Levy was chief pathologist at Veterans Health Care System of the Ozarks in Fayetteville, Arkansas. During his 12-year tenure at the US Department of Veterans Affairs (VA), he read almost 34,000 pathology slides. However, at the same time, he was working under the influence of alcohol and 2-methyl-2-butanol (2M2B)—a substance that intoxicates but cannot be detected in routine tests.

The VA fired Levy last year, and the VA Office of the Inspector General (OIG) began an investigation of his actions and of agency lapses in overseeing him. The 18-month review found that 8.9% of Levy’s diagnoses involved clinical errors—the normal misdiagnosis rate for pathologists is 0.7%. Hundreds of Levy’s misdiagnoses were not serious, but ≥ 15 may have led to deaths and harmful illness in 15 other patients. Some patients were not diagnosed when they should have been. Some were told they were sick when they were not and suffered unnecessary invasive treatment.

Levy knowingly falsified diagnoses for  3 veterans. One patient was diagnosed with diffuse large B-cell lymphoma—a type of cancer he did not have. He received the wrong treatment and died. Levy diagnosed another patient, also wrongly, with small cell carcinoma; that patient died of squamous cell carcinoma that spread. The third patient was given a benign test result for prostate cancer. Untreated, he died after the cancer spread.

One patient was given antibiotics instead of treatment for what was later diagnosed as late-stage neck and throat cancer. In an interview with the Washington Post he said, “I went from ‘Your earache isn’t anything’ to stage 4.”

How was Levy able to wreak such havoc? One reason was that despite concerns and complaints from colleagues, he looked good on paper. He falsified records to indicate that his deputy concurred with his diagnoses in mandated peer reviews. He also appeared “clean” in inspections through using 2M2B.

Levy was fired not for his work performance but for being arrested for driving while intoxicated. He had been a “star hire” with an medical degree from the University of Chicago, who had completed a pathology residency at the University of California at San Francisco and a fellowship at Duke University focusing on disease of the blood. But he also had a 1996 arrest for a driving under the influence (DUI) on his record when he joined the VA in 2005.

He was suspended again in 2017 for being under the influence but allowed to continue with nonclinical work until he was again arrested for DUI in 2018, when the police toxicology test detected 2M2B. He was finally dismissed in April 2018. Nonetheless, even after he had arrived impaired at the laboratory twice, the VA had awarded him 2 performance bonuses, based on the supposedly low clinical error rate and 42 urine and blood samples that turned up negative for alcohol and drugs.

In addition to 3 counts of involuntary manslaughter, the indictment charges that Levy devised a scheme to defraud the VA and to obtain money and property from the VA in the form of salary, benefits, and performance awards. He is charged with 12 counts of wire fraud, 12 counts of mail fraud, and 4 counts of making false statements related to 12 occasions between 2017 and 2018, when Levy was reportedly buying 2M2B over the Internet while he was contractually obligated to submit to random drug and alcohol screens.

After being fired, Levy moved to a small island in the Dutch Caribbean and found a position teaching pathology at a local medical school. At the time of his VA hiring, Levy held a medical license issued by Mississippi. His active medical licenses in California and Florida were revoked only this spring. The VA did not notify the3 states where Levy was licensed that he could no longer practice until June 2018.

The Office of Inspector General (OIG) has identified other VA physicians who continued to practice even after they were found to have compromised patient care, and the Government Accountability Office found “weak systems” for ensuring that problems are addressed in a timely fashion. A VA spokesperson, however, quoted in The Washington Post, said the Levy case was “an isolated incident,” and that the agency has “strengthened internal controls” to ensure that errors are more quickly identified and addressed. The Fayetteville Medical Center also has increased monitoring of its clinical laboratory, according to a Washington Post report. VA officials also said they have added oversight of small specialty staffs across the system to ensure “independent and objective oversight.”

The VA has contacted the families in the 30 most serious cases to advise them of their legal and treatment options, according to the Washington Post.

“The arrest of Dr. Levy was accomplished as a result of the strong leadership of the US Attorney’s Office and the extensive work of special agents of the VA OIG, supported by the medical expertise of the OIG’s health care inspection professionals,” said Michael Missal, the VA’s inspector general, in a press release issued by the US Attorney’s Office in the Western District of Arkansas. “These charges send a clear signal that anyone entrusted with the care of veterans will be held accountable for placing them at risk by working while impaired or through other misconduct.”

Levy is in jail in Fayetteville. The trial date for his case is set for October 7.

Levy was chief pathologist at Veterans Health Care System of the Ozarks in Fayetteville, Arkansas. During his 12-year tenure at the US Department of Veterans Affairs (VA), he read almost 34,000 pathology slides. However, at the same time, he was working under the influence of alcohol and 2-methyl-2-butanol (2M2B)—a substance that intoxicates but cannot be detected in routine tests.

The VA fired Levy last year, and the VA Office of the Inspector General (OIG) began an investigation of his actions and of agency lapses in overseeing him. The 18-month review found that 8.9% of Levy’s diagnoses involved clinical errors—the normal misdiagnosis rate for pathologists is 0.7%. Hundreds of Levy’s misdiagnoses were not serious, but ≥ 15 may have led to deaths and harmful illness in 15 other patients. Some patients were not diagnosed when they should have been. Some were told they were sick when they were not and suffered unnecessary invasive treatment.

Levy knowingly falsified diagnoses for  3 veterans. One patient was diagnosed with diffuse large B-cell lymphoma—a type of cancer he did not have. He received the wrong treatment and died. Levy diagnosed another patient, also wrongly, with small cell carcinoma; that patient died of squamous cell carcinoma that spread. The third patient was given a benign test result for prostate cancer. Untreated, he died after the cancer spread.

One patient was given antibiotics instead of treatment for what was later diagnosed as late-stage neck and throat cancer. In an interview with the Washington Post he said, “I went from ‘Your earache isn’t anything’ to stage 4.”

How was Levy able to wreak such havoc? One reason was that despite concerns and complaints from colleagues, he looked good on paper. He falsified records to indicate that his deputy concurred with his diagnoses in mandated peer reviews. He also appeared “clean” in inspections through using 2M2B.

Levy was fired not for his work performance but for being arrested for driving while intoxicated. He had been a “star hire” with an medical degree from the University of Chicago, who had completed a pathology residency at the University of California at San Francisco and a fellowship at Duke University focusing on disease of the blood. But he also had a 1996 arrest for a driving under the influence (DUI) on his record when he joined the VA in 2005.

He was suspended again in 2017 for being under the influence but allowed to continue with nonclinical work until he was again arrested for DUI in 2018, when the police toxicology test detected 2M2B. He was finally dismissed in April 2018. Nonetheless, even after he had arrived impaired at the laboratory twice, the VA had awarded him 2 performance bonuses, based on the supposedly low clinical error rate and 42 urine and blood samples that turned up negative for alcohol and drugs.

In addition to 3 counts of involuntary manslaughter, the indictment charges that Levy devised a scheme to defraud the VA and to obtain money and property from the VA in the form of salary, benefits, and performance awards. He is charged with 12 counts of wire fraud, 12 counts of mail fraud, and 4 counts of making false statements related to 12 occasions between 2017 and 2018, when Levy was reportedly buying 2M2B over the Internet while he was contractually obligated to submit to random drug and alcohol screens.

After being fired, Levy moved to a small island in the Dutch Caribbean and found a position teaching pathology at a local medical school. At the time of his VA hiring, Levy held a medical license issued by Mississippi. His active medical licenses in California and Florida were revoked only this spring. The VA did not notify the3 states where Levy was licensed that he could no longer practice until June 2018.

The Office of Inspector General (OIG) has identified other VA physicians who continued to practice even after they were found to have compromised patient care, and the Government Accountability Office found “weak systems” for ensuring that problems are addressed in a timely fashion. A VA spokesperson, however, quoted in The Washington Post, said the Levy case was “an isolated incident,” and that the agency has “strengthened internal controls” to ensure that errors are more quickly identified and addressed. The Fayetteville Medical Center also has increased monitoring of its clinical laboratory, according to a Washington Post report. VA officials also said they have added oversight of small specialty staffs across the system to ensure “independent and objective oversight.”

The VA has contacted the families in the 30 most serious cases to advise them of their legal and treatment options, according to the Washington Post.

“The arrest of Dr. Levy was accomplished as a result of the strong leadership of the US Attorney’s Office and the extensive work of special agents of the VA OIG, supported by the medical expertise of the OIG’s health care inspection professionals,” said Michael Missal, the VA’s inspector general, in a press release issued by the US Attorney’s Office in the Western District of Arkansas. “These charges send a clear signal that anyone entrusted with the care of veterans will be held accountable for placing them at risk by working while impaired or through other misconduct.”

Levy is in jail in Fayetteville. The trial date for his case is set for October 7.

Levy was chief pathologist at Veterans Health Care System of the Ozarks in Fayetteville, Arkansas. During his 12-year tenure at the US Department of Veterans Affairs (VA), he read almost 34,000 pathology slides. However, at the same time, he was working under the influence of alcohol and 2-methyl-2-butanol (2M2B)—a substance that intoxicates but cannot be detected in routine tests.

The VA fired Levy last year, and the VA Office of the Inspector General (OIG) began an investigation of his actions and of agency lapses in overseeing him. The 18-month review found that 8.9% of Levy’s diagnoses involved clinical errors—the normal misdiagnosis rate for pathologists is 0.7%. Hundreds of Levy’s misdiagnoses were not serious, but ≥ 15 may have led to deaths and harmful illness in 15 other patients. Some patients were not diagnosed when they should have been. Some were told they were sick when they were not and suffered unnecessary invasive treatment.

Levy knowingly falsified diagnoses for  3 veterans. One patient was diagnosed with diffuse large B-cell lymphoma—a type of cancer he did not have. He received the wrong treatment and died. Levy diagnosed another patient, also wrongly, with small cell carcinoma; that patient died of squamous cell carcinoma that spread. The third patient was given a benign test result for prostate cancer. Untreated, he died after the cancer spread.

One patient was given antibiotics instead of treatment for what was later diagnosed as late-stage neck and throat cancer. In an interview with the Washington Post he said, “I went from ‘Your earache isn’t anything’ to stage 4.”

How was Levy able to wreak such havoc? One reason was that despite concerns and complaints from colleagues, he looked good on paper. He falsified records to indicate that his deputy concurred with his diagnoses in mandated peer reviews. He also appeared “clean” in inspections through using 2M2B.

Levy was fired not for his work performance but for being arrested for driving while intoxicated. He had been a “star hire” with an medical degree from the University of Chicago, who had completed a pathology residency at the University of California at San Francisco and a fellowship at Duke University focusing on disease of the blood. But he also had a 1996 arrest for a driving under the influence (DUI) on his record when he joined the VA in 2005.

He was suspended again in 2017 for being under the influence but allowed to continue with nonclinical work until he was again arrested for DUI in 2018, when the police toxicology test detected 2M2B. He was finally dismissed in April 2018. Nonetheless, even after he had arrived impaired at the laboratory twice, the VA had awarded him 2 performance bonuses, based on the supposedly low clinical error rate and 42 urine and blood samples that turned up negative for alcohol and drugs.

In addition to 3 counts of involuntary manslaughter, the indictment charges that Levy devised a scheme to defraud the VA and to obtain money and property from the VA in the form of salary, benefits, and performance awards. He is charged with 12 counts of wire fraud, 12 counts of mail fraud, and 4 counts of making false statements related to 12 occasions between 2017 and 2018, when Levy was reportedly buying 2M2B over the Internet while he was contractually obligated to submit to random drug and alcohol screens.

After being fired, Levy moved to a small island in the Dutch Caribbean and found a position teaching pathology at a local medical school. At the time of his VA hiring, Levy held a medical license issued by Mississippi. His active medical licenses in California and Florida were revoked only this spring. The VA did not notify the3 states where Levy was licensed that he could no longer practice until June 2018.

The Office of Inspector General (OIG) has identified other VA physicians who continued to practice even after they were found to have compromised patient care, and the Government Accountability Office found “weak systems” for ensuring that problems are addressed in a timely fashion. A VA spokesperson, however, quoted in The Washington Post, said the Levy case was “an isolated incident,” and that the agency has “strengthened internal controls” to ensure that errors are more quickly identified and addressed. The Fayetteville Medical Center also has increased monitoring of its clinical laboratory, according to a Washington Post report. VA officials also said they have added oversight of small specialty staffs across the system to ensure “independent and objective oversight.”

The VA has contacted the families in the 30 most serious cases to advise them of their legal and treatment options, according to the Washington Post.

“The arrest of Dr. Levy was accomplished as a result of the strong leadership of the US Attorney’s Office and the extensive work of special agents of the VA OIG, supported by the medical expertise of the OIG’s health care inspection professionals,” said Michael Missal, the VA’s inspector general, in a press release issued by the US Attorney’s Office in the Western District of Arkansas. “These charges send a clear signal that anyone entrusted with the care of veterans will be held accountable for placing them at risk by working while impaired or through other misconduct.”

Levy is in jail in Fayetteville. The trial date for his case is set for October 7.

ALEXANDRIA, VA. – Patients with metastatic non–small cell lung cancer (NSCLC) who enrolled in clinical trials had a near 50% lower risk of death versus patients who received treatment outside a clinical trial, according to results of a single-center, retrospective medical record review.

Median survival was almost doubled for those patients with NSCLC enrolled in therapeutic drug trials, according to lead author Christina Merkhofer, MD, a hematology-oncology fellow at the University of Washington and Fred Hutchinson Cancer Center, both in Seattle.

The findings suggest that clinical trials, beyond supporting drug development, provide a direct benefit to NSCLC patients through provision of promising agents, enhanced supportive care, or both, according to Dr. Merkhofer and coauthors, who will present their findings in a poster at the Quality Care Symposium, sponsored by the American Society of Clinical Oncology.

The retrospective study included a total of 371 patients diagnosed with metastatic NSCLC between 2001 and 2015, of whom 118 (32%) enrolled in at least one clinical trial, Dr. Merkhofer reported at a press briefing ahead of the symposium.

