certain treatments and certain conditions where the success rate of appeals is high enough, you shouldn’t be subjecting these treatments to these [preauthorization] policies,” he said.

Calls for prior authorization reform

Most patients in the study (71%) had private insurance. But the findings also have implications for Medicare, Dr. Wallace said, as recent federal policies have expanded Medicare Advantage plans’ authority to use prior authorization in conjunction with step therapy for medications administered under Part B. Step therapy favors primary use of what insurers deem the most cost-effective therapies.

The ACR is one of almost 370 physician, patient, and health care organizations that are urging Congress to pass a bipartisan bill aimed at streamlining and standardizing prior authorization under the Medicare Advantage program. The legislation – Improving Seniors’ Timely Access to Care Act of 2019 (H.R. 3107) – was introduced by Reps. Suzan DelBene (D-Wash.), Mike Kelly (R-Pa.), Roger Marshall, MD (R-Kan.), and Ami Bera, MD (D-Calif.).

The bill calls for the creation of an electronic prior authorization program and a “real-time process for items and services that are routinely approved,” as well as greater Centers for Medicare & Medicaid Services oversight on how Medicare Advantage plans use prior authorization. Plans would be required to report to the CMS on the extent of their use of prior authorization and the rate of approvals or denials. They would also be held accountable for making timely prior authorization determinations and providing rationales for denials, according to a letter to Congress cosigned by the ACR.

In a press release about the legislation, Paula Marchetta, MD, president of the ACR, said that “the unregulated use of prior authorization has devolved into a time-consuming and obstructive process that often stalls or outright revokes patient access to medically necessary therapies.” She added that “many health care plans now use prior authorization indiscriminately.”

Cathryn Donaldson, director of communications for America’s Health Insurance Plans (AHIP), said in an email that prior authorization is used for less than 15% of covered services, and that, along with step therapy, it “helps ensure that patients receive care that is safe, effective, and necessary.” AHIP “knows that prior authorization can be improved,” she said, and is committed to streamlining the process.

A demonstration project on the automation of various parts of prior authorization is being coordinated with health information technology companies, plans, and providers, she noted.

The federal legislation is based at least partly on a consensus statement drafted by AHIP, the American Medical Association, and four other organizations representing hospitals, medical groups, and health plans on ways to improve the prior authorization process. Among the items mentioned in the statement is that “regular review” of services subject to prior authorization could help identify therapies that “no longer warrant” prior authorization because of low denial rates.

Outside of Medicare Advantage, the AMA is aware of at least 85 bills being introduced in states this year that address utilization management in commercial plans. Nearly all these bills attempt to reform prior authorization programs in some way, according to R. J. Mills, media relations coordinator for the AMA.

Rheumatologic patients hard hit

Off-label medication use was the most common reason (82%) for a prior authorization denial in the Massachusetts General study, even though 78% of the patients for whom infusible medications were prescribed had a condition with no Food and Drug Administration–approved treatment. Having such a condition was associated with 120% or 190% higher odds of having a denial in unadjusted and adjusted (for age and sex) analyses, Dr. Wallace and colleagues reported.

Moreover, nearly half (48%) of the patients with denials had already tried or were currently taking an oral disease-modifying antirheumatic drug, such as methotrexate.

The majority of denials were for the use of rituximab (70%), followed by infliximab (12%) and tocilizumab (12%). Most of the denials (79%) were appealed successfully through a peer-to-peer discussion. In five cases, the insurer’s preferred drug (for example, adalimumab) had to be used rather than the requested infusion (for example, infliximab).

Infused medications, many of which are biologics, are among the most expensive drugs prescribed for patients with rheumatic diseases. They were easiest for Dr. Wallace to study because of the way prior authorizations are handled in his unit, but prior authorization requirements are “widespread” in rheumatology practices across treatment types, he and Dr. Phillips said.

“Some of our relatively inexpensive treatments are subject to prior authorization requirements,” Dr. Phillips said. “We hear stories about prednisone needing a prior authorization sometimes.”

With respect to infusible medications, the insurance subcommittee is hearing from ACR members about seemingly increasing numbers of both clinical coverage reviews – for example, reviews of prior treatments – and site-of-care restrictions, Dr. Phillips noted. “Some carriers are insisting on infusions in non-hospital-based settings, for cost savings, or on home infusions, which are concerning because of [possible] infusion reactions and medical service availability.”

The application of step therapy to rheumatologic patients is troubling because of the “often unique medical circumstances of the patient,” Dr. Phillips said. “There are enough differences among the [tumor necrosis factor] antagonists, for instance, that make one more appropriate for a certain patient than another. Those differences are not brought into consideration with these policies.”

There are other ways in which prior authorization processes “are not well informed medically,” he said, recalling a case brought to the attention of the subcommittee in which a patient prescribed a biologic drug for psoriatic arthritis was denied authorization because “the documentation did not include a [disease activity measure] that is specific to RA and not used for psoriatic arthritis.”

