Artificial intelligence (AI) and machine learning (ML) are promoted as the solution to many health care problems, but the area risks becoming technology led – with only secondary consideration to the safe clinical application of the technology, says Robert Challen, PhD.

Dr. Challen, of the University of Exeter (England), is the lead author of a recent paper that examines the short-, medium-, and long-term issues with medical applications of AI. “In the short term, AI systems will effectively function like laboratory screening tests, identifying patients who are at higher risk than others of disease, or who could benefit more from a particular treatment,” Dr. Challen said. “We usually accept that laboratory tests are useful to help make a diagnosis; however, clinicians are aware that they might not always be accurate and interpret their output in the clinical context. AI systems are no different in that they will be a useful tool so long as they are designed with safety in mind and used with a pragmatic attitude to their interpretation.”

The paper also suggests a set of short-and medium-term clinical safety issues that need addressing when bringing these systems from laboratory to bedside.

In the longer term, as more continuously learning and autonomous systems are developed, the safety risks will need to be continuously reevaluated, he added. “Any new technology comes with limitations and understanding those limitations is key to safe use of that technology. In the same way a new screening test has limitations on its sensitivity and specificity that define how it can be used, AL and ML systems have limitations on accuracy and which patients they can be used on,” Dr. Challen said. If hospitalists understand these limitations, they can participate better in their development.

Dr. Challen recommends that hospitalists help the development of AI tools by participating in studies that assess AI applications in the clinical environment. “Try to make sure that where AI research is taking place, there is strong clinical involvement.”

Reference

1. Challen R et al. Artificial intelligence, bias and clinical safety. BMJ Qual Saf. 2019 Jan 12. doi: 10.1136/bmjqs-2018-008370.

Artificial intelligence (AI) and machine learning (ML) are promoted as the solution to many health care problems, but the area risks becoming technology led – with only secondary consideration to the safe clinical application of the technology, says Robert Challen, PhD.

Dr. Challen, of the University of Exeter (England), is the lead author of a recent paper that examines the short-, medium-, and long-term issues with medical applications of AI. “In the short term, AI systems will effectively function like laboratory screening tests, identifying patients who are at higher risk than others of disease, or who could benefit more from a particular treatment,” Dr. Challen said. “We usually accept that laboratory tests are useful to help make a diagnosis; however, clinicians are aware that they might not always be accurate and interpret their output in the clinical context. AI systems are no different in that they will be a useful tool so long as they are designed with safety in mind and used with a pragmatic attitude to their interpretation.”

The paper also suggests a set of short-and medium-term clinical safety issues that need addressing when bringing these systems from laboratory to bedside.

In the longer term, as more continuously learning and autonomous systems are developed, the safety risks will need to be continuously reevaluated, he added. “Any new technology comes with limitations and understanding those limitations is key to safe use of that technology. In the same way a new screening test has limitations on its sensitivity and specificity that define how it can be used, AL and ML systems have limitations on accuracy and which patients they can be used on,” Dr. Challen said. If hospitalists understand these limitations, they can participate better in their development.

Dr. Challen recommends that hospitalists help the development of AI tools by participating in studies that assess AI applications in the clinical environment. “Try to make sure that where AI research is taking place, there is strong clinical involvement.”

Reference

1. Challen R et al. Artificial intelligence, bias and clinical safety. BMJ Qual Saf. 2019 Jan 12. doi: 10.1136/bmjqs-2018-008370.

Artificial intelligence (AI) and machine learning (ML) are promoted as the solution to many health care problems, but the area risks becoming technology led – with only secondary consideration to the safe clinical application of the technology, says Robert Challen, PhD.

Dr. Challen, of the University of Exeter (England), is the lead author of a recent paper that examines the short-, medium-, and long-term issues with medical applications of AI. “In the short term, AI systems will effectively function like laboratory screening tests, identifying patients who are at higher risk than others of disease, or who could benefit more from a particular treatment,” Dr. Challen said. “We usually accept that laboratory tests are useful to help make a diagnosis; however, clinicians are aware that they might not always be accurate and interpret their output in the clinical context. AI systems are no different in that they will be a useful tool so long as they are designed with safety in mind and used with a pragmatic attitude to their interpretation.”

The paper also suggests a set of short-and medium-term clinical safety issues that need addressing when bringing these systems from laboratory to bedside.