Median survival was 838 days for the clinical trial enrollees versus 454 days for nonenrollees, according to the investigators. The risk of death was 47% lower (hazard ratio, 0.53; 95% confidence interval, 0.13-0.92; P = .002) for enrollees relative to nonenrollees after adjustment for variables including sex, performance status, smoking history, histology, presence of brain metastases, and EGFR/ALK status.

Based on this study by Dr. Merkhofer and colleagues, participating in therapeutic drug trials appears to improve survival in patients with advanced lung cancer, ASCO expert Merry-Jennifer Markham, MD, said in a statement.

Oncologists have a “duty” to enroll patients in clinical trials as appropriate, said Dr. Markham, chair of the Quality Care Symposium’s news planning team.

“We must work to better understand factors associated with enrollment so that the prospective benefits can be made accessible to all who are eligible,” she said.

The research is part of a larger investigation looking at “areas of uncertainty” in clinical trial participation, such as whether specific trial design characteristics are linked to survival benefit, according to Dr. Merkhofer.

“The study can support research evaluating health care policies or research that looks at incentives for patient participation in trials, such as financing transportation or lodging, [and] can help with research that addresses some of these important barriers to trial participation,” Dr. Merkhofer said in an ASCO press release.

Dr. Merkhofer had no disclosures related to the study. Her coauthors reported disclosures related to numerous pharmaceutical companies.

SOURCE: Merkhofer C et al. QCS2019, Abstract 137.

ALEXANDRIA, VA. – Patients with metastatic non–small cell lung cancer (NSCLC) who enrolled in clinical trials had a near 50% lower risk of death versus patients who received treatment outside a clinical trial, according to results of a single-center, retrospective medical record review.

Median survival was almost doubled for those patients with NSCLC enrolled in therapeutic drug trials, according to lead author Christina Merkhofer, MD, a hematology-oncology fellow at the University of Washington and Fred Hutchinson Cancer Center, both in Seattle.

The findings suggest that clinical trials, beyond supporting drug development, provide a direct benefit to NSCLC patients through provision of promising agents, enhanced supportive care, or both, according to Dr. Merkhofer and coauthors, who will present their findings in a poster at the Quality Care Symposium, sponsored by the American Society of Clinical Oncology.

The retrospective study included a total of 371 patients diagnosed with metastatic NSCLC between 2001 and 2015, of whom 118 (32%) enrolled in at least one clinical trial, Dr. Merkhofer reported at a press briefing ahead of the symposium.

Median survival was 838 days for the clinical trial enrollees versus 454 days for nonenrollees, according to the investigators. The risk of death was 47% lower (hazard ratio, 0.53; 95% confidence interval, 0.13-0.92; P = .002) for enrollees relative to nonenrollees after adjustment for variables including sex, performance status, smoking history, histology, presence of brain metastases, and EGFR/ALK status.

Based on this study by Dr. Merkhofer and colleagues, participating in therapeutic drug trials appears to improve survival in patients with advanced lung cancer, ASCO expert Merry-Jennifer Markham, MD, said in a statement.

Oncologists have a “duty” to enroll patients in clinical trials as appropriate, said Dr. Markham, chair of the Quality Care Symposium’s news planning team.

“We must work to better understand factors associated with enrollment so that the prospective benefits can be made accessible to all who are eligible,” she said.

The research is part of a larger investigation looking at “areas of uncertainty” in clinical trial participation, such as whether specific trial design characteristics are linked to survival benefit, according to Dr. Merkhofer.

“The study can support research evaluating health care policies or research that looks at incentives for patient participation in trials, such as financing transportation or lodging, [and] can help with research that addresses some of these important barriers to trial participation,” Dr. Merkhofer said in an ASCO press release.

Dr. Merkhofer had no disclosures related to the study. Her coauthors reported disclosures related to numerous pharmaceutical companies.

SOURCE: Merkhofer C et al. QCS2019, Abstract 137.

ALEXANDRIA, VA. – Patients with metastatic non–small cell lung cancer (NSCLC) who enrolled in clinical trials had a near 50% lower risk of death versus patients who received treatment outside a clinical trial, according to results of a single-center, retrospective medical record review.

Median survival was almost doubled for those patients with NSCLC enrolled in therapeutic drug trials, according to lead author Christina Merkhofer, MD, a hematology-oncology fellow at the University of Washington and Fred Hutchinson Cancer Center, both in Seattle.

The findings suggest that clinical trials, beyond supporting drug development, provide a direct benefit to NSCLC patients through provision of promising agents, enhanced supportive care, or both, according to Dr. Merkhofer and coauthors, who will present their findings in a poster at the Quality Care Symposium, sponsored by the American Society of Clinical Oncology.

The retrospective study included a total of 371 patients diagnosed with metastatic NSCLC between 2001 and 2015, of whom 118 (32%) enrolled in at least one clinical trial, Dr. Merkhofer reported at a press briefing ahead of the symposium.

Median survival was 838 days for the clinical trial enrollees versus 454 days for nonenrollees, according to the investigators. The risk of death was 47% lower (hazard ratio, 0.53; 95% confidence interval, 0.13-0.92; P = .002) for enrollees relative to nonenrollees after adjustment for variables including sex, performance status, smoking history, histology, presence of brain metastases, and EGFR/ALK status.

Based on this study by Dr. Merkhofer and colleagues, participating in therapeutic drug trials appears to improve survival in patients with advanced lung cancer, ASCO expert Merry-Jennifer Markham, MD, said in a statement.

Oncologists have a “duty” to enroll patients in clinical trials as appropriate, said Dr. Markham, chair of the Quality Care Symposium’s news planning team.

“We must work to better understand factors associated with enrollment so that the prospective benefits can be made accessible to all who are eligible,” she said.

The research is part of a larger investigation looking at “areas of uncertainty” in clinical trial participation, such as whether specific trial design characteristics are linked to survival benefit, according to Dr. Merkhofer.

“The study can support research evaluating health care policies or research that looks at incentives for patient participation in trials, such as financing transportation or lodging, [and] can help with research that addresses some of these important barriers to trial participation,” Dr. Merkhofer said in an ASCO press release.

Dr. Merkhofer had no disclosures related to the study. Her coauthors reported disclosures related to numerous pharmaceutical companies.

SOURCE: Merkhofer C et al. QCS2019, Abstract 137.

Background: A critical juncture in the American Heart Association/American College of Cardiology 2014 perioperative guidelines relies on clinicians categorizing patients undergoing noncardiac surgery as either low risk (less than 1%) or elevated risk (greater than or equal to 1%) for a MACE. The purpose of this study is to determine whether there is variability between the three risk calculators endorsed by the ACC/AHA guidelines as prediction tools to make this risk stratification.

Dr. Bordin-Wosk is an assistant clinical professor in the division of hospital medicine at the University of California, San Diego.

Background: A critical juncture in the American Heart Association/American College of Cardiology 2014 perioperative guidelines relies on clinicians categorizing patients undergoing noncardiac surgery as either low risk (less than 1%) or elevated risk (greater than or equal to 1%) for a MACE. The purpose of this study is to determine whether there is variability between the three risk calculators endorsed by the ACC/AHA guidelines as prediction tools to make this risk stratification.

Dr. Bordin-Wosk is an assistant clinical professor in the division of hospital medicine at the University of California, San Diego.

Background: A critical juncture in the American Heart Association/American College of Cardiology 2014 perioperative guidelines relies on clinicians categorizing patients undergoing noncardiac surgery as either low risk (less than 1%) or elevated risk (greater than or equal to 1%) for a MACE. The purpose of this study is to determine whether there is variability between the three risk calculators endorsed by the ACC/AHA guidelines as prediction tools to make this risk stratification.

Dr. Bordin-Wosk is an assistant clinical professor in the division of hospital medicine at the University of California, San Diego.

CHICAGO – Because gastroparesis and functional dyspepsia share several symptoms (e.g., upper abdominal pain, fullness, and bloating) and pathophysiological abnormalities (e.g., delayed gastric emptying, impaired gastric accommodation, and visceral hypersensitivity), it can be hard to distinguish the two conditions, according to a lecture presented at Freston Conference 2019, sponsored by the American Gastroenterological Association. Additional research into the role of diet in these conditions will improve the treatment of these patients, said Linda Nguyen, MD, director of neurogastroenterology and motility at Stanford (Calif.) University.

Distinguishing the disorders

The accepted definition of gastroparesis is abnormal gastric emptying in the absence of a mechanical obstruction. The condition’s symptoms include nausea, vomiting, bloating, early satiety, abdominal pain, and weight loss. A previous consensus held that if a patient had abdominal pain, he or she did not have gastroparesis. Yet studies indicate that up to 80% of patients with gastroparesis have pain.

Functional dyspepsia is defined as bothersome postprandial fullness, early satiety, and epigastric pain or burning in the absence of structural abnormality. The disorder can be subdivided into postprandial distress (i.e., meal-related symptomatology) and epigastric pain syndrome (i.e., pain or burning that may or may not be related to meals). Either of these alternatives may entail nausea and vomiting.

Comparing the pathophysiologies of gastroparesis and functional dyspepsia helps to distinguish these disorders from each other. A 2019 review described rapid gastric emptying and duodenal eosinophilia in patients with functional dyspepsia, but not in patients with gastroparesis. Patients with epigastric pain syndrome had sensitivity to acid, bile, and fats. Patients with idiopathic gastroparesis, which is the most common type, had a weak antral pump and abnormal duodenal feedback, but patients with functional dyspepsia did not have these characteristics (J Neurogastroenterol Motil. 2019;25[1]:27-35).
 

Examining symptoms and severity

One examination of patients with gastroparesis found that approximately 46% of them had a body mass index of 25 or greater. About 26% of patients had a BMI greater than 30. Yet these patients were eating less than 60% of their recommended daily allowances, based on their age, height, weight, and sex (Clin Gastroenterol Hepatol. 2011;9[12]:1056-64).

Accelerating gastric emptying may not relieve symptoms completely in a patient with gastroparesis, said Dr. Nguyen. A 2007 study of patients with gastroparesis found that 43% had impaired accommodation, and 29% had visceral hypersensitivity (Gut. 2007;56[1]:29-36). The same data indicated that gastric emptying time was not correlated with symptom severity. Impaired accommodation, however, was associated with early satiety and weight loss. Visceral hypersensitivity was associated with pain, early satiety, and weight loss. These data suggest that accommodation and visceral hypersensitivity may influence symptom severity in gastroparesis, said Dr. Nguyen.

Other researchers compared mild, moderate, and severe symptoms of early satiety in patients with gastroparesis. They found that patients with severe symptoms of early satiety have more delayed gastric emptying than do patients with mild or moderate symptoms of early satiety (Neurogastroenterol Motil. 2017;29[4].).

Dr. Nguyen and colleagues examined normal gastric emptying, compared with severely delayed gastric emptying, which they defined as greater than 35% retention at 4 hours. They found that severely delayed gastric emptying was associated with more severe symptoms, particularly nausea and vomiting, as measured by Gastroparesis Cardinal Symptom Index (GCSI). Extreme symptoms may help differentiate between gastroparesis and functional dyspepsia, said Dr. Nguyen.
 

Dietary and pharmacologic treatment

Although clinicians might consider recommending dietary modifications to treat gastroparesis or functional dyspepsia, the literature contains little evidence about their efficacy in these indications, said Dr. Nguyen. Based on a study by Tack and colleagues, some clinicians recommend small, frequent meals that are low in fat and low in fiber to patients with gastroparesis. Such a diet could be harmful, however, to patients with comorbid diabetes, irritable bowel syndrome, or renal failure.

Common dietary recommendations for functional dyspepsia include small, frequent meals; decreased fat consumption; and avoidance of citrus and spicy foods. These recommendations are based on small studies in which patients reported which foods tended to cause their symptoms. Trials of dietary modifications in functional dyspepsia, however, are lacking.

Nevertheless, the literature can guide the selection of pharmacotherapy for these disorders. Talley et al. examined the effects of neuromodulators such as amitriptyline, a tricyclic antidepressant, and escitalopram in functional dyspepsia. About 70% of the sample had postprandial distress syndrome, and 20% met criteria for idiopathic gastroparesis. Amitriptyline provided greater symptomatic relief to these patients than did placebo, but escitalopram did not. Patients who met criteria for idiopathic gastroparesis did not respond well to tricyclic antidepressants, but patients with epigastric pain syndrome did. Furthermore, compared with patients with normal gastric emptying, those with delayed emptying did not respond to tricyclic antidepressants. A separate study found that the tricyclic antidepressant nortriptyline did not improve symptoms of gastroparesis (JAMA. 2013;310[24]:2640-9).

Promotility agents may be beneficial for certain patients. A study published this year suggests that, compared with placebo, prucalopride is effective for nausea, vomiting, fullness, bloating, and gastric emptying in patients with idiopathic gastroparesis (Am J Gastroenterol. 2019;114[8]:1265-74.). A 2017 meta-analysis, however, found that proton pump inhibitors were more effective than promotility agents in patients with functional dyspepsia (Am J Gastroenterol. 2017;112[7]:988-1013.).

Pyloric dysfunction may accompany gastroparesis in some patients. Increased severity of gastric emptying delay is associated with increased pylorospasm. Endoscopists have gained experience in performing pyloric myotomy, and this treatment has become more popular. Uncontrolled studies indicate that the proportion of patients with decreased symptom severity after this procedure is higher than 70% and can be as high as 86% (Gastrointest Endosc. 2017;85[1]:123-8). The predictors of a good response include idiopathic etiology, male sex, moderate symptom severity, and greater delay in gastric emptying.

Functional dyspepsia should perhaps be understood as normal gastric emptying and symptoms of epigastric pain syndrome, said Dr. Nguyen. Those patients may respond to neuromodulators, she added. Idiopathic gastroparesis appears to be characterized by severe delay in gastric emptying, postprandial symptoms, nausea, and vomiting. “In the middle is the gray zone, where you have these patients with postprandial distress with or without delayed gastric emptying,” said Dr. Nguyen. Functional dyspepsia and gastroparesis could be two ends of a spectrum, and the best management for patients with symptoms that occur in both disorders is unclear.