It is not uncommon for authorizations for infusible medications to take 2 weeks or longer to secure – even when initially approved. In the AMA’s 2018 Prior Authorization Physician Survey, 65% reported waiting at least 1 business day for a decision and 26% reported waiting at least 3 business days for responses. “With infusibles, we’re absolutely dealing with a much longer time,” Dr. Phillips said.

In Dr. Wallace’s study, the finding that prior authorizations facilitated greater prednisone-equivalent glucocorticoid exposure is important, he and his colleagues wrote, because these medications may put patients at higher risk of infection, cardiovascular disease, and diabetes – even in low doses and with short-term use. Notably, the median delay to the initiation of treatment was 29 days, regardless of prior authorization requirements. Dr. Wallace said the delays “likely reflect a combination of factors” – including infusion center waiting lists and patient-level factors – and that his team is “thinking about how to facilitate better access [to their practice’s infusion center] for those who are approved for treatment.”

The most common conditions for which infused medication was ordered were inflammatory arthritis (32%), vasculitis (23%), and IgG4-related disease (17%). The 225 patients in the study had an average age of 53 years.

Dr. Wallace reported that he has no relevant financial disclosures.

SOURCE: Wallace ZS et al. Arthritis Care Res. 2019 Sep 10. doi: 10.1002/acr.24062.

Rheumatologist Zachary S. Wallace, MD, knew just how prior authorization requirements were impacting his staff time and work flow when he embarked on a study several years ago. Managing authorizations for infusible medications alone was about to become a full-time job for one of the administrative assistants in the rheumatology unit at Massachusetts General Hospital in Boston.

His research questions concerned patients. “There’s a lot of talk about how much onus prior authorization requirements put on providers and the practice,” Dr. Wallace said. ”I was interested in understanding what impact [these requirements] have on patients themselves.”

Dr. Wallace led a review of the EHRs of 225 patients for whom an infusible medication such as rituximab and infliximab was ordered by 1 of the 16 physicians in the rheumatology unit between July 2016 and June 2018. The findings – that patients who needed prior authorizations for infusible medications had a significantly longer time to treatment initiation and higher prednisone-equivalent glucocorticoid exposure – were reported online in Arthritis Care & Research.

Among patients whose authorizations were initially denied, these differences were “pretty drastic,” Dr. Wallace said. The median time to receiving a first infusion was 50 days, compared with 27 days when permission was not required, and glucocorticoid exposure during the 3 months following the request was 605 mg versus 160 mg.

Among patients whose authorizations were not denied, the median time to first infusion was 31 days, compared with 27 days when authorization was not required, and the mean glucocorticoid exposure over 3 months was 364 mg versus 160 mg.

“I hope that our findings will help facilitate discussions with insurance providers, pharmacy benefit managers, and state and federal legislators about the need to address the impact that prior authorization requirements have on patients and providers,” said Dr. Wallace, also of the clinical epidemiology program in the division of rheumatology, allergy and immunology at Massachusetts General, and an assistant professor of medicine at Harvard Medical School, Boston.

Of the 225 patients for whom an infusible medication was ordered, 71% required preauthorization. Of these, 79% were approved and 21% were denied after the first request. And in a finding that Dr. Wallace called “somewhat surprising,” 82% of the authorizations originally denied were approved after appeal.

All told, prior authorizations for infusible medications were eventually approved in all but a small number of cases. “We go through all this effort to get these prior authorizations approved, and 96% of the time, they were ultimately approved,” he said in an interview.

Christopher Phillips, MD, a community rheumatologist in Paducah, Ky., who serves as chair of the insurance subcommittee of the American College of Rheumatology’s committee on rheumatologic care, said the findings “give further credence” to rheumatologists’ concerns. “We know [from our own experiences] that prior authorizations delay care, and we know that delays can cause harm to patients. We now have hard data backing up this assertion.”

Regarding the high number of authorization approvals, “there’s an argument to be made that for certain treatments and certain conditions where the success rate of appeals is high enough, you shouldn’t be subjecting these treatments to these [preauthorization] policies,” he said.

Calls for prior authorization reform

Most patients in the study (71%) had private insurance. But the findings also have implications for Medicare, Dr. Wallace said, as recent federal policies have expanded Medicare Advantage plans’ authority to use prior authorization in conjunction with step therapy for medications administered under Part B. Step therapy favors primary use of what insurers deem the most cost-effective therapies.

The ACR is one of almost 370 physician, patient, and health care organizations that are urging Congress to pass a bipartisan bill aimed at streamlining and standardizing prior authorization under the Medicare Advantage program. The legislation – Improving Seniors’ Timely Access to Care Act of 2019 (H.R. 3107) – was introduced by Reps. Suzan DelBene (D-Wash.), Mike Kelly (R-Pa.), Roger Marshall, MD (R-Kan.), and Ami Bera, MD (D-Calif.).

The bill calls for the creation of an electronic prior authorization program and a “real-time process for items and services that are routinely approved,” as well as greater Centers for Medicare & Medicaid Services oversight on how Medicare Advantage plans use prior authorization. Plans would be required to report to the CMS on the extent of their use of prior authorization and the rate of approvals or denials. They would also be held accountable for making timely prior authorization determinations and providing rationales for denials, according to a letter to Congress cosigned by the ACR.