In the longer term, as more continuously learning and autonomous systems are developed, the safety risks will need to be continuously reevaluated, he added. “Any new technology comes with limitations and understanding those limitations is key to safe use of that technology. In the same way a new screening test has limitations on its sensitivity and specificity that define how it can be used, AL and ML systems have limitations on accuracy and which patients they can be used on,” Dr. Challen said. If hospitalists understand these limitations, they can participate better in their development.

Dr. Challen recommends that hospitalists help the development of AI tools by participating in studies that assess AI applications in the clinical environment. “Try to make sure that where AI research is taking place, there is strong clinical involvement.”

Reference

1. Challen R et al. Artificial intelligence, bias and clinical safety. BMJ Qual Saf. 2019 Jan 12. doi: 10.1136/bmjqs-2018-008370.

Children with eosinophilic esophagitis often experience respiratory and motor disturbances during sleep, which appear related to dysregulated sleep architecture, Rasintra Siriwat, MD, and colleagues have ascertained.

©Alex Vasilev/Fotolia.com

Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.

The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m². A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.

Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.

Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).

All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.

“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.

The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).

Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.

“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”

Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.

msullivan@mdedge.com

SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.

Children with eosinophilic esophagitis often experience respiratory and motor disturbances during sleep, which appear related to dysregulated sleep architecture, Rasintra Siriwat, MD, and colleagues have ascertained.

©Alex Vasilev/Fotolia.com

Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.

The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m². A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.

Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.

Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).

All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.

“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.

The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).

Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.

“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”

Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.

msullivan@mdedge.com

SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.

Children with eosinophilic esophagitis often experience respiratory and motor disturbances during sleep, which appear related to dysregulated sleep architecture, Rasintra Siriwat, MD, and colleagues have ascertained.

©Alex Vasilev/Fotolia.com

Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.

The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m². A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.

Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.

Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).

All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.

“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.

The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).

Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.

“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”

Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.

msullivan@mdedge.com

SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.

LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.

There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”

In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
 

Defining difficult to treat

In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).

“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”

The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.

Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).

The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.

Approaches to treatment

New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”

Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.

“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”

Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.

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

jremaly@mdedge.com

LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.

There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”

In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
 

Defining difficult to treat

In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).

“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”

The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.

Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).

The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.

Approaches to treatment

New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”

Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.

“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”

Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.

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

jremaly@mdedge.com

LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.

There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”

In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
 

Defining difficult to treat

In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).

“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”

The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.

Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).

The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.

Approaches to treatment

New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”

Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.

“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”

Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.

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

jremaly@mdedge.com

Elderly patients with colorectal cancer have better perioperative outcomes than do those who undergo open surgery, although in this sample, long-term outcomes are similar, Sicheng Zhou, and colleagues wrote in BMC Surgery.

HRAUN/Getty Images

“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”

The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).

Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.

Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.

Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).

The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).

Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”

The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.

msullivan@mdedge.com

SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.

Elderly patients with colorectal cancer have better perioperative outcomes than do those who undergo open surgery, although in this sample, long-term outcomes are similar, Sicheng Zhou, and colleagues wrote in BMC Surgery.

HRAUN/Getty Images

“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”

The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).

Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.

Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.

Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).

The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).

Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”

The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.

msullivan@mdedge.com

SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.

Elderly patients with colorectal cancer have better perioperative outcomes than do those who undergo open surgery, although in this sample, long-term outcomes are similar, Sicheng Zhou, and colleagues wrote in BMC Surgery.

HRAUN/Getty Images

“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”

The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).

Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.

Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.

Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).

The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).

Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”

The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.

msullivan@mdedge.com

SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.

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.

jremaly@mdedge.com

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.

jremaly@mdedge.com

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.

jremaly@mdedge.com

SAN FRANCISCO – Should patients with multiple myeloma receive maintenance therapy until progression?

Jennifer Smith/MDedge News

Yvonne A. Efebera, MD, of The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital in Columbus, and Nina Shah, MD, of the University of California San Francisco Health, faced off on this question at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Treat until progression

Dr. Shah cited studies suggesting that maintenance improves progression-free survival (PFS) and may prolong overall survival (OS) in multiple myeloma.

A meta-analysis of data from the IFM 2005-02, CALGB 100104, and GIMEMA RV-MM-PI-209 trials showed that lenalidomide maintenance prolonged PFS and OS. The median PFS was 52.8 months in patients who received maintenance and 23.5 months in those who received placebo or observation (hazard ratio [HR], 0.48). At a median follow-up of 79.5 months, the median OS was not reached for the maintenance group and was 86.0 months for the no-maintenance group (HR, 0.75; P = .001; J Clin Oncol. 2017 Oct 10;35[29]:3279-89).