[email protected]

CHICAGO – Because gastroparesis and functional dyspepsia share several symptoms (e.g., upper abdominal pain, fullness, and bloating) and pathophysiological abnormalities (e.g., delayed gastric emptying, impaired gastric accommodation, and visceral hypersensitivity), it can be hard to distinguish the two conditions, according to a lecture presented at Freston Conference 2019, sponsored by the American Gastroenterological Association. Additional research into the role of diet in these conditions will improve the treatment of these patients, said Linda Nguyen, MD, director of neurogastroenterology and motility at Stanford (Calif.) University.

Distinguishing the disorders

The accepted definition of gastroparesis is abnormal gastric emptying in the absence of a mechanical obstruction. The condition’s symptoms include nausea, vomiting, bloating, early satiety, abdominal pain, and weight loss. A previous consensus held that if a patient had abdominal pain, he or she did not have gastroparesis. Yet studies indicate that up to 80% of patients with gastroparesis have pain.

Functional dyspepsia is defined as bothersome postprandial fullness, early satiety, and epigastric pain or burning in the absence of structural abnormality. The disorder can be subdivided into postprandial distress (i.e., meal-related symptomatology) and epigastric pain syndrome (i.e., pain or burning that may or may not be related to meals). Either of these alternatives may entail nausea and vomiting.

Comparing the pathophysiologies of gastroparesis and functional dyspepsia helps to distinguish these disorders from each other. A 2019 review described rapid gastric emptying and duodenal eosinophilia in patients with functional dyspepsia, but not in patients with gastroparesis. Patients with epigastric pain syndrome had sensitivity to acid, bile, and fats. Patients with idiopathic gastroparesis, which is the most common type, had a weak antral pump and abnormal duodenal feedback, but patients with functional dyspepsia did not have these characteristics (J Neurogastroenterol Motil. 2019;25[1]:27-35).
 

Examining symptoms and severity

One examination of patients with gastroparesis found that approximately 46% of them had a body mass index of 25 or greater. About 26% of patients had a BMI greater than 30. Yet these patients were eating less than 60% of their recommended daily allowances, based on their age, height, weight, and sex (Clin Gastroenterol Hepatol. 2011;9[12]:1056-64).

Accelerating gastric emptying may not relieve symptoms completely in a patient with gastroparesis, said Dr. Nguyen. A 2007 study of patients with gastroparesis found that 43% had impaired accommodation, and 29% had visceral hypersensitivity (Gut. 2007;56[1]:29-36). The same data indicated that gastric emptying time was not correlated with symptom severity. Impaired accommodation, however, was associated with early satiety and weight loss. Visceral hypersensitivity was associated with pain, early satiety, and weight loss. These data suggest that accommodation and visceral hypersensitivity may influence symptom severity in gastroparesis, said Dr. Nguyen.

Other researchers compared mild, moderate, and severe symptoms of early satiety in patients with gastroparesis. They found that patients with severe symptoms of early satiety have more delayed gastric emptying than do patients with mild or moderate symptoms of early satiety (Neurogastroenterol Motil. 2017;29[4].).

Dr. Nguyen and colleagues examined normal gastric emptying, compared with severely delayed gastric emptying, which they defined as greater than 35% retention at 4 hours. They found that severely delayed gastric emptying was associated with more severe symptoms, particularly nausea and vomiting, as measured by Gastroparesis Cardinal Symptom Index (GCSI). Extreme symptoms may help differentiate between gastroparesis and functional dyspepsia, said Dr. Nguyen.
 

Dietary and pharmacologic treatment

Although clinicians might consider recommending dietary modifications to treat gastroparesis or functional dyspepsia, the literature contains little evidence about their efficacy in these indications, said Dr. Nguyen. Based on a study by Tack and colleagues, some clinicians recommend small, frequent meals that are low in fat and low in fiber to patients with gastroparesis. Such a diet could be harmful, however, to patients with comorbid diabetes, irritable bowel syndrome, or renal failure.

Common dietary recommendations for functional dyspepsia include small, frequent meals; decreased fat consumption; and avoidance of citrus and spicy foods. These recommendations are based on small studies in which patients reported which foods tended to cause their symptoms. Trials of dietary modifications in functional dyspepsia, however, are lacking.

Nevertheless, the literature can guide the selection of pharmacotherapy for these disorders. Talley et al. examined the effects of neuromodulators such as amitriptyline, a tricyclic antidepressant, and escitalopram in functional dyspepsia. About 70% of the sample had postprandial distress syndrome, and 20% met criteria for idiopathic gastroparesis. Amitriptyline provided greater symptomatic relief to these patients than did placebo, but escitalopram did not. Patients who met criteria for idiopathic gastroparesis did not respond well to tricyclic antidepressants, but patients with epigastric pain syndrome did. Furthermore, compared with patients with normal gastric emptying, those with delayed emptying did not respond to tricyclic antidepressants. A separate study found that the tricyclic antidepressant nortriptyline did not improve symptoms of gastroparesis (JAMA. 2013;310[24]:2640-9).

Promotility agents may be beneficial for certain patients. A study published this year suggests that, compared with placebo, prucalopride is effective for nausea, vomiting, fullness, bloating, and gastric emptying in patients with idiopathic gastroparesis (Am J Gastroenterol. 2019;114[8]:1265-74.). A 2017 meta-analysis, however, found that proton pump inhibitors were more effective than promotility agents in patients with functional dyspepsia (Am J Gastroenterol. 2017;112[7]:988-1013.).

Pyloric dysfunction may accompany gastroparesis in some patients. Increased severity of gastric emptying delay is associated with increased pylorospasm. Endoscopists have gained experience in performing pyloric myotomy, and this treatment has become more popular. Uncontrolled studies indicate that the proportion of patients with decreased symptom severity after this procedure is higher than 70% and can be as high as 86% (Gastrointest Endosc. 2017;85[1]:123-8). The predictors of a good response include idiopathic etiology, male sex, moderate symptom severity, and greater delay in gastric emptying.

Functional dyspepsia should perhaps be understood as normal gastric emptying and symptoms of epigastric pain syndrome, said Dr. Nguyen. Those patients may respond to neuromodulators, she added. Idiopathic gastroparesis appears to be characterized by severe delay in gastric emptying, postprandial symptoms, nausea, and vomiting. “In the middle is the gray zone, where you have these patients with postprandial distress with or without delayed gastric emptying,” said Dr. Nguyen. Functional dyspepsia and gastroparesis could be two ends of a spectrum, and the best management for patients with symptoms that occur in both disorders is unclear.

[email protected]

CHICAGO – Because gastroparesis and functional dyspepsia share several symptoms (e.g., upper abdominal pain, fullness, and bloating) and pathophysiological abnormalities (e.g., delayed gastric emptying, impaired gastric accommodation, and visceral hypersensitivity), it can be hard to distinguish the two conditions, according to a lecture presented at Freston Conference 2019, sponsored by the American Gastroenterological Association. Additional research into the role of diet in these conditions will improve the treatment of these patients, said Linda Nguyen, MD, director of neurogastroenterology and motility at Stanford (Calif.) University.

Distinguishing the disorders

The accepted definition of gastroparesis is abnormal gastric emptying in the absence of a mechanical obstruction. The condition’s symptoms include nausea, vomiting, bloating, early satiety, abdominal pain, and weight loss. A previous consensus held that if a patient had abdominal pain, he or she did not have gastroparesis. Yet studies indicate that up to 80% of patients with gastroparesis have pain.

Functional dyspepsia is defined as bothersome postprandial fullness, early satiety, and epigastric pain or burning in the absence of structural abnormality. The disorder can be subdivided into postprandial distress (i.e., meal-related symptomatology) and epigastric pain syndrome (i.e., pain or burning that may or may not be related to meals). Either of these alternatives may entail nausea and vomiting.

Comparing the pathophysiologies of gastroparesis and functional dyspepsia helps to distinguish these disorders from each other. A 2019 review described rapid gastric emptying and duodenal eosinophilia in patients with functional dyspepsia, but not in patients with gastroparesis. Patients with epigastric pain syndrome had sensitivity to acid, bile, and fats. Patients with idiopathic gastroparesis, which is the most common type, had a weak antral pump and abnormal duodenal feedback, but patients with functional dyspepsia did not have these characteristics (J Neurogastroenterol Motil. 2019;25[1]:27-35).
 

Examining symptoms and severity

One examination of patients with gastroparesis found that approximately 46% of them had a body mass index of 25 or greater. About 26% of patients had a BMI greater than 30. Yet these patients were eating less than 60% of their recommended daily allowances, based on their age, height, weight, and sex (Clin Gastroenterol Hepatol. 2011;9[12]:1056-64).

Accelerating gastric emptying may not relieve symptoms completely in a patient with gastroparesis, said Dr. Nguyen. A 2007 study of patients with gastroparesis found that 43% had impaired accommodation, and 29% had visceral hypersensitivity (Gut. 2007;56[1]:29-36). The same data indicated that gastric emptying time was not correlated with symptom severity. Impaired accommodation, however, was associated with early satiety and weight loss. Visceral hypersensitivity was associated with pain, early satiety, and weight loss. These data suggest that accommodation and visceral hypersensitivity may influence symptom severity in gastroparesis, said Dr. Nguyen.

Other researchers compared mild, moderate, and severe symptoms of early satiety in patients with gastroparesis. They found that patients with severe symptoms of early satiety have more delayed gastric emptying than do patients with mild or moderate symptoms of early satiety (Neurogastroenterol Motil. 2017;29[4].).

Dr. Nguyen and colleagues examined normal gastric emptying, compared with severely delayed gastric emptying, which they defined as greater than 35% retention at 4 hours. They found that severely delayed gastric emptying was associated with more severe symptoms, particularly nausea and vomiting, as measured by Gastroparesis Cardinal Symptom Index (GCSI). Extreme symptoms may help differentiate between gastroparesis and functional dyspepsia, said Dr. Nguyen.
 

Dietary and pharmacologic treatment

Although clinicians might consider recommending dietary modifications to treat gastroparesis or functional dyspepsia, the literature contains little evidence about their efficacy in these indications, said Dr. Nguyen. Based on a study by Tack and colleagues, some clinicians recommend small, frequent meals that are low in fat and low in fiber to patients with gastroparesis. Such a diet could be harmful, however, to patients with comorbid diabetes, irritable bowel syndrome, or renal failure.

Common dietary recommendations for functional dyspepsia include small, frequent meals; decreased fat consumption; and avoidance of citrus and spicy foods. These recommendations are based on small studies in which patients reported which foods tended to cause their symptoms. Trials of dietary modifications in functional dyspepsia, however, are lacking.

Nevertheless, the literature can guide the selection of pharmacotherapy for these disorders. Talley et al. examined the effects of neuromodulators such as amitriptyline, a tricyclic antidepressant, and escitalopram in functional dyspepsia. About 70% of the sample had postprandial distress syndrome, and 20% met criteria for idiopathic gastroparesis. Amitriptyline provided greater symptomatic relief to these patients than did placebo, but escitalopram did not. Patients who met criteria for idiopathic gastroparesis did not respond well to tricyclic antidepressants, but patients with epigastric pain syndrome did. Furthermore, compared with patients with normal gastric emptying, those with delayed emptying did not respond to tricyclic antidepressants. A separate study found that the tricyclic antidepressant nortriptyline did not improve symptoms of gastroparesis (JAMA. 2013;310[24]:2640-9).

Promotility agents may be beneficial for certain patients. A study published this year suggests that, compared with placebo, prucalopride is effective for nausea, vomiting, fullness, bloating, and gastric emptying in patients with idiopathic gastroparesis (Am J Gastroenterol. 2019;114[8]:1265-74.). A 2017 meta-analysis, however, found that proton pump inhibitors were more effective than promotility agents in patients with functional dyspepsia (Am J Gastroenterol. 2017;112[7]:988-1013.).

Pyloric dysfunction may accompany gastroparesis in some patients. Increased severity of gastric emptying delay is associated with increased pylorospasm. Endoscopists have gained experience in performing pyloric myotomy, and this treatment has become more popular. Uncontrolled studies indicate that the proportion of patients with decreased symptom severity after this procedure is higher than 70% and can be as high as 86% (Gastrointest Endosc. 2017;85[1]:123-8). The predictors of a good response include idiopathic etiology, male sex, moderate symptom severity, and greater delay in gastric emptying.

Functional dyspepsia should perhaps be understood as normal gastric emptying and symptoms of epigastric pain syndrome, said Dr. Nguyen. Those patients may respond to neuromodulators, she added. Idiopathic gastroparesis appears to be characterized by severe delay in gastric emptying, postprandial symptoms, nausea, and vomiting. “In the middle is the gray zone, where you have these patients with postprandial distress with or without delayed gastric emptying,” said Dr. Nguyen. Functional dyspepsia and gastroparesis could be two ends of a spectrum, and the best management for patients with symptoms that occur in both disorders is unclear.

[email protected]

ALEXANDRIA, VA. – Higher out-of-pocket costs for oral tyrosine kinase inhibitors (TKIs) were linked to inferior survival in patients with advanced, biomarker-positive lung cancers in an analysis of state-level registry data, an investigator reported at a press conference ahead of the Quality Care Symposium, sponsored by the American Society of Clinical Oncology.

Higher out-of-pocket cost burden was also linked to lower numbers of TKI prescriptions and shorter duration of TKI therapy in the study, which included patients diagnosed with EGFR- and ALK-positive non–small cell lung cancer (NSCLC) between 2010 and 2016.

The findings would suggest a need for a review of coverage for these effective medications, according to Bernardo H. L. Goulart, MD, a thoracic oncologist and health services researcher at the University of Washington and Fred Hutchinson Cancer Research Center, both in Seattle.