In a press release about the legislation, Paula Marchetta, MD, president of the ACR, said that “the unregulated use of prior authorization has devolved into a time-consuming and obstructive process that often stalls or outright revokes patient access to medically necessary therapies.” She added that “many health care plans now use prior authorization indiscriminately.”

Cathryn Donaldson, director of communications for America’s Health Insurance Plans (AHIP), said in an email that prior authorization is used for less than 15% of covered services, and that, along with step therapy, it “helps ensure that patients receive care that is safe, effective, and necessary.” AHIP “knows that prior authorization can be improved,” she said, and is committed to streamlining the process.

A demonstration project on the automation of various parts of prior authorization is being coordinated with health information technology companies, plans, and providers, she noted.

The federal legislation is based at least partly on a consensus statement drafted by AHIP, the American Medical Association, and four other organizations representing hospitals, medical groups, and health plans on ways to improve the prior authorization process. Among the items mentioned in the statement is that “regular review” of services subject to prior authorization could help identify therapies that “no longer warrant” prior authorization because of low denial rates.

Outside of Medicare Advantage, the AMA is aware of at least 85 bills being introduced in states this year that address utilization management in commercial plans. Nearly all these bills attempt to reform prior authorization programs in some way, according to R. J. Mills, media relations coordinator for the AMA.

Rheumatologic patients hard hit

Off-label medication use was the most common reason (82%) for a prior authorization denial in the Massachusetts General study, even though 78% of the patients for whom infusible medications were prescribed had a condition with no Food and Drug Administration–approved treatment. Having such a condition was associated with 120% or 190% higher odds of having a denial in unadjusted and adjusted (for age and sex) analyses, Dr. Wallace and colleagues reported.

Moreover, nearly half (48%) of the patients with denials had already tried or were currently taking an oral disease-modifying antirheumatic drug, such as methotrexate.

The majority of denials were for the use of rituximab (70%), followed by infliximab (12%) and tocilizumab (12%). Most of the denials (79%) were appealed successfully through a peer-to-peer discussion. In five cases, the insurer’s preferred drug (for example, adalimumab) had to be used rather than the requested infusion (for example, infliximab).

Infused medications, many of which are biologics, are among the most expensive drugs prescribed for patients with rheumatic diseases. They were easiest for Dr. Wallace to study because of the way prior authorizations are handled in his unit, but prior authorization requirements are “widespread” in rheumatology practices across treatment types, he and Dr. Phillips said.

“Some of our relatively inexpensive treatments are subject to prior authorization requirements,” Dr. Phillips said. “We hear stories about prednisone needing a prior authorization sometimes.”

With respect to infusible medications, the insurance subcommittee is hearing from ACR members about seemingly increasing numbers of both clinical coverage reviews – for example, reviews of prior treatments – and site-of-care restrictions, Dr. Phillips noted. “Some carriers are insisting on infusions in non-hospital-based settings, for cost savings, or on home infusions, which are concerning because of [possible] infusion reactions and medical service availability.”

The application of step therapy to rheumatologic patients is troubling because of the “often unique medical circumstances of the patient,” Dr. Phillips said. “There are enough differences among the [tumor necrosis factor] antagonists, for instance, that make one more appropriate for a certain patient than another. Those differences are not brought into consideration with these policies.”

There are other ways in which prior authorization processes “are not well informed medically,” he said, recalling a case brought to the attention of the subcommittee in which a patient prescribed a biologic drug for psoriatic arthritis was denied authorization because “the documentation did not include a [disease activity measure] that is specific to RA and not used for psoriatic arthritis.”

It is not uncommon for authorizations for infusible medications to take 2 weeks or longer to secure – even when initially approved. In the AMA’s 2018 Prior Authorization Physician Survey, 65% reported waiting at least 1 business day for a decision and 26% reported waiting at least 3 business days for responses. “With infusibles, we’re absolutely dealing with a much longer time,” Dr. Phillips said.

In Dr. Wallace’s study, the finding that prior authorizations facilitated greater prednisone-equivalent glucocorticoid exposure is important, he and his colleagues wrote, because these medications may put patients at higher risk of infection, cardiovascular disease, and diabetes – even in low doses and with short-term use. Notably, the median delay to the initiation of treatment was 29 days, regardless of prior authorization requirements. Dr. Wallace said the delays “likely reflect a combination of factors” – including infusion center waiting lists and patient-level factors – and that his team is “thinking about how to facilitate better access [to their practice’s infusion center] for those who are approved for treatment.”

The most common conditions for which infused medication was ordered were inflammatory arthritis (32%), vasculitis (23%), and IgG4-related disease (17%). The 225 patients in the study had an average age of 53 years.

Dr. Wallace reported that he has no relevant financial disclosures.

SOURCE: Wallace ZS et al. Arthritis Care Res. 2019 Sep 10. doi: 10.1002/acr.24062.