In the Myeloma XI trial, maintenance improved PFS, but not OS, in both transplant-eligible and ineligible patients. Overall, the median PFS was 39 months in the lenalidomide maintenance arm and 20 months in the observation arm (P less than .0001). Among transplant-eligible patients, the median PFS was 57 months and 30 months, respectively (P less than .0001). Among transplant-ineligible patients, the median PFS was 26 months and 11 months, respectively (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:57-73).

These data suggest maintenance can improve survival, “but the question is, how long should we have therapy,” Dr. Shah said. “No one has looked at this in a prospective manner, so we really have to look at our retrospective data.”

One study suggested a longer duration of lenalidomide maintenance improves PFS. The HR for progression or death was 0.39 for patients who received maintenance for 12-24 months, compared with those who received maintenance for less than 12 months. The HR was 0.13 for patients who received maintenance for more than 24 months, compared with less than 12 months (Leuk Lymphoma. 2019 Feb;60[2]:511-4).

Dr. Shah also cited a pooled analysis of three phase 3 trials suggesting that continuous therapy is superior to fixed-duration therapy in patients with newly diagnosed myeloma. The median PFS was 32 months with continuous therapy and 16 months with fixed-duration therapy (P less than .001). The 4-year OS was 69% and 60%, respectively (P = .003; J Clin Oncol. 2015 Oct 20;33[30]:3459-66).

These data suggest that “continuous therapy, more therapy, has a survival advantage,” Dr. Shah said.
 

Don’t treat until progression

Dr. Efebera also discussed data from studies showing that lenalidomide maintenance can prolong survival in multiple myeloma. However, she said, it’s unclear how long maintenance should last.

Different durations of maintenance have proved effective in different trials. In the CALGB 100104 trial, the median duration of maintenance was 31 months (Lancet Haematol. 2017 Sep;4[9]:e431-e442). In the meta-analysis of the CALGB, IFM, and GIMEMA trials, the median duration was 22 months. And in Myeloma XI, the median duration was 18 months.

As there is no randomized trial comparing different durations of maintenance, Dr. Efebera proposed that researchers conduct one. She said this “perfect study” would involve induction with an immunomodulatory agent, a proteasome inhibitor, dexamethasone, and perhaps an anti-CD38 therapy. Transplant-eligible patients would receive four cycles of induction before transplant. Transplant-ineligible patients would receive eight cycles of induction. Then, all patients would be randomized to lenalidomide maintenance for 3 years, 5 years, or 7-10 years.

Until a trial like this reveals the optimal duration of maintenance, we cannot conclude that treating patients until progression is better, Dr. Efebera said.

She added that maintenance has been shown to have detrimental effects, and these should be taken into consideration. For instance, neutropenia, other hematologic adverse events, and second primary malignancies have been shown to be more common among patients who receive lenalidomide maintenance (N Engl J Med. 2012; 366:1782-91).

The cost of maintenance is another factor to consider. Researchers analyzed data from the CALGB 100104 and IFM 2005-02 trials to compare the cost of lenalidomide maintenance with no maintenance. In the CALGB 100104 trial, patients who received lenalidomide maintenance had 5.72 quality-adjusted life years (QALYs), and those who received no maintenance had 4.61 QALYs. The incremental cost-utility ratio (ICUR) was more than 277,000 euros per QALY.

In the IFM2005-02 trial, patients in the lenalidomide group had 5.13 QALYs, and those who didn’t receive maintenance had 4.98 QALYs. The ICUR was more than 1.5 million euros per QALY. The researchers said the high ICURs and budgetary impact add “uncertainty about the maximum prudent duration of the treatment” (Bone Marrow Transplant. 2019 May 31. doi: 10.1038/s41409-019-0574-5).

Dr. Efebera reported relationships with Akcea Therapeutics, Janssen, and Takeda. Dr. Shah reported having no relevant financial relationships.

jensmith@mdedge.com

SAN FRANCISCO – Should patients with multiple myeloma receive maintenance therapy until progression?

Jennifer Smith/MDedge News

Yvonne A. Efebera, MD, of The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital in Columbus, and Nina Shah, MD, of the University of California San Francisco Health, faced off on this question at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Treat until progression

Dr. Shah cited studies suggesting that maintenance improves progression-free survival (PFS) and may prolong overall survival (OS) in multiple myeloma.