“Making sure that the cost to the patients is affordable could mitigate this financial toxicity, and hopefully help patients stay on therapy and derive the survival benefit that these medications are supposed to offer,” Dr. Goulart said in an interview.

The study included data on 106 patients with EGFR- and ALK-positive stage IV NSCLC in the Washington Surveillance, Epidemiology, and End Results registry who had at least one oral TKI prescription. Investigators linked that registry data with commercial and Medicare claims, then divided this patient cohort into quartiles based on out-of-pocket costs.

In the top quartile, the median monthly out-of-pocket cost for TKI treatment was $2,888, compared with just $1,431 in the other three quartiles – essentially half the cost, Dr. Goulart said.

Median survival in the patients in the top out-of-pocket cost quartile was just 9 months, compared with 22 months in the lower three quartiles, he added.

“That difference is remarkable,” Dr. Goulart said, adding that the survival in the top-cost quartile reflects a survival that might be expected with conventional, nontargeted chemotherapy, while survival in the remaining patients mirrored what might be expected based on clinical trials of TKIs in this setting.

Patients in the high-cost quartile were 2.31 times as likely to die as patients in the lower quartiles, according to results of a multivariable analysis that adjusted for patient, disease-specific, and financial characteristics including qualification for low-income subsidies.

The mean medication possession ratio, a measure of medication adherence, was lower in the high-cost quartile (1.06 vs. 1.20 for the lower three quartiles; P = .02), and median duration of therapy was likewise lower in the high-cost quartile (4 vs. 8 months; P less than .01), according to data reported in the study abstract.

While multiple previous studies have linked out-of-pocket costs to decreased adherence and duration of therapy, the present study is one of the few to evaluate the link between cost of oral cancer medications and survival, according to Dr. Goulart.

In one other recent study showing a relationship between financial toxicity and survival, researchers at Fred Hutch showing that Washington cancer patients who filed for bankruptcy were more likely to die, compared with cancer patients not filing for bankruptcy, even after adjustment for a variety of patient characteristics.

The present study results raise a “serious concern” that some patients are unable to afford their medications, which is having a detrimental effect on survival, Dr. Goulart said. Alternatively, the out-of-pocket costs may not have an effect on survival; rather, they may be a “marker of very poor insurance coverage” that reflects higher costs for multiple other aspects of their care.

“The out-of-pocket cost for these drugs can be pretty astronomical, and we have at least a plausible hypothesis that they are taking a toll on patient’s survival,” he added.

If the findings of this study are confirmed in more and larger studies, there could be important implications for health policy and oncology practice, according to Dr. Goulart.

“The biggest action would be to involve patient advocates and physician groups such as ASCO, and advocate for changes in policy for coverage and out-of-pocket costs for these oral TKIs, at least for the patients that have the mutations,” he explained.

Another action, according to Dr. Goulart, would be to try to equip oncology clinics everywhere with patient financial-assistance programs to link patients to entities that can help them afford the cost of TKIs.

“Patients who attend small, remote cancer clinics might not have access to a financial specialist who can help them navigate these costs,” he said.

Funding for the study came from the National Institutes of Health. Dr. Goulart reported disclosures related to Flatiron Health (travel, accommodations, and expenses).
 

SOURCE: Goulart BHL et al. SCS 2019, Abstract 3.

ALEXANDRIA, VA. – Higher out-of-pocket costs for oral tyrosine kinase inhibitors (TKIs) were linked to inferior survival in patients with advanced, biomarker-positive lung cancers in an analysis of state-level registry data, an investigator reported at a press conference ahead of the Quality Care Symposium, sponsored by the American Society of Clinical Oncology.

Higher out-of-pocket cost burden was also linked to lower numbers of TKI prescriptions and shorter duration of TKI therapy in the study, which included patients diagnosed with EGFR- and ALK-positive non–small cell lung cancer (NSCLC) between 2010 and 2016.

The findings would suggest a need for a review of coverage for these effective medications, according to Bernardo H. L. Goulart, MD, a thoracic oncologist and health services researcher at the University of Washington and Fred Hutchinson Cancer Research Center, both in Seattle.

“Making sure that the cost to the patients is affordable could mitigate this financial toxicity, and hopefully help patients stay on therapy and derive the survival benefit that these medications are supposed to offer,” Dr. Goulart said in an interview.

The study included data on 106 patients with EGFR- and ALK-positive stage IV NSCLC in the Washington Surveillance, Epidemiology, and End Results registry who had at least one oral TKI prescription. Investigators linked that registry data with commercial and Medicare claims, then divided this patient cohort into quartiles based on out-of-pocket costs.

In the top quartile, the median monthly out-of-pocket cost for TKI treatment was $2,888, compared with just $1,431 in the other three quartiles – essentially half the cost, Dr. Goulart said.

Median survival in the patients in the top out-of-pocket cost quartile was just 9 months, compared with 22 months in the lower three quartiles, he added.

“That difference is remarkable,” Dr. Goulart said, adding that the survival in the top-cost quartile reflects a survival that might be expected with conventional, nontargeted chemotherapy, while survival in the remaining patients mirrored what might be expected based on clinical trials of TKIs in this setting.

Patients in the high-cost quartile were 2.31 times as likely to die as patients in the lower quartiles, according to results of a multivariable analysis that adjusted for patient, disease-specific, and financial characteristics including qualification for low-income subsidies.

The mean medication possession ratio, a measure of medication adherence, was lower in the high-cost quartile (1.06 vs. 1.20 for the lower three quartiles; P = .02), and median duration of therapy was likewise lower in the high-cost quartile (4 vs. 8 months; P less than .01), according to data reported in the study abstract.

While multiple previous studies have linked out-of-pocket costs to decreased adherence and duration of therapy, the present study is one of the few to evaluate the link between cost of oral cancer medications and survival, according to Dr. Goulart.

In one other recent study showing a relationship between financial toxicity and survival, researchers at Fred Hutch showing that Washington cancer patients who filed for bankruptcy were more likely to die, compared with cancer patients not filing for bankruptcy, even after adjustment for a variety of patient characteristics.

The present study results raise a “serious concern” that some patients are unable to afford their medications, which is having a detrimental effect on survival, Dr. Goulart said. Alternatively, the out-of-pocket costs may not have an effect on survival; rather, they may be a “marker of very poor insurance coverage” that reflects higher costs for multiple other aspects of their care.

“The out-of-pocket cost for these drugs can be pretty astronomical, and we have at least a plausible hypothesis that they are taking a toll on patient’s survival,” he added.

If the findings of this study are confirmed in more and larger studies, there could be important implications for health policy and oncology practice, according to Dr. Goulart.

“The biggest action would be to involve patient advocates and physician groups such as ASCO, and advocate for changes in policy for coverage and out-of-pocket costs for these oral TKIs, at least for the patients that have the mutations,” he explained.

Another action, according to Dr. Goulart, would be to try to equip oncology clinics everywhere with patient financial-assistance programs to link patients to entities that can help them afford the cost of TKIs.

“Patients who attend small, remote cancer clinics might not have access to a financial specialist who can help them navigate these costs,” he said.

Funding for the study came from the National Institutes of Health. Dr. Goulart reported disclosures related to Flatiron Health (travel, accommodations, and expenses).
 

SOURCE: Goulart BHL et al. SCS 2019, Abstract 3.

ALEXANDRIA, VA. – Higher out-of-pocket costs for oral tyrosine kinase inhibitors (TKIs) were linked to inferior survival in patients with advanced, biomarker-positive lung cancers in an analysis of state-level registry data, an investigator reported at a press conference ahead of the Quality Care Symposium, sponsored by the American Society of Clinical Oncology.

Higher out-of-pocket cost burden was also linked to lower numbers of TKI prescriptions and shorter duration of TKI therapy in the study, which included patients diagnosed with EGFR- and ALK-positive non–small cell lung cancer (NSCLC) between 2010 and 2016.

The findings would suggest a need for a review of coverage for these effective medications, according to Bernardo H. L. Goulart, MD, a thoracic oncologist and health services researcher at the University of Washington and Fred Hutchinson Cancer Research Center, both in Seattle.

“Making sure that the cost to the patients is affordable could mitigate this financial toxicity, and hopefully help patients stay on therapy and derive the survival benefit that these medications are supposed to offer,” Dr. Goulart said in an interview.

The study included data on 106 patients with EGFR- and ALK-positive stage IV NSCLC in the Washington Surveillance, Epidemiology, and End Results registry who had at least one oral TKI prescription. Investigators linked that registry data with commercial and Medicare claims, then divided this patient cohort into quartiles based on out-of-pocket costs.

In the top quartile, the median monthly out-of-pocket cost for TKI treatment was $2,888, compared with just $1,431 in the other three quartiles – essentially half the cost, Dr. Goulart said.

Median survival in the patients in the top out-of-pocket cost quartile was just 9 months, compared with 22 months in the lower three quartiles, he added.

“That difference is remarkable,” Dr. Goulart said, adding that the survival in the top-cost quartile reflects a survival that might be expected with conventional, nontargeted chemotherapy, while survival in the remaining patients mirrored what might be expected based on clinical trials of TKIs in this setting.

Patients in the high-cost quartile were 2.31 times as likely to die as patients in the lower quartiles, according to results of a multivariable analysis that adjusted for patient, disease-specific, and financial characteristics including qualification for low-income subsidies.

The mean medication possession ratio, a measure of medication adherence, was lower in the high-cost quartile (1.06 vs. 1.20 for the lower three quartiles; P = .02), and median duration of therapy was likewise lower in the high-cost quartile (4 vs. 8 months; P less than .01), according to data reported in the study abstract.

While multiple previous studies have linked out-of-pocket costs to decreased adherence and duration of therapy, the present study is one of the few to evaluate the link between cost of oral cancer medications and survival, according to Dr. Goulart.

In one other recent study showing a relationship between financial toxicity and survival, researchers at Fred Hutch showing that Washington cancer patients who filed for bankruptcy were more likely to die, compared with cancer patients not filing for bankruptcy, even after adjustment for a variety of patient characteristics.

The present study results raise a “serious concern” that some patients are unable to afford their medications, which is having a detrimental effect on survival, Dr. Goulart said. Alternatively, the out-of-pocket costs may not have an effect on survival; rather, they may be a “marker of very poor insurance coverage” that reflects higher costs for multiple other aspects of their care.

“The out-of-pocket cost for these drugs can be pretty astronomical, and we have at least a plausible hypothesis that they are taking a toll on patient’s survival,” he added.

If the findings of this study are confirmed in more and larger studies, there could be important implications for health policy and oncology practice, according to Dr. Goulart.

“The biggest action would be to involve patient advocates and physician groups such as ASCO, and advocate for changes in policy for coverage and out-of-pocket costs for these oral TKIs, at least for the patients that have the mutations,” he explained.

Another action, according to Dr. Goulart, would be to try to equip oncology clinics everywhere with patient financial-assistance programs to link patients to entities that can help them afford the cost of TKIs.

“Patients who attend small, remote cancer clinics might not have access to a financial specialist who can help them navigate these costs,” he said.

Funding for the study came from the National Institutes of Health. Dr. Goulart reported disclosures related to Flatiron Health (travel, accommodations, and expenses).
 

SOURCE: Goulart BHL et al. SCS 2019, Abstract 3.

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a lifetime prevalence of 15% to 20% in industrialized countries.¹ It affects both children and adults and is predominantly characterized by a waxing and waning course of eczematous skin lesions and pruritus. In recent years, there is increasing recognition that AD can present with extracutaneous findings. Large-scale epidemiologic studies have reported a notably higher prevalence of ophthalmic complications in the AD population compared to the general population, in a severity-dependent manner.^2,3 Potential complications include blepharitis, keratoconjunctivitis, keratoconus, glaucoma, cataracts, retinal detachment, ophthalmic herpes simplex virus infections, and dupilumab-associated ocular complications.

The etiology of each ocular complication in the context of AD is complex and likely multifactorial. Intrinsic immune dysregulation, physical trauma from eye rubbing, AD medication side effects, and genetics all have been speculated to play a role.² Some of these ocular complications have a chronic course, while others present with sudden onset of symptoms; many of them can result in visual impairment if undiagnosed or left untreated. This article reviews several of the most common ocular comorbidities associated with AD. We discuss the clinical presentation, pathophysiology, and management strategies for each condition.

Blepharitis

Blepharitis, an inflammatory condition of the eyelids, is estimated to affect more than 6% of patients with AD compared to less than 1% of the general population.² Blepharitis can be classified as anterior or posterior, based on the anatomic location of the affected region relative to the lash margin. Affected individuals may experience pruritus and irritation of the eyelids, tearing, a foreign body or burning sensation, crusting of the eyelids, and photophobia.⁴ Anterior blepharitis commonly is due to staphylococcal disease, and posterior blepharitis is secondary to structural changes and obstruction of meibomian gland orifices.

Although the pathophysiology is not well defined, xerosis in atopic patients is accompanied by barrier disruption and transepidermal water loss, which promote eyelid skin inflammation.

The mainstay of therapy for atopic blepharitis consists of conventional lid hygiene regimens, such as warm compresses and gentle scrubbing of the lid margins to remove crust and debris, which can be done with nonprescription cleansers, pads, and baby shampoos. Acute exacerbations may require topical antibiotics (ie, erythromycin or bacitracin applied to the lid margins once daily), topical calcineurin inhibitors (ie, cyclosporine ophthalmic emulsion 0.05%), or low-potency topical corticosteroids (ie, fluorometholone 0.1% or loteprednol etabonate 0.5% ophthalmic suspensions).⁵ Due to potential side effects of medications, especially topical corticosteroids, patients should be referred to ophthalmologists for definitive diagnosis and treatment.