A meta-analysis of data from the IFM 2005-02, CALGB 100104, and GIMEMA RV-MM-PI-209 trials showed that lenalidomide maintenance prolonged PFS and OS. The median PFS was 52.8 months in patients who received maintenance and 23.5 months in those who received placebo or observation (hazard ratio [HR], 0.48). At a median follow-up of 79.5 months, the median OS was not reached for the maintenance group and was 86.0 months for the no-maintenance group (HR, 0.75; P = .001; J Clin Oncol. 2017 Oct 10;35[29]:3279-89).

In the Myeloma XI trial, maintenance improved PFS, but not OS, in both transplant-eligible and ineligible patients. Overall, the median PFS was 39 months in the lenalidomide maintenance arm and 20 months in the observation arm (P less than .0001). Among transplant-eligible patients, the median PFS was 57 months and 30 months, respectively (P less than .0001). Among transplant-ineligible patients, the median PFS was 26 months and 11 months, respectively (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:57-73).

These data suggest maintenance can improve survival, “but the question is, how long should we have therapy,” Dr. Shah said. “No one has looked at this in a prospective manner, so we really have to look at our retrospective data.”

One study suggested a longer duration of lenalidomide maintenance improves PFS. The HR for progression or death was 0.39 for patients who received maintenance for 12-24 months, compared with those who received maintenance for less than 12 months. The HR was 0.13 for patients who received maintenance for more than 24 months, compared with less than 12 months (Leuk Lymphoma. 2019 Feb;60[2]:511-4).

Dr. Shah also cited a pooled analysis of three phase 3 trials suggesting that continuous therapy is superior to fixed-duration therapy in patients with newly diagnosed myeloma. The median PFS was 32 months with continuous therapy and 16 months with fixed-duration therapy (P less than .001). The 4-year OS was 69% and 60%, respectively (P = .003; J Clin Oncol. 2015 Oct 20;33[30]:3459-66).

These data suggest that “continuous therapy, more therapy, has a survival advantage,” Dr. Shah said.
 

Don’t treat until progression

Dr. Efebera also discussed data from studies showing that lenalidomide maintenance can prolong survival in multiple myeloma. However, she said, it’s unclear how long maintenance should last.

Different durations of maintenance have proved effective in different trials. In the CALGB 100104 trial, the median duration of maintenance was 31 months (Lancet Haematol. 2017 Sep;4[9]:e431-e442). In the meta-analysis of the CALGB, IFM, and GIMEMA trials, the median duration was 22 months. And in Myeloma XI, the median duration was 18 months.

As there is no randomized trial comparing different durations of maintenance, Dr. Efebera proposed that researchers conduct one. She said this “perfect study” would involve induction with an immunomodulatory agent, a proteasome inhibitor, dexamethasone, and perhaps an anti-CD38 therapy. Transplant-eligible patients would receive four cycles of induction before transplant. Transplant-ineligible patients would receive eight cycles of induction. Then, all patients would be randomized to lenalidomide maintenance for 3 years, 5 years, or 7-10 years.

Until a trial like this reveals the optimal duration of maintenance, we cannot conclude that treating patients until progression is better, Dr. Efebera said.

She added that maintenance has been shown to have detrimental effects, and these should be taken into consideration. For instance, neutropenia, other hematologic adverse events, and second primary malignancies have been shown to be more common among patients who receive lenalidomide maintenance (N Engl J Med. 2012; 366:1782-91).

The cost of maintenance is another factor to consider. Researchers analyzed data from the CALGB 100104 and IFM 2005-02 trials to compare the cost of lenalidomide maintenance with no maintenance. In the CALGB 100104 trial, patients who received lenalidomide maintenance had 5.72 quality-adjusted life years (QALYs), and those who received no maintenance had 4.61 QALYs. The incremental cost-utility ratio (ICUR) was more than 277,000 euros per QALY.

In the IFM2005-02 trial, patients in the lenalidomide group had 5.13 QALYs, and those who didn’t receive maintenance had 4.98 QALYs. The ICUR was more than 1.5 million euros per QALY. The researchers said the high ICURs and budgetary impact add “uncertainty about the maximum prudent duration of the treatment” (Bone Marrow Transplant. 2019 May 31. doi: 10.1038/s41409-019-0574-5).

Dr. Efebera reported relationships with Akcea Therapeutics, Janssen, and Takeda. Dr. Shah reported having no relevant financial relationships.

jensmith@mdedge.com

SAN FRANCISCO – Should patients with multiple myeloma receive maintenance therapy until progression?

Jennifer Smith/MDedge News

Yvonne A. Efebera, MD, of The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital in Columbus, and Nina Shah, MD, of the University of California San Francisco Health, faced off on this question at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Treat until progression

Dr. Shah cited studies suggesting that maintenance improves progression-free survival (PFS) and may prolong overall survival (OS) in multiple myeloma.

A meta-analysis of data from the IFM 2005-02, CALGB 100104, and GIMEMA RV-MM-PI-209 trials showed that lenalidomide maintenance prolonged PFS and OS. The median PFS was 52.8 months in patients who received maintenance and 23.5 months in those who received placebo or observation (hazard ratio [HR], 0.48). At a median follow-up of 79.5 months, the median OS was not reached for the maintenance group and was 86.0 months for the no-maintenance group (HR, 0.75; P = .001; J Clin Oncol. 2017 Oct 10;35[29]:3279-89).

In the Myeloma XI trial, maintenance improved PFS, but not OS, in both transplant-eligible and ineligible patients. Overall, the median PFS was 39 months in the lenalidomide maintenance arm and 20 months in the observation arm (P less than .0001). Among transplant-eligible patients, the median PFS was 57 months and 30 months, respectively (P less than .0001). Among transplant-ineligible patients, the median PFS was 26 months and 11 months, respectively (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:57-73).

These data suggest maintenance can improve survival, “but the question is, how long should we have therapy,” Dr. Shah said. “No one has looked at this in a prospective manner, so we really have to look at our retrospective data.”

One study suggested a longer duration of lenalidomide maintenance improves PFS. The HR for progression or death was 0.39 for patients who received maintenance for 12-24 months, compared with those who received maintenance for less than 12 months. The HR was 0.13 for patients who received maintenance for more than 24 months, compared with less than 12 months (Leuk Lymphoma. 2019 Feb;60[2]:511-4).

Dr. Shah also cited a pooled analysis of three phase 3 trials suggesting that continuous therapy is superior to fixed-duration therapy in patients with newly diagnosed myeloma. The median PFS was 32 months with continuous therapy and 16 months with fixed-duration therapy (P less than .001). The 4-year OS was 69% and 60%, respectively (P = .003; J Clin Oncol. 2015 Oct 20;33[30]:3459-66).

These data suggest that “continuous therapy, more therapy, has a survival advantage,” Dr. Shah said.
 

Don’t treat until progression

Dr. Efebera also discussed data from studies showing that lenalidomide maintenance can prolong survival in multiple myeloma. However, she said, it’s unclear how long maintenance should last.

Different durations of maintenance have proved effective in different trials. In the CALGB 100104 trial, the median duration of maintenance was 31 months (Lancet Haematol. 2017 Sep;4[9]:e431-e442). In the meta-analysis of the CALGB, IFM, and GIMEMA trials, the median duration was 22 months. And in Myeloma XI, the median duration was 18 months.

As there is no randomized trial comparing different durations of maintenance, Dr. Efebera proposed that researchers conduct one. She said this “perfect study” would involve induction with an immunomodulatory agent, a proteasome inhibitor, dexamethasone, and perhaps an anti-CD38 therapy. Transplant-eligible patients would receive four cycles of induction before transplant. Transplant-ineligible patients would receive eight cycles of induction. Then, all patients would be randomized to lenalidomide maintenance for 3 years, 5 years, or 7-10 years.

Until a trial like this reveals the optimal duration of maintenance, we cannot conclude that treating patients until progression is better, Dr. Efebera said.

She added that maintenance has been shown to have detrimental effects, and these should be taken into consideration. For instance, neutropenia, other hematologic adverse events, and second primary malignancies have been shown to be more common among patients who receive lenalidomide maintenance (N Engl J Med. 2012; 366:1782-91).

The cost of maintenance is another factor to consider. Researchers analyzed data from the CALGB 100104 and IFM 2005-02 trials to compare the cost of lenalidomide maintenance with no maintenance. In the CALGB 100104 trial, patients who received lenalidomide maintenance had 5.72 quality-adjusted life years (QALYs), and those who received no maintenance had 4.61 QALYs. The incremental cost-utility ratio (ICUR) was more than 277,000 euros per QALY.