Keratoconjunctivitis

Atopic keratoconjunctivitis (AKC) is a noninfectious inflammatory condition of the cornea and conjunctiva that occurs in an estimated 25% to 42% of patients with AD.^6,7 It frequently presents in late adolescence and has a peak incidence between 30 and 50 years of age.⁸ The symptoms of AKC include ocular pruritus, redness, ropy mucoid discharge, burning discomfort, photophobia, and blurring of vision. Corneal involvement can progress to corneal neovascularization and punctate or macroepithelial erosions and ulcerations, which increase the risk for corneal scarring and visual impairment.⁷

Keratoconjunctivitis is a complex inflammatory disease characterized by infiltration of the conjunctival epithelium by eosinophils, mast cells, and lymphocytes. On examination, patients frequently are found to have concurrent AD of the periorbital skin as well as papillary hypertrophy of the tarsal conjunctiva with accompanying fibrosis, which can lead to entropion (turning inward of the lid margins and lashes) in severe cases.⁷ Ophthalmic evaluation is strongly recommended for patients with AKC to control symptoms, to limit exacerbations, and to prevent sight-threatening inflammation leading to vision loss. Treatment can be challenging given the chronicity of the condition and may require multiple treatment arms. Conservative measures include cool compresses and treatment with ophthalmic eye drops containing antihistamines (ie, ketotifen 0.025% [available over-the-counter]) and mast cell stabilizers (ie, olopatadine ophthalmic solution 0.1%).⁸ Atopic keratoconjunctivitis exacerbations may require short-term use of topical steroids or calcineurin inhibitors, or systemic equivalents for refractory cases.⁶ Long-term maintenance therapy typically consists of proper eye hygiene and steroid-sparing agents that reduce ocular inflammation, such as topical cyclosporine and tacrolimus, neither of which are associated with increased intraocular pressure (IOP)(Figure 1).⁸ Cornea disease resulting from chronic conjunctival/lid microtrauma can be managed with soft or scleral contact lenses.

Keratoconus

Keratoconus is a noninflammatory ocular disorder characterized by progressive thinning and conelike protrusion of the cornea. The corneal topographic changes result in high irregular astigmatism and reduced visual acuity, which can manifest as image blurring or distortion (Figure 2).^2,9 Multiple case series and controlled studies have reported a positive association between keratoconus and a history of atopic disease.^10,11

The precise etiology of keratoconus in the context of AD is unclear and likely is multifactorial. Habitual eye rubbing from periocular pruritus and discomfort has been reported to be a notable contributor to keratoconus.¹² In addition, intrinsic inflammation and imbalance of cytokines and proteases also may contribute to development of keratoconus.¹³

Keratoconus is a progressive condition that can severely impact vision, making it critical to diagnose patients before irreversible vision loss occurs. Individuals with risk factors, such as AD of the eyelids, history of eye rubbing, or family history of keratoconus, should be advised to receive routine vision screening for worsening astigmatism, especially during the first few decades of life when keratoconus progresses rapidly.

The conservative management for early keratoconus includes glasses and gas-permeable contact lenses for correction of visual acuity and astigmatism. For advanced keratoconus, scleral lenses often are prescribed. These large-diameter, gas-permeable lenses are designed to rest on the sclera and arch over the entire cornea.⁹ Alternatively, corneal collagen cross-linking is a newer technique that utilizes riboflavin and UVA irradiation to strengthen the corneal tissue. It has proven to be safe and effective in slowing or stopping the progression of keratoconus, particularly when treated at the early stage, and received US Food and Drug Administration approval in 2016.⁹

Glaucoma

Glaucoma is a well-known complication of AD and can lead to irreversible ocular hypertension and optic nerve damage. Corticosteroid use is a major risk factor for glaucoma, and the rise in IOP is thought to be due to increased aqueous outflow resistance.¹⁴

Multiple case reports have linked glaucoma to long-term use of potent topical corticosteroids in the facial and palpebral regions, which has been attributed to direct steroid contact and absorption by ocular tissues, as glaucoma rarely occurs with topical steroid application elsewhere on the body.^15-17 Systemic steroids (ie, prednisolone) taken for more than 8 weeks also have been associated with a marked rise in IOP.¹⁸

Certain risk factors may predispose a steroid user to increased IOP, including existing open-angle glaucoma, diabetes mellitus, collagen disease, and high myopia.^15,19 Steroid responders and younger individuals also demonstrate increased sensitivity to steroids.²⁰

Given that glaucoma often is asymptomatic until advanced stages, early detection is the key for proper intervention. Periodic glaucoma screening by an ophthalmologist would be appropriate for known steroid responders, as well as patients with a prolonged history of topical steroid application in the palpebral region and systemic steroid use, family history of glaucoma, or known ocular pathology.²¹ Furthermore, patients with concurrent glaucoma and AD should be jointly managed by dermatology and ophthalmology, and systemic and topical corticosteroid use should be minimized in favor of alterative agents such as calcineurin inhibitors.²²

In addition to steroid-induced glaucoma, intrinsic atopic glaucoma recently has been proposed as a clinical entity and is characterized by increased inflammatory cytokines—IL-8 and CCL2—in the aqueous humor and abnormal accumulation of fibers in corneoscleral meshwork.²³

Cataracts

Cataracts are estimated to affect 8% to 25% of patients with AD.^21,24 Unlike age-related cataracts, cataracts associated with AD are observed in adolescents and young adults in addition to the older population. The progression of lenticular opacity can rapidly occur and has been reported to coincide with AD flares.^25,26

Patients with AD typically present with anterior or posterior subcapsular cataracts instead of nuclear and cortical cataracts, which are more common in the general population.^27,28 Anterior subcapsular cataracts are more specific to AD, whereas posterior subcapsular cataracts are associated with both prolonged corticosteroid use and AD.²⁶ Children generally are more sensitive to steroids than adults and may develop cataracts more rapidly and at lower concentrations.²⁹

The pathophysiology of cataract formation and progression in the context of AD is multifactorial. Cataract patients with AD have compromised blood-retinal barrier integrity as well as increased oxidative damage in the lens.^30,31 Genetics and blunt trauma from eye rubbing are thought to play a role, and the latter has been associated with faster progression of cataracts.²⁸ In contrast, corticosteroid-induced cataracts likely are caused by transcriptional changes and disrupted osmotic balance in the lens fibers, which can lead to fiber rupture and lens opacification.^26,32 Systemic corticosteroids show the strongest association with cataract development, but inhaled and topical steroids also have been implicated.²⁶

Although cataracts can be surgically corrected, prevention is critical. Patients with early-onset periorbital AD, prolonged use of topical or systemic corticosteroids, and family history of cataracts should be routinely screened. Anterior and posterior subcapsular cataracts are diagnosed with red reflex examinations that can be readily performed by the primary care physician or ophthalmologist.³³ Atopic dermatitis patients with cataracts should be advised to use calcineurin inhibitors and alternative treatments in place of corticosteroids.

Retinal Detachment

Retinal detachment (RD) is a serious complication of AD that can present in individuals younger than 35 years. The incidence of RD in patients with AD has been estimated to be 4% to 8%.³⁴ Retinal detachment manifests with visual disturbances such as flashing lights, shadows, visual field defect, and blurring of vision, but also may occur in the absence of vision changes.^35,36

Across multiple case series, patients who developed RD were consistently found to have AD in the facial or periorbital region and a history of chronic eye rubbing. Multiple patients also presented with concurrent proliferative vitreoretinopathy, lens subluxation, and/or cataracts.^35,37 The mechanism for RD has been attributed to ocular contusion from vigorous eye rubbing, as fundus findings between traumatic and AD-associated RD are similarly characterized by tractional breaks in the retina at vitreous base borders.³⁷

Avoidance of eye rubbing and optimized treatment of facial AD may help prevent RD in patients with AD. Furthermore, all patients with symptoms of RD should be immediately referred to ophthalmology for surgical repair.

Herpetic Ocular Disease

Ocular herpes simplex virus infections cause ocular pain and are associated with notable visual morbidity, as recurrences can result in irreversible corneal scarring and neovascularization. Two retrospective case-control studies independently reported that individuals with a history of AD are at greater risk for herpetic ocular disease compared to age-matched controls.^38,39 Furthermore, atopic disease is associated with higher recurrence rates and slower regeneration of the corneal epithelium.⁴⁰

These findings suggest that AD patients with a history of recurrent herpetic ocular diseases should be closely monitored and treated with antiviral prophylaxis and/or topical corticosteroids, depending on the type of keratitis (epithelial or stromal).⁴⁰ Furthermore, active ocular herpetic infections warrant urgent referral to an ophthalmologist.

Dupilumab-Associated Ocular Complications

Dupilumab, a monoclonal antibody that blocks IL-4 and IL-13 signaling, is the first biologic therapy to be approved for treatment of moderate to severe AD. Prior clinical trials have described a higher incidence of anterior conjunctivitis in dupilumab-treated AD patients (5%–28%) compared to placebo (2%–11%).⁴¹ Of note, the incidence may be as high as 70%, as reported in a recent case series.⁴² Interestingly, independent trials assessing dupilumab treatment in asthma, nasal polyposis, and eosinophilic esophagitis patients did not observe a higher incidence of conjunctivitis in dupilumab-treated patients compared to placebo, suggesting an AD-specific mechanism.⁴³

Prominent features of dupilumab-associated conjunctivitis include hyperemia of the conjunctiva and limbus, in addition to ocular symptoms such as tearing, burning, and bilateral decrease in visual acuity. Marked reduction of conjunctival goblet cells has been reported.⁴⁴ In addition to conjunctivitis, blepharitis also has been reported during dupilumab treatment.⁴⁵

Standardized treatment guidelines for dupilumab-associated ocular complications have not yet been established. Surprisingly, antihistamine eye drops appear to be inefficacious in the treatment of dupilumab-associated conjunctivitis.⁴¹ However, the condition has been successfully managed with topical steroids (fluorometholone ophthalmic suspension 0.1%) and tacrolimus ointment 0.03%.⁴¹ Lifitegrast, an anti-inflammatory agent approved for chronic dry eye, also has been suggested as a treatment option for patients refractory to topical steroids.⁴⁵ Alternatively, cessation of dupilumab could be considered in AD patients who experience severe ocular complications. Atopic dermatitis patients taking dupilumab who have any concerning signs for ocular complications should be referred to an ophthalmologist for further diagnosis and management.

Conclusion

Practicing dermatologists likely will encounter patients with concurrent AD and ocular complications. Although eye examinations are not routinely performed in the care of AD patients, dermatologists can proactively inquire about ocular symptoms and monitor patients longitudinally. Early diagnosis and treatment of these ocular conditions can prevent vision loss in these patients. Furthermore, symptomatic control of AD and careful consideration of the side-effect profiles of medications can potentially reduce the incidence of ocular complications in individuals with AD.

Patients with visual concerns or risk factors, such as a history of vigorous eye rubbing or chronic corticosteroid use, should be jointly managed with an ophthalmologist for optimized care. Moreover, acute exacerbations of ocular symptoms and visual deterioration warrant urgent referral to ophthalmology.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a lifetime prevalence of 15% to 20% in industrialized countries.¹ It affects both children and adults and is predominantly characterized by a waxing and waning course of eczematous skin lesions and pruritus. In recent years, there is increasing recognition that AD can present with extracutaneous findings. Large-scale epidemiologic studies have reported a notably higher prevalence of ophthalmic complications in the AD population compared to the general population, in a severity-dependent manner.^2,3 Potential complications include blepharitis, keratoconjunctivitis, keratoconus, glaucoma, cataracts, retinal detachment, ophthalmic herpes simplex virus infections, and dupilumab-associated ocular complications.

The etiology of each ocular complication in the context of AD is complex and likely multifactorial. Intrinsic immune dysregulation, physical trauma from eye rubbing, AD medication side effects, and genetics all have been speculated to play a role.² Some of these ocular complications have a chronic course, while others present with sudden onset of symptoms; many of them can result in visual impairment if undiagnosed or left untreated. This article reviews several of the most common ocular comorbidities associated with AD. We discuss the clinical presentation, pathophysiology, and management strategies for each condition.

Blepharitis

Blepharitis, an inflammatory condition of the eyelids, is estimated to affect more than 6% of patients with AD compared to less than 1% of the general population.² Blepharitis can be classified as anterior or posterior, based on the anatomic location of the affected region relative to the lash margin. Affected individuals may experience pruritus and irritation of the eyelids, tearing, a foreign body or burning sensation, crusting of the eyelids, and photophobia.⁴ Anterior blepharitis commonly is due to staphylococcal disease, and posterior blepharitis is secondary to structural changes and obstruction of meibomian gland orifices.

Although the pathophysiology is not well defined, xerosis in atopic patients is accompanied by barrier disruption and transepidermal water loss, which promote eyelid skin inflammation.

The mainstay of therapy for atopic blepharitis consists of conventional lid hygiene regimens, such as warm compresses and gentle scrubbing of the lid margins to remove crust and debris, which can be done with nonprescription cleansers, pads, and baby shampoos. Acute exacerbations may require topical antibiotics (ie, erythromycin or bacitracin applied to the lid margins once daily), topical calcineurin inhibitors (ie, cyclosporine ophthalmic emulsion 0.05%), or low-potency topical corticosteroids (ie, fluorometholone 0.1% or loteprednol etabonate 0.5% ophthalmic suspensions).⁵ Due to potential side effects of medications, especially topical corticosteroids, patients should be referred to ophthalmologists for definitive diagnosis and treatment.