In the IFM2005-02 trial, patients in the lenalidomide group had 5.13 QALYs, and those who didn’t receive maintenance had 4.98 QALYs. The ICUR was more than 1.5 million euros per QALY. The researchers said the high ICURs and budgetary impact add “uncertainty about the maximum prudent duration of the treatment” (Bone Marrow Transplant. 2019 May 31. doi: 10.1038/s41409-019-0574-5).

Dr. Efebera reported relationships with Akcea Therapeutics, Janssen, and Takeda. Dr. Shah reported having no relevant financial relationships.

jensmith@mdedge.com

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[5]:286-287,295).

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[5]:286-287,295).

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[5]:286-287,295).

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

sworcester@mdedge.com

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

sworcester@mdedge.com

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

sworcester@mdedge.com

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

Case Reports

Patient 1
A 65-year-old woman presented to the dermatology clinic in July with a pruritic rash of 2 days’ duration that started on the back and spread diffusely. The patient gardened regularly. Physical examination showed inflammatory papules and pustules on the back (Figure 1), as well as the groin, breasts, and ears. There was a punctate black dot in the center of some papules, and dermoscopy revealed ticks (Figure 2). Removal and microscopic examination confirmed larval-stage lone star ticks (Figure 3). The patient was prescribed topical steroids for pruritus as well as oral doxycycline for prophylaxis against tick-borne illnesses.

Patient 2
A 54-year-old man presented to the same clinic in July with pruritic lesions on the back, legs, ankles, and scrotum of 3 days’ duration that first appeared 24 hours after performing yardwork. Physical examination revealed diffusely distributed papules, pustules, and vesicles on the back (Figure 4). Some papules featured a punctate black dot in the center (similar to patient 1), and dermoscopy again revealed ticks. Removal and microscopic examination confirmed larval-stage ticks. The patient was treated with topical steroids and oral antihistamines for pruritus as well as prophylactic oral doxycycline.

Comment

Ticks are well-known human parasites, representing the second most common vector of human infectious disease.¹ Ticks have 3 motile stages: larva (or “seed”), nymph, and adult. They can bite humans during all stages. Larval ticks, distinguished by having 6 legs rather than 8 legs in nymphs and adults, can attack in droves and cause an infestation that presents as diffuse, pruritic, erythematous papules and pustules.^2-4 The first report of larval tick infestation in humans may have been in 1728 by William Byrd who described finding ticks on the skin that were too small to see without a microscope.⁵

Identification
The ticks in both of our cases were lone star ticks (Amblyomma americanum). The larval stage of A americanum is a proven cause of cutaneous reaction.^6,7 A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the terms tick, seed tick, or tick bite in combination with rash, eruption, infestation, papule, pustule, or pruritic revealed 6 reported cases of larval tick infestation in the literature (including our case); 5 were caused by A americanum and 1 by Ixodes dammini (now known as Ixodes scapularis); all occurred in July or August.^3,7-10 This time frame is consistent with the general tick life cycle across species: Adults feed from April to June, then lay eggs that hatch into larval ticks within 4 to 6 weeks. After hatching, larval ticks climb grass and weeds awaiting a passing host.⁴

Diagnosis
Larval tick infestation remains a frequently misdiagnosed etiology of diffuse pruritic papules and pustules, especially in urban settings where physicians are less likely to be familiar with this type of manifestation.^3,9-11 Larval ticks are submillimeter in size and difficult to appreciate with the naked eye, contributing to misdiagnosis. A punctate black dot may sometimes be seen in papules; however, dermoscopy is critical for accurate diagnosis, as hemorrhagic crust is a frequent misdiagnosis.

Management
In addition to symptomatic therapy, both of our patients received doxycycline as antibiotic prophylaxis for tick-borne illnesses given that a high number of ticks had been attached for more than 2 days.^12,13 Antibiotic prophylaxis for tick-borne illness is controversial. The exception is Lyme disease transmitted by nymphal or adult I scapularis when specific conditions are met: the bite must have occurred in an endemic area, doxycycline cannot be contraindicated, estimated duration of attachment is at least 36 hours, and prophylaxis must be started within 72 hours of tick removal.¹³ There are no official recommendations for the A americanum species or for larval-stage ticks of any species. Larval-stage ticks acting as vectors for disease transmission is not well documented in recent literature, and there currently is limited evidence supporting prophylactic antibiotics for larval tick bites. The presence of spotted fever rickettsioses has been reported (with the exception of Rickettsia rickettsii and Ehrlichia chaffeensis) in larval A americanum ticks, suggesting a theoretical possibility that they could act as disease vectors.^3,8,11,14-17 At a minimum, both prompt tick removal and close patient follow-up is warranted.

Conclusion

Human infestation with larval ticks is a common occurrence but can present a diagnostic challenge to an unfamiliar physician. We encourage consideration of larval tick infestation as the etiology of multiple or diffuse pruritic papules with a history of outdoor exposure.

Case Reports

Patient 1
A 65-year-old woman presented to the dermatology clinic in July with a pruritic rash of 2 days’ duration that started on the back and spread diffusely. The patient gardened regularly. Physical examination showed inflammatory papules and pustules on the back (Figure 1), as well as the groin, breasts, and ears. There was a punctate black dot in the center of some papules, and dermoscopy revealed ticks (Figure 2). Removal and microscopic examination confirmed larval-stage lone star ticks (Figure 3). The patient was prescribed topical steroids for pruritus as well as oral doxycycline for prophylaxis against tick-borne illnesses.

Patient 2
A 54-year-old man presented to the same clinic in July with pruritic lesions on the back, legs, ankles, and scrotum of 3 days’ duration that first appeared 24 hours after performing yardwork. Physical examination revealed diffusely distributed papules, pustules, and vesicles on the back (Figure 4). Some papules featured a punctate black dot in the center (similar to patient 1), and dermoscopy again revealed ticks. Removal and microscopic examination confirmed larval-stage ticks. The patient was treated with topical steroids and oral antihistamines for pruritus as well as prophylactic oral doxycycline.

Comment

Ticks are well-known human parasites, representing the second most common vector of human infectious disease.¹ Ticks have 3 motile stages: larva (or “seed”), nymph, and adult. They can bite humans during all stages. Larval ticks, distinguished by having 6 legs rather than 8 legs in nymphs and adults, can attack in droves and cause an infestation that presents as diffuse, pruritic, erythematous papules and pustules.^2-4 The first report of larval tick infestation in humans may have been in 1728 by William Byrd who described finding ticks on the skin that were too small to see without a microscope.⁵

Identification
The ticks in both of our cases were lone star ticks (Amblyomma americanum). The larval stage of A americanum is a proven cause of cutaneous reaction.^6,7 A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the terms tick, seed tick, or tick bite in combination with rash, eruption, infestation, papule, pustule, or pruritic revealed 6 reported cases of larval tick infestation in the literature (including our case); 5 were caused by A americanum and 1 by Ixodes dammini (now known as Ixodes scapularis); all occurred in July or August.^3,7-10 This time frame is consistent with the general tick life cycle across species: Adults feed from April to June, then lay eggs that hatch into larval ticks within 4 to 6 weeks. After hatching, larval ticks climb grass and weeds awaiting a passing host.⁴

Diagnosis
Larval tick infestation remains a frequently misdiagnosed etiology of diffuse pruritic papules and pustules, especially in urban settings where physicians are less likely to be familiar with this type of manifestation.^3,9-11 Larval ticks are submillimeter in size and difficult to appreciate with the naked eye, contributing to misdiagnosis. A punctate black dot may sometimes be seen in papules; however, dermoscopy is critical for accurate diagnosis, as hemorrhagic crust is a frequent misdiagnosis.

Management
In addition to symptomatic therapy, both of our patients received doxycycline as antibiotic prophylaxis for tick-borne illnesses given that a high number of ticks had been attached for more than 2 days.^12,13 Antibiotic prophylaxis for tick-borne illness is controversial. The exception is Lyme disease transmitted by nymphal or adult I scapularis when specific conditions are met: the bite must have occurred in an endemic area, doxycycline cannot be contraindicated, estimated duration of attachment is at least 36 hours, and prophylaxis must be started within 72 hours of tick removal.¹³ There are no official recommendations for the A americanum species or for larval-stage ticks of any species. Larval-stage ticks acting as vectors for disease transmission is not well documented in recent literature, and there currently is limited evidence supporting prophylactic antibiotics for larval tick bites. The presence of spotted fever rickettsioses has been reported (with the exception of Rickettsia rickettsii and Ehrlichia chaffeensis) in larval A americanum ticks, suggesting a theoretical possibility that they could act as disease vectors.^3,8,11,14-17 At a minimum, both prompt tick removal and close patient follow-up is warranted.