Keratoconjunctivitis

Atopic keratoconjunctivitis (AKC) is a noninfectious inflammatory condition of the cornea and conjunctiva that occurs in an estimated 25% to 42% of patients with AD.^6,7 It frequently presents in late adolescence and has a peak incidence between 30 and 50 years of age.⁸ The symptoms of AKC include ocular pruritus, redness, ropy mucoid discharge, burning discomfort, photophobia, and blurring of vision. Corneal involvement can progress to corneal neovascularization and punctate or macroepithelial erosions and ulcerations, which increase the risk for corneal scarring and visual impairment.⁷

Keratoconjunctivitis is a complex inflammatory disease characterized by infiltration of the conjunctival epithelium by eosinophils, mast cells, and lymphocytes. On examination, patients frequently are found to have concurrent AD of the periorbital skin as well as papillary hypertrophy of the tarsal conjunctiva with accompanying fibrosis, which can lead to entropion (turning inward of the lid margins and lashes) in severe cases.⁷ Ophthalmic evaluation is strongly recommended for patients with AKC to control symptoms, to limit exacerbations, and to prevent sight-threatening inflammation leading to vision loss. Treatment can be challenging given the chronicity of the condition and may require multiple treatment arms. Conservative measures include cool compresses and treatment with ophthalmic eye drops containing antihistamines (ie, ketotifen 0.025% [available over-the-counter]) and mast cell stabilizers (ie, olopatadine ophthalmic solution 0.1%).⁸ Atopic keratoconjunctivitis exacerbations may require short-term use of topical steroids or calcineurin inhibitors, or systemic equivalents for refractory cases.⁶ Long-term maintenance therapy typically consists of proper eye hygiene and steroid-sparing agents that reduce ocular inflammation, such as topical cyclosporine and tacrolimus, neither of which are associated with increased intraocular pressure (IOP)(Figure 1).⁸ Cornea disease resulting from chronic conjunctival/lid microtrauma can be managed with soft or scleral contact lenses.

Keratoconus

Keratoconus is a noninflammatory ocular disorder characterized by progressive thinning and conelike protrusion of the cornea. The corneal topographic changes result in high irregular astigmatism and reduced visual acuity, which can manifest as image blurring or distortion (Figure 2).^2,9 Multiple case series and controlled studies have reported a positive association between keratoconus and a history of atopic disease.^10,11

The precise etiology of keratoconus in the context of AD is unclear and likely is multifactorial. Habitual eye rubbing from periocular pruritus and discomfort has been reported to be a notable contributor to keratoconus.¹² In addition, intrinsic inflammation and imbalance of cytokines and proteases also may contribute to development of keratoconus.¹³

Keratoconus is a progressive condition that can severely impact vision, making it critical to diagnose patients before irreversible vision loss occurs. Individuals with risk factors, such as AD of the eyelids, history of eye rubbing, or family history of keratoconus, should be advised to receive routine vision screening for worsening astigmatism, especially during the first few decades of life when keratoconus progresses rapidly.

The conservative management for early keratoconus includes glasses and gas-permeable contact lenses for correction of visual acuity and astigmatism. For advanced keratoconus, scleral lenses often are prescribed. These large-diameter, gas-permeable lenses are designed to rest on the sclera and arch over the entire cornea.⁹ Alternatively, corneal collagen cross-linking is a newer technique that utilizes riboflavin and UVA irradiation to strengthen the corneal tissue. It has proven to be safe and effective in slowing or stopping the progression of keratoconus, particularly when treated at the early stage, and received US Food and Drug Administration approval in 2016.⁹

Glaucoma

Glaucoma is a well-known complication of AD and can lead to irreversible ocular hypertension and optic nerve damage. Corticosteroid use is a major risk factor for glaucoma, and the rise in IOP is thought to be due to increased aqueous outflow resistance.¹⁴

Multiple case reports have linked glaucoma to long-term use of potent topical corticosteroids in the facial and palpebral regions, which has been attributed to direct steroid contact and absorption by ocular tissues, as glaucoma rarely occurs with topical steroid application elsewhere on the body.^15-17 Systemic steroids (ie, prednisolone) taken for more than 8 weeks also have been associated with a marked rise in IOP.¹⁸

Certain risk factors may predispose a steroid user to increased IOP, including existing open-angle glaucoma, diabetes mellitus, collagen disease, and high myopia.^15,19 Steroid responders and younger individuals also demonstrate increased sensitivity to steroids.²⁰

Given that glaucoma often is asymptomatic until advanced stages, early detection is the key for proper intervention. Periodic glaucoma screening by an ophthalmologist would be appropriate for known steroid responders, as well as patients with a prolonged history of topical steroid application in the palpebral region and systemic steroid use, family history of glaucoma, or known ocular pathology.²¹ Furthermore, patients with concurrent glaucoma and AD should be jointly managed by dermatology and ophthalmology, and systemic and topical corticosteroid use should be minimized in favor of alterative agents such as calcineurin inhibitors.²²

In addition to steroid-induced glaucoma, intrinsic atopic glaucoma recently has been proposed as a clinical entity and is characterized by increased inflammatory cytokines—IL-8 and CCL2—in the aqueous humor and abnormal accumulation of fibers in corneoscleral meshwork.²³

Cataracts

Cataracts are estimated to affect 8% to 25% of patients with AD.^21,24 Unlike age-related cataracts, cataracts associated with AD are observed in adolescents and young adults in addition to the older population. The progression of lenticular opacity can rapidly occur and has been reported to coincide with AD flares.^25,26

Patients with AD typically present with anterior or posterior subcapsular cataracts instead of nuclear and cortical cataracts, which are more common in the general population.^27,28 Anterior subcapsular cataracts are more specific to AD, whereas posterior subcapsular cataracts are associated with both prolonged corticosteroid use and AD.²⁶ Children generally are more sensitive to steroids than adults and may develop cataracts more rapidly and at lower concentrations.²⁹

The pathophysiology of cataract formation and progression in the context of AD is multifactorial. Cataract patients with AD have compromised blood-retinal barrier integrity as well as increased oxidative damage in the lens.^30,31 Genetics and blunt trauma from eye rubbing are thought to play a role, and the latter has been associated with faster progression of cataracts.²⁸ In contrast, corticosteroid-induced cataracts likely are caused by transcriptional changes and disrupted osmotic balance in the lens fibers, which can lead to fiber rupture and lens opacification.^26,32 Systemic corticosteroids show the strongest association with cataract development, but inhaled and topical steroids also have been implicated.²⁶

Although cataracts can be surgically corrected, prevention is critical. Patients with early-onset periorbital AD, prolonged use of topical or systemic corticosteroids, and family history of cataracts should be routinely screened. Anterior and posterior subcapsular cataracts are diagnosed with red reflex examinations that can be readily performed by the primary care physician or ophthalmologist.³³ Atopic dermatitis patients with cataracts should be advised to use calcineurin inhibitors and alternative treatments in place of corticosteroids.

Retinal Detachment

Retinal detachment (RD) is a serious complication of AD that can present in individuals younger than 35 years. The incidence of RD in patients with AD has been estimated to be 4% to 8%.³⁴ Retinal detachment manifests with visual disturbances such as flashing lights, shadows, visual field defect, and blurring of vision, but also may occur in the absence of vision changes.^35,36

Across multiple case series, patients who developed RD were consistently found to have AD in the facial or periorbital region and a history of chronic eye rubbing. Multiple patients also presented with concurrent proliferative vitreoretinopathy, lens subluxation, and/or cataracts.^35,37 The mechanism for RD has been attributed to ocular contusion from vigorous eye rubbing, as fundus findings between traumatic and AD-associated RD are similarly characterized by tractional breaks in the retina at vitreous base borders.³⁷

Avoidance of eye rubbing and optimized treatment of facial AD may help prevent RD in patients with AD. Furthermore, all patients with symptoms of RD should be immediately referred to ophthalmology for surgical repair.

Herpetic Ocular Disease

Ocular herpes simplex virus infections cause ocular pain and are associated with notable visual morbidity, as recurrences can result in irreversible corneal scarring and neovascularization. Two retrospective case-control studies independently reported that individuals with a history of AD are at greater risk for herpetic ocular disease compared to age-matched controls.^38,39 Furthermore, atopic disease is associated with higher recurrence rates and slower regeneration of the corneal epithelium.⁴⁰

These findings suggest that AD patients with a history of recurrent herpetic ocular diseases should be closely monitored and treated with antiviral prophylaxis and/or topical corticosteroids, depending on the type of keratitis (epithelial or stromal).⁴⁰ Furthermore, active ocular herpetic infections warrant urgent referral to an ophthalmologist.

Dupilumab-Associated Ocular Complications

Dupilumab, a monoclonal antibody that blocks IL-4 and IL-13 signaling, is the first biologic therapy to be approved for treatment of moderate to severe AD. Prior clinical trials have described a higher incidence of anterior conjunctivitis in dupilumab-treated AD patients (5%–28%) compared to placebo (2%–11%).⁴¹ Of note, the incidence may be as high as 70%, as reported in a recent case series.⁴² Interestingly, independent trials assessing dupilumab treatment in asthma, nasal polyposis, and eosinophilic esophagitis patients did not observe a higher incidence of conjunctivitis in dupilumab-treated patients compared to placebo, suggesting an AD-specific mechanism.⁴³

Prominent features of dupilumab-associated conjunctivitis include hyperemia of the conjunctiva and limbus, in addition to ocular symptoms such as tearing, burning, and bilateral decrease in visual acuity. Marked reduction of conjunctival goblet cells has been reported.⁴⁴ In addition to conjunctivitis, blepharitis also has been reported during dupilumab treatment.⁴⁵

Standardized treatment guidelines for dupilumab-associated ocular complications have not yet been established. Surprisingly, antihistamine eye drops appear to be inefficacious in the treatment of dupilumab-associated conjunctivitis.⁴¹ However, the condition has been successfully managed with topical steroids (fluorometholone ophthalmic suspension 0.1%) and tacrolimus ointment 0.03%.⁴¹ Lifitegrast, an anti-inflammatory agent approved for chronic dry eye, also has been suggested as a treatment option for patients refractory to topical steroids.⁴⁵ Alternatively, cessation of dupilumab could be considered in AD patients who experience severe ocular complications. Atopic dermatitis patients taking dupilumab who have any concerning signs for ocular complications should be referred to an ophthalmologist for further diagnosis and management.

Conclusion

Practicing dermatologists likely will encounter patients with concurrent AD and ocular complications. Although eye examinations are not routinely performed in the care of AD patients, dermatologists can proactively inquire about ocular symptoms and monitor patients longitudinally. Early diagnosis and treatment of these ocular conditions can prevent vision loss in these patients. Furthermore, symptomatic control of AD and careful consideration of the side-effect profiles of medications can potentially reduce the incidence of ocular complications in individuals with AD.

Patients with visual concerns or risk factors, such as a history of vigorous eye rubbing or chronic corticosteroid use, should be jointly managed with an ophthalmologist for optimized care. Moreover, acute exacerbations of ocular symptoms and visual deterioration warrant urgent referral to ophthalmology.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a lifetime prevalence of 15% to 20% in industrialized countries.¹ It affects both children and adults and is predominantly characterized by a waxing and waning course of eczematous skin lesions and pruritus. In recent years, there is increasing recognition that AD can present with extracutaneous findings. Large-scale epidemiologic studies have reported a notably higher prevalence of ophthalmic complications in the AD population compared to the general population, in a severity-dependent manner.^2,3 Potential complications include blepharitis, keratoconjunctivitis, keratoconus, glaucoma, cataracts, retinal detachment, ophthalmic herpes simplex virus infections, and dupilumab-associated ocular complications.

The etiology of each ocular complication in the context of AD is complex and likely multifactorial. Intrinsic immune dysregulation, physical trauma from eye rubbing, AD medication side effects, and genetics all have been speculated to play a role.² Some of these ocular complications have a chronic course, while others present with sudden onset of symptoms; many of them can result in visual impairment if undiagnosed or left untreated. This article reviews several of the most common ocular comorbidities associated with AD. We discuss the clinical presentation, pathophysiology, and management strategies for each condition.

Blepharitis

Blepharitis, an inflammatory condition of the eyelids, is estimated to affect more than 6% of patients with AD compared to less than 1% of the general population.² Blepharitis can be classified as anterior or posterior, based on the anatomic location of the affected region relative to the lash margin. Affected individuals may experience pruritus and irritation of the eyelids, tearing, a foreign body or burning sensation, crusting of the eyelids, and photophobia.⁴ Anterior blepharitis commonly is due to staphylococcal disease, and posterior blepharitis is secondary to structural changes and obstruction of meibomian gland orifices.

Although the pathophysiology is not well defined, xerosis in atopic patients is accompanied by barrier disruption and transepidermal water loss, which promote eyelid skin inflammation.

The mainstay of therapy for atopic blepharitis consists of conventional lid hygiene regimens, such as warm compresses and gentle scrubbing of the lid margins to remove crust and debris, which can be done with nonprescription cleansers, pads, and baby shampoos. Acute exacerbations may require topical antibiotics (ie, erythromycin or bacitracin applied to the lid margins once daily), topical calcineurin inhibitors (ie, cyclosporine ophthalmic emulsion 0.05%), or low-potency topical corticosteroids (ie, fluorometholone 0.1% or loteprednol etabonate 0.5% ophthalmic suspensions).⁵ Due to potential side effects of medications, especially topical corticosteroids, patients should be referred to ophthalmologists for definitive diagnosis and treatment.

Keratoconjunctivitis

Atopic keratoconjunctivitis (AKC) is a noninfectious inflammatory condition of the cornea and conjunctiva that occurs in an estimated 25% to 42% of patients with AD.^6,7 It frequently presents in late adolescence and has a peak incidence between 30 and 50 years of age.⁸ The symptoms of AKC include ocular pruritus, redness, ropy mucoid discharge, burning discomfort, photophobia, and blurring of vision. Corneal involvement can progress to corneal neovascularization and punctate or macroepithelial erosions and ulcerations, which increase the risk for corneal scarring and visual impairment.⁷

Keratoconjunctivitis is a complex inflammatory disease characterized by infiltration of the conjunctival epithelium by eosinophils, mast cells, and lymphocytes. On examination, patients frequently are found to have concurrent AD of the periorbital skin as well as papillary hypertrophy of the tarsal conjunctiva with accompanying fibrosis, which can lead to entropion (turning inward of the lid margins and lashes) in severe cases.⁷ Ophthalmic evaluation is strongly recommended for patients with AKC to control symptoms, to limit exacerbations, and to prevent sight-threatening inflammation leading to vision loss. Treatment can be challenging given the chronicity of the condition and may require multiple treatment arms. Conservative measures include cool compresses and treatment with ophthalmic eye drops containing antihistamines (ie, ketotifen 0.025% [available over-the-counter]) and mast cell stabilizers (ie, olopatadine ophthalmic solution 0.1%).⁸ Atopic keratoconjunctivitis exacerbations may require short-term use of topical steroids or calcineurin inhibitors, or systemic equivalents for refractory cases.⁶ Long-term maintenance therapy typically consists of proper eye hygiene and steroid-sparing agents that reduce ocular inflammation, such as topical cyclosporine and tacrolimus, neither of which are associated with increased intraocular pressure (IOP)(Figure 1).⁸ Cornea disease resulting from chronic conjunctival/lid microtrauma can be managed with soft or scleral contact lenses.