Conclusion

Human infestation with larval ticks is a common occurrence but can present a diagnostic challenge to an unfamiliar physician. We encourage consideration of larval tick infestation as the etiology of multiple or diffuse pruritic papules with a history of outdoor exposure.

Case Reports

Patient 1
A 65-year-old woman presented to the dermatology clinic in July with a pruritic rash of 2 days’ duration that started on the back and spread diffusely. The patient gardened regularly. Physical examination showed inflammatory papules and pustules on the back (Figure 1), as well as the groin, breasts, and ears. There was a punctate black dot in the center of some papules, and dermoscopy revealed ticks (Figure 2). Removal and microscopic examination confirmed larval-stage lone star ticks (Figure 3). The patient was prescribed topical steroids for pruritus as well as oral doxycycline for prophylaxis against tick-borne illnesses.

Patient 2
A 54-year-old man presented to the same clinic in July with pruritic lesions on the back, legs, ankles, and scrotum of 3 days’ duration that first appeared 24 hours after performing yardwork. Physical examination revealed diffusely distributed papules, pustules, and vesicles on the back (Figure 4). Some papules featured a punctate black dot in the center (similar to patient 1), and dermoscopy again revealed ticks. Removal and microscopic examination confirmed larval-stage ticks. The patient was treated with topical steroids and oral antihistamines for pruritus as well as prophylactic oral doxycycline.

Comment

Ticks are well-known human parasites, representing the second most common vector of human infectious disease.¹ Ticks have 3 motile stages: larva (or “seed”), nymph, and adult. They can bite humans during all stages. Larval ticks, distinguished by having 6 legs rather than 8 legs in nymphs and adults, can attack in droves and cause an infestation that presents as diffuse, pruritic, erythematous papules and pustules.^2-4 The first report of larval tick infestation in humans may have been in 1728 by William Byrd who described finding ticks on the skin that were too small to see without a microscope.⁵

Identification
The ticks in both of our cases were lone star ticks (Amblyomma americanum). The larval stage of A americanum is a proven cause of cutaneous reaction.^6,7 A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the terms tick, seed tick, or tick bite in combination with rash, eruption, infestation, papule, pustule, or pruritic revealed 6 reported cases of larval tick infestation in the literature (including our case); 5 were caused by A americanum and 1 by Ixodes dammini (now known as Ixodes scapularis); all occurred in July or August.^3,7-10 This time frame is consistent with the general tick life cycle across species: Adults feed from April to June, then lay eggs that hatch into larval ticks within 4 to 6 weeks. After hatching, larval ticks climb grass and weeds awaiting a passing host.⁴

Diagnosis
Larval tick infestation remains a frequently misdiagnosed etiology of diffuse pruritic papules and pustules, especially in urban settings where physicians are less likely to be familiar with this type of manifestation.^3,9-11 Larval ticks are submillimeter in size and difficult to appreciate with the naked eye, contributing to misdiagnosis. A punctate black dot may sometimes be seen in papules; however, dermoscopy is critical for accurate diagnosis, as hemorrhagic crust is a frequent misdiagnosis.

Management
In addition to symptomatic therapy, both of our patients received doxycycline as antibiotic prophylaxis for tick-borne illnesses given that a high number of ticks had been attached for more than 2 days.^12,13 Antibiotic prophylaxis for tick-borne illness is controversial. The exception is Lyme disease transmitted by nymphal or adult I scapularis when specific conditions are met: the bite must have occurred in an endemic area, doxycycline cannot be contraindicated, estimated duration of attachment is at least 36 hours, and prophylaxis must be started within 72 hours of tick removal.¹³ There are no official recommendations for the A americanum species or for larval-stage ticks of any species. Larval-stage ticks acting as vectors for disease transmission is not well documented in recent literature, and there currently is limited evidence supporting prophylactic antibiotics for larval tick bites. The presence of spotted fever rickettsioses has been reported (with the exception of Rickettsia rickettsii and Ehrlichia chaffeensis) in larval A americanum ticks, suggesting a theoretical possibility that they could act as disease vectors.^3,8,11,14-17 At a minimum, both prompt tick removal and close patient follow-up is warranted.

Conclusion

Human infestation with larval ticks is a common occurrence but can present a diagnostic challenge to an unfamiliar physician. We encourage consideration of larval tick infestation as the etiology of multiple or diffuse pruritic papules with a history of outdoor exposure.