Keratoconus

Keratoconus is a noninflammatory ocular disorder characterized by progressive thinning and conelike protrusion of the cornea. The corneal topographic changes result in high irregular astigmatism and reduced visual acuity, which can manifest as image blurring or distortion (Figure 2).^2,9 Multiple case series and controlled studies have reported a positive association between keratoconus and a history of atopic disease.^10,11

The precise etiology of keratoconus in the context of AD is unclear and likely is multifactorial. Habitual eye rubbing from periocular pruritus and discomfort has been reported to be a notable contributor to keratoconus.¹² In addition, intrinsic inflammation and imbalance of cytokines and proteases also may contribute to development of keratoconus.¹³

Keratoconus is a progressive condition that can severely impact vision, making it critical to diagnose patients before irreversible vision loss occurs. Individuals with risk factors, such as AD of the eyelids, history of eye rubbing, or family history of keratoconus, should be advised to receive routine vision screening for worsening astigmatism, especially during the first few decades of life when keratoconus progresses rapidly.

The conservative management for early keratoconus includes glasses and gas-permeable contact lenses for correction of visual acuity and astigmatism. For advanced keratoconus, scleral lenses often are prescribed. These large-diameter, gas-permeable lenses are designed to rest on the sclera and arch over the entire cornea.⁹ Alternatively, corneal collagen cross-linking is a newer technique that utilizes riboflavin and UVA irradiation to strengthen the corneal tissue. It has proven to be safe and effective in slowing or stopping the progression of keratoconus, particularly when treated at the early stage, and received US Food and Drug Administration approval in 2016.⁹

Glaucoma

Glaucoma is a well-known complication of AD and can lead to irreversible ocular hypertension and optic nerve damage. Corticosteroid use is a major risk factor for glaucoma, and the rise in IOP is thought to be due to increased aqueous outflow resistance.¹⁴

Multiple case reports have linked glaucoma to long-term use of potent topical corticosteroids in the facial and palpebral regions, which has been attributed to direct steroid contact and absorption by ocular tissues, as glaucoma rarely occurs with topical steroid application elsewhere on the body.^15-17 Systemic steroids (ie, prednisolone) taken for more than 8 weeks also have been associated with a marked rise in IOP.¹⁸

Certain risk factors may predispose a steroid user to increased IOP, including existing open-angle glaucoma, diabetes mellitus, collagen disease, and high myopia.^15,19 Steroid responders and younger individuals also demonstrate increased sensitivity to steroids.²⁰

Given that glaucoma often is asymptomatic until advanced stages, early detection is the key for proper intervention. Periodic glaucoma screening by an ophthalmologist would be appropriate for known steroid responders, as well as patients with a prolonged history of topical steroid application in the palpebral region and systemic steroid use, family history of glaucoma, or known ocular pathology.²¹ Furthermore, patients with concurrent glaucoma and AD should be jointly managed by dermatology and ophthalmology, and systemic and topical corticosteroid use should be minimized in favor of alterative agents such as calcineurin inhibitors.²²

In addition to steroid-induced glaucoma, intrinsic atopic glaucoma recently has been proposed as a clinical entity and is characterized by increased inflammatory cytokines—IL-8 and CCL2—in the aqueous humor and abnormal accumulation of fibers in corneoscleral meshwork.²³

Cataracts

Cataracts are estimated to affect 8% to 25% of patients with AD.^21,24 Unlike age-related cataracts, cataracts associated with AD are observed in adolescents and young adults in addition to the older population. The progression of lenticular opacity can rapidly occur and has been reported to coincide with AD flares.^25,26

Patients with AD typically present with anterior or posterior subcapsular cataracts instead of nuclear and cortical cataracts, which are more common in the general population.^27,28 Anterior subcapsular cataracts are more specific to AD, whereas posterior subcapsular cataracts are associated with both prolonged corticosteroid use and AD.²⁶ Children generally are more sensitive to steroids than adults and may develop cataracts more rapidly and at lower concentrations.²⁹

The pathophysiology of cataract formation and progression in the context of AD is multifactorial. Cataract patients with AD have compromised blood-retinal barrier integrity as well as increased oxidative damage in the lens.^30,31 Genetics and blunt trauma from eye rubbing are thought to play a role, and the latter has been associated with faster progression of cataracts.²⁸ In contrast, corticosteroid-induced cataracts likely are caused by transcriptional changes and disrupted osmotic balance in the lens fibers, which can lead to fiber rupture and lens opacification.^26,32 Systemic corticosteroids show the strongest association with cataract development, but inhaled and topical steroids also have been implicated.²⁶

Although cataracts can be surgically corrected, prevention is critical. Patients with early-onset periorbital AD, prolonged use of topical or systemic corticosteroids, and family history of cataracts should be routinely screened. Anterior and posterior subcapsular cataracts are diagnosed with red reflex examinations that can be readily performed by the primary care physician or ophthalmologist.³³ Atopic dermatitis patients with cataracts should be advised to use calcineurin inhibitors and alternative treatments in place of corticosteroids.

Retinal Detachment

Retinal detachment (RD) is a serious complication of AD that can present in individuals younger than 35 years. The incidence of RD in patients with AD has been estimated to be 4% to 8%.³⁴ Retinal detachment manifests with visual disturbances such as flashing lights, shadows, visual field defect, and blurring of vision, but also may occur in the absence of vision changes.^35,36

Across multiple case series, patients who developed RD were consistently found to have AD in the facial or periorbital region and a history of chronic eye rubbing. Multiple patients also presented with concurrent proliferative vitreoretinopathy, lens subluxation, and/or cataracts.^35,37 The mechanism for RD has been attributed to ocular contusion from vigorous eye rubbing, as fundus findings between traumatic and AD-associated RD are similarly characterized by tractional breaks in the retina at vitreous base borders.³⁷

Avoidance of eye rubbing and optimized treatment of facial AD may help prevent RD in patients with AD. Furthermore, all patients with symptoms of RD should be immediately referred to ophthalmology for surgical repair.

Herpetic Ocular Disease

Ocular herpes simplex virus infections cause ocular pain and are associated with notable visual morbidity, as recurrences can result in irreversible corneal scarring and neovascularization. Two retrospective case-control studies independently reported that individuals with a history of AD are at greater risk for herpetic ocular disease compared to age-matched controls.^38,39 Furthermore, atopic disease is associated with higher recurrence rates and slower regeneration of the corneal epithelium.⁴⁰

These findings suggest that AD patients with a history of recurrent herpetic ocular diseases should be closely monitored and treated with antiviral prophylaxis and/or topical corticosteroids, depending on the type of keratitis (epithelial or stromal).⁴⁰ Furthermore, active ocular herpetic infections warrant urgent referral to an ophthalmologist.

Dupilumab-Associated Ocular Complications

Dupilumab, a monoclonal antibody that blocks IL-4 and IL-13 signaling, is the first biologic therapy to be approved for treatment of moderate to severe AD. Prior clinical trials have described a higher incidence of anterior conjunctivitis in dupilumab-treated AD patients (5%–28%) compared to placebo (2%–11%).⁴¹ Of note, the incidence may be as high as 70%, as reported in a recent case series.⁴² Interestingly, independent trials assessing dupilumab treatment in asthma, nasal polyposis, and eosinophilic esophagitis patients did not observe a higher incidence of conjunctivitis in dupilumab-treated patients compared to placebo, suggesting an AD-specific mechanism.⁴³

Prominent features of dupilumab-associated conjunctivitis include hyperemia of the conjunctiva and limbus, in addition to ocular symptoms such as tearing, burning, and bilateral decrease in visual acuity. Marked reduction of conjunctival goblet cells has been reported.⁴⁴ In addition to conjunctivitis, blepharitis also has been reported during dupilumab treatment.⁴⁵

Standardized treatment guidelines for dupilumab-associated ocular complications have not yet been established. Surprisingly, antihistamine eye drops appear to be inefficacious in the treatment of dupilumab-associated conjunctivitis.⁴¹ However, the condition has been successfully managed with topical steroids (fluorometholone ophthalmic suspension 0.1%) and tacrolimus ointment 0.03%.⁴¹ Lifitegrast, an anti-inflammatory agent approved for chronic dry eye, also has been suggested as a treatment option for patients refractory to topical steroids.⁴⁵ Alternatively, cessation of dupilumab could be considered in AD patients who experience severe ocular complications. Atopic dermatitis patients taking dupilumab who have any concerning signs for ocular complications should be referred to an ophthalmologist for further diagnosis and management.

Conclusion

Practicing dermatologists likely will encounter patients with concurrent AD and ocular complications. Although eye examinations are not routinely performed in the care of AD patients, dermatologists can proactively inquire about ocular symptoms and monitor patients longitudinally. Early diagnosis and treatment of these ocular conditions can prevent vision loss in these patients. Furthermore, symptomatic control of AD and careful consideration of the side-effect profiles of medications can potentially reduce the incidence of ocular complications in individuals with AD.

Patients with visual concerns or risk factors, such as a history of vigorous eye rubbing or chronic corticosteroid use, should be jointly managed with an ophthalmologist for optimized care. Moreover, acute exacerbations of ocular symptoms and visual deterioration warrant urgent referral to ophthalmology.

Sorbitan sesquioleate (SSO), sorbitan monooleate (SMO), and related compounds are increasingly recognized contact allergens. Sorbitan sesquioleate and SMO are nonionic emulsifying agents derived from sorbitol.¹

Sorbitan sesquioleate, SMO, and other sorbitol derivatives are used as emulsifiers and dispersing agents in cosmetics, topical medications, topical emollients, produce, and other commercial products. Related compounds also are found in foods such as apples, berries, cherries, and sucrose-free cakes and cookies.¹ We present a case of allergic contact dermatitis (ACD) with positive patch testing to sorbitans and clinical correlation with beer and bread exposure.

Case Report

A 62-year-old man presented with a persistent pruritic rash of 6 months’ duration. Erythematous eczematous papules and plaques were observed on the face, neck, chest, abdomen, back, and upper and lower extremities, affecting approximately 60% of the body surface area. His current list of medications was reviewed and included a multivitamin, fish oil, and vitamin C. A punch biopsy revealed spongiotic dermatitis with eosinophils. Patch testing using the North American Contact Dermatitis Group Standard Series with supplemental allergens found in toiletries revealed a positive reaction to SSO and SMO that was persistent at 48 and 96 hours. Notably, patch testing for sodium benzoate, nickel, potassium dichromate, and balsam of Peru were negative. Investigation into the personal care products the patient used identified the presence of sorbitol solution in Vanicream bar soap and Vanicream moisturizing cream (Pharmaceutical Specialties Inc). These products were started after the development of the rash and were discontinued after positive patch testing, but the patient continued to experience the eruption with no improvement.

Retrospectively, the patient was able to correlate exacerbations with drinking beer and eating sandwiches. He habitually ate a sandwich on the same type of bread every single day and enjoyed the same brand of beer 2 to 4 times per week without much variation. To limit allergens, the patient gave up the daily sandwich and avoided bread altogether, noting remarkable clinical improvement over a few weeks. Later, he described even more improvement while on a trip where he did not have access to his usual beer. The eruption recurred when he returned home and excessively indulged in his favorite beer. He also noted recurrence with exposure to certain breads. No new lesions developed with avoidance of beer and bread, and he had less than 1% body surface area involvement at 2-month follow-up and 0% involvement at 1 year. For educational purposes, follow-up patch testing was performed using Vanicream sorbitol solution and the specific beer and bread the patient consumed. The Vanicream solution was obtained from the manufacturer. The beer was placed directly onto a test disc. The bread was moistened with a drop of saline and then placed directly onto a test disc. All were negative at 48 and 96 hours.

Comment

Sorbitol Ingredients
We report a case of systemic ACD with a positive patch test to sorbitans that was exacerbated with consumption of beer and bread and resolved with avoidance of these products. Although it was determined that the patient used personal care products containing a sorbitol solution, discontinuation did not result in clinical improvement. Sorbitol, sorbitans, and sorbitol derivatives are not commonly reported in the ingredient lists of foods such as beer and bread. Both beer and bread are created with the addition of yeast cultures, for fermentation in beer and for leavening in bread. Sorbitol is used as an osmotic stabilizer in the preparation of yeast strains² and also is a by-product of fermentation by certain bacteria³ found in beer. Additionally, review of commercially available preparations of baker’s and brewer’s yeasts, such as Fleischmann’s and Red Star, list sorbitan monostearate in the ingredients.^4-7 We propose that trace amounts are present in the yeast preparations for brewing and baking.

In this case, the offending beer and bread were locally made products (Abita Beer, Covington, Louisiana; Leidenheimer Bread, New Orleans, Louisiana). Both companies were unable to share their yeast sources, limiting our ability to confirm the use of sorbitol in their preparation. We hypothesize that if sorbitol is commonly used in yeast culture preparation and can be a by-product of fermentation, then it is present in trace amounts in many beers and breads and is not specific to these two products.

Contact Allergy
There are few prior reports of ACD due to beer. A case series in 1969 described 4 patients with positive patch testing to ethanol and alcohol by-products and clinical resolution with avoidance of alcohol.⁸ Another case from 1985 described ACD to beer where patch testing was positive to the beer itself.⁹ Other published cases of cutaneous reactions to beer demonstrated immediate-type hypersensitivity resulting from both ingestion and skin contact, which is thought to be caused by IgE antibodies to malt and barley proteins.^10,11

It is important to distinguish between systemic ACD and oral allergy syndrome (OAS). Although the defining features and criteria for diagnosing OAS have not been officially established, OAS is an IgE-mediated immune reaction commonly described as itching, tingling, or swelling, usually confined to the oral cavity after recent consumption of foods such as raw fruits, vegetables, and nuts.¹² Oral allergy syndrome is treated with antihistamines and avoidance of known food allergens. In comparison, ACD is a type IV hypersensitivity, delayed cell-mediated reaction, commonly presenting with widespread rash.

Occupational contact dermatitis is common in bakers and food handlers and is more often irritant than allergic. Several relevant allergens have been identified in these groups^13,14 and do not include sorbitans; our patient tested positive to both SSO and SMO. Sorbitan sesquioleate and SMO have been increasingly recognized as contact allergens over the last several years, both as standalone allergens and as potential cross-reactors.¹ Sorbitan sesquioleate, SMO, and other sorbitol derivatives are found in cosmetics, topical and oral medications, topical emollients, produce, and other commercial products, including but not limited to topical clindamycin, topical metronidazole, topical ketoconazole, tazarotene cream 0.05% and 0.1%, toothpastes, acetaminophen maximum strength liquid, apples, berries, and sucrose-free cakes and cookies.^1,15,16

In 2014, a study evaluated 12 oral antihistamines as potential sources for systemic contact allergens; 55% of these 12 oral antihistamine preparations included at least 1 of 10 allergen groups specifically identified. The sorbitans and sorbitol derivatives group ranked highest among the group of allergens found listed in these oral medications.¹⁷

Most patients found to have a contact allergy to the products containing SSO, SMO, or sorbitol derivatives reported notable improvement with discontinuation and change to sorbitol-free product use.^1,18 It should be noted that SSO is added as an emulsifier to many of the fragrances used for patch testing. A positive patch test to fragrance mix without concomitant sorbitan testing may incorrectly diagnose the allergen.¹⁹

Patients with atopic dermatitis, particularly those with a filaggrin mutation, are at increased risk for ACD to sorbitans due to a compromised skin barrier and frequent use of topical steroids. In one study, 75% of patients (n=12) with a positive patch test to SSO were using a topical steroid emulsified with sorbitol or sorbitan derivatives.¹⁹

Conclusion

Sorbitan sesquioleate and SMO are increasingly relevant contact allergens. Sorbitol and related substances have been identified in numerous products and may be present in yeast-fermented and leavened goods. When patch testing is positive to SSO and SMO, the dermatologist should inquire about dietary habits with specific attention to beer and bread, in addition to inventorying other dietary preferences, prescription and over-the-counter medications, and personal care products. We suggest dietary considerations only if topical exposures have been eliminated and the rash has not improved.

Sorbitan sesquioleate (SSO), sorbitan monooleate (SMO), and related compounds are increasingly recognized contact allergens. Sorbitan sesquioleate and SMO are nonionic emulsifying agents derived from sorbitol.¹

Sorbitan sesquioleate, SMO, and other sorbitol derivatives are used as emulsifiers and dispersing agents in cosmetics, topical medications, topical emollients, produce, and other commercial products. Related compounds also are found in foods such as apples, berries, cherries, and sucrose-free cakes and cookies.¹ We present a case of allergic contact dermatitis (ACD) with positive patch testing to sorbitans and clinical correlation with beer and bread exposure.

Case Report

A 62-year-old man presented with a persistent pruritic rash of 6 months’ duration. Erythematous eczematous papules and plaques were observed on the face, neck, chest, abdomen, back, and upper and lower extremities, affecting approximately 60% of the body surface area. His current list of medications was reviewed and included a multivitamin, fish oil, and vitamin C. A punch biopsy revealed spongiotic dermatitis with eosinophils. Patch testing using the North American Contact Dermatitis Group Standard Series with supplemental allergens found in toiletries revealed a positive reaction to SSO and SMO that was persistent at 48 and 96 hours. Notably, patch testing for sodium benzoate, nickel, potassium dichromate, and balsam of Peru were negative. Investigation into the personal care products the patient used identified the presence of sorbitol solution in Vanicream bar soap and Vanicream moisturizing cream (Pharmaceutical Specialties Inc). These products were started after the development of the rash and were discontinued after positive patch testing, but the patient continued to experience the eruption with no improvement.

Retrospectively, the patient was able to correlate exacerbations with drinking beer and eating sandwiches. He habitually ate a sandwich on the same type of bread every single day and enjoyed the same brand of beer 2 to 4 times per week without much variation. To limit allergens, the patient gave up the daily sandwich and avoided bread altogether, noting remarkable clinical improvement over a few weeks. Later, he described even more improvement while on a trip where he did not have access to his usual beer. The eruption recurred when he returned home and excessively indulged in his favorite beer. He also noted recurrence with exposure to certain breads. No new lesions developed with avoidance of beer and bread, and he had less than 1% body surface area involvement at 2-month follow-up and 0% involvement at 1 year. For educational purposes, follow-up patch testing was performed using Vanicream sorbitol solution and the specific beer and bread the patient consumed. The Vanicream solution was obtained from the manufacturer. The beer was placed directly onto a test disc. The bread was moistened with a drop of saline and then placed directly onto a test disc. All were negative at 48 and 96 hours.

Comment

Sorbitol Ingredients
We report a case of systemic ACD with a positive patch test to sorbitans that was exacerbated with consumption of beer and bread and resolved with avoidance of these products. Although it was determined that the patient used personal care products containing a sorbitol solution, discontinuation did not result in clinical improvement. Sorbitol, sorbitans, and sorbitol derivatives are not commonly reported in the ingredient lists of foods such as beer and bread. Both beer and bread are created with the addition of yeast cultures, for fermentation in beer and for leavening in bread. Sorbitol is used as an osmotic stabilizer in the preparation of yeast strains² and also is a by-product of fermentation by certain bacteria³ found in beer. Additionally, review of commercially available preparations of baker’s and brewer’s yeasts, such as Fleischmann’s and Red Star, list sorbitan monostearate in the ingredients.^4-7 We propose that trace amounts are present in the yeast preparations for brewing and baking.

In this case, the offending beer and bread were locally made products (Abita Beer, Covington, Louisiana; Leidenheimer Bread, New Orleans, Louisiana). Both companies were unable to share their yeast sources, limiting our ability to confirm the use of sorbitol in their preparation. We hypothesize that if sorbitol is commonly used in yeast culture preparation and can be a by-product of fermentation, then it is present in trace amounts in many beers and breads and is not specific to these two products.

Contact Allergy
There are few prior reports of ACD due to beer. A case series in 1969 described 4 patients with positive patch testing to ethanol and alcohol by-products and clinical resolution with avoidance of alcohol.⁸ Another case from 1985 described ACD to beer where patch testing was positive to the beer itself.⁹ Other published cases of cutaneous reactions to beer demonstrated immediate-type hypersensitivity resulting from both ingestion and skin contact, which is thought to be caused by IgE antibodies to malt and barley proteins.^10,11

It is important to distinguish between systemic ACD and oral allergy syndrome (OAS). Although the defining features and criteria for diagnosing OAS have not been officially established, OAS is an IgE-mediated immune reaction commonly described as itching, tingling, or swelling, usually confined to the oral cavity after recent consumption of foods such as raw fruits, vegetables, and nuts.¹² Oral allergy syndrome is treated with antihistamines and avoidance of known food allergens. In comparison, ACD is a type IV hypersensitivity, delayed cell-mediated reaction, commonly presenting with widespread rash.

Occupational contact dermatitis is common in bakers and food handlers and is more often irritant than allergic. Several relevant allergens have been identified in these groups^13,14 and do not include sorbitans; our patient tested positive to both SSO and SMO. Sorbitan sesquioleate and SMO have been increasingly recognized as contact allergens over the last several years, both as standalone allergens and as potential cross-reactors.¹ Sorbitan sesquioleate, SMO, and other sorbitol derivatives are found in cosmetics, topical and oral medications, topical emollients, produce, and other commercial products, including but not limited to topical clindamycin, topical metronidazole, topical ketoconazole, tazarotene cream 0.05% and 0.1%, toothpastes, acetaminophen maximum strength liquid, apples, berries, and sucrose-free cakes and cookies.^1,15,16

In 2014, a study evaluated 12 oral antihistamines as potential sources for systemic contact allergens; 55% of these 12 oral antihistamine preparations included at least 1 of 10 allergen groups specifically identified. The sorbitans and sorbitol derivatives group ranked highest among the group of allergens found listed in these oral medications.¹⁷

Most patients found to have a contact allergy to the products containing SSO, SMO, or sorbitol derivatives reported notable improvement with discontinuation and change to sorbitol-free product use.^1,18 It should be noted that SSO is added as an emulsifier to many of the fragrances used for patch testing. A positive patch test to fragrance mix without concomitant sorbitan testing may incorrectly diagnose the allergen.¹⁹

Patients with atopic dermatitis, particularly those with a filaggrin mutation, are at increased risk for ACD to sorbitans due to a compromised skin barrier and frequent use of topical steroids. In one study, 75% of patients (n=12) with a positive patch test to SSO were using a topical steroid emulsified with sorbitol or sorbitan derivatives.¹⁹

Conclusion

Sorbitan sesquioleate and SMO are increasingly relevant contact allergens. Sorbitol and related substances have been identified in numerous products and may be present in yeast-fermented and leavened goods. When patch testing is positive to SSO and SMO, the dermatologist should inquire about dietary habits with specific attention to beer and bread, in addition to inventorying other dietary preferences, prescription and over-the-counter medications, and personal care products. We suggest dietary considerations only if topical exposures have been eliminated and the rash has not improved.

Sorbitan sesquioleate (SSO), sorbitan monooleate (SMO), and related compounds are increasingly recognized contact allergens. Sorbitan sesquioleate and SMO are nonionic emulsifying agents derived from sorbitol.¹

Sorbitan sesquioleate, SMO, and other sorbitol derivatives are used as emulsifiers and dispersing agents in cosmetics, topical medications, topical emollients, produce, and other commercial products. Related compounds also are found in foods such as apples, berries, cherries, and sucrose-free cakes and cookies.¹ We present a case of allergic contact dermatitis (ACD) with positive patch testing to sorbitans and clinical correlation with beer and bread exposure.

Case Report

A 62-year-old man presented with a persistent pruritic rash of 6 months’ duration. Erythematous eczematous papules and plaques were observed on the face, neck, chest, abdomen, back, and upper and lower extremities, affecting approximately 60% of the body surface area. His current list of medications was reviewed and included a multivitamin, fish oil, and vitamin C. A punch biopsy revealed spongiotic dermatitis with eosinophils. Patch testing using the North American Contact Dermatitis Group Standard Series with supplemental allergens found in toiletries revealed a positive reaction to SSO and SMO that was persistent at 48 and 96 hours. Notably, patch testing for sodium benzoate, nickel, potassium dichromate, and balsam of Peru were negative. Investigation into the personal care products the patient used identified the presence of sorbitol solution in Vanicream bar soap and Vanicream moisturizing cream (Pharmaceutical Specialties Inc). These products were started after the development of the rash and were discontinued after positive patch testing, but the patient continued to experience the eruption with no improvement.

Retrospectively, the patient was able to correlate exacerbations with drinking beer and eating sandwiches. He habitually ate a sandwich on the same type of bread every single day and enjoyed the same brand of beer 2 to 4 times per week without much variation. To limit allergens, the patient gave up the daily sandwich and avoided bread altogether, noting remarkable clinical improvement over a few weeks. Later, he described even more improvement while on a trip where he did not have access to his usual beer. The eruption recurred when he returned home and excessively indulged in his favorite beer. He also noted recurrence with exposure to certain breads. No new lesions developed with avoidance of beer and bread, and he had less than 1% body surface area involvement at 2-month follow-up and 0% involvement at 1 year. For educational purposes, follow-up patch testing was performed using Vanicream sorbitol solution and the specific beer and bread the patient consumed. The Vanicream solution was obtained from the manufacturer. The beer was placed directly onto a test disc. The bread was moistened with a drop of saline and then placed directly onto a test disc. All were negative at 48 and 96 hours.

Comment

Sorbitol Ingredients
We report a case of systemic ACD with a positive patch test to sorbitans that was exacerbated with consumption of beer and bread and resolved with avoidance of these products. Although it was determined that the patient used personal care products containing a sorbitol solution, discontinuation did not result in clinical improvement. Sorbitol, sorbitans, and sorbitol derivatives are not commonly reported in the ingredient lists of foods such as beer and bread. Both beer and bread are created with the addition of yeast cultures, for fermentation in beer and for leavening in bread. Sorbitol is used as an osmotic stabilizer in the preparation of yeast strains² and also is a by-product of fermentation by certain bacteria³ found in beer. Additionally, review of commercially available preparations of baker’s and brewer’s yeasts, such as Fleischmann’s and Red Star, list sorbitan monostearate in the ingredients.^4-7 We propose that trace amounts are present in the yeast preparations for brewing and baking.

In this case, the offending beer and bread were locally made products (Abita Beer, Covington, Louisiana; Leidenheimer Bread, New Orleans, Louisiana). Both companies were unable to share their yeast sources, limiting our ability to confirm the use of sorbitol in their preparation. We hypothesize that if sorbitol is commonly used in yeast culture preparation and can be a by-product of fermentation, then it is present in trace amounts in many beers and breads and is not specific to these two products.

Contact Allergy
There are few prior reports of ACD due to beer. A case series in 1969 described 4 patients with positive patch testing to ethanol and alcohol by-products and clinical resolution with avoidance of alcohol.⁸ Another case from 1985 described ACD to beer where patch testing was positive to the beer itself.⁹ Other published cases of cutaneous reactions to beer demonstrated immediate-type hypersensitivity resulting from both ingestion and skin contact, which is thought to be caused by IgE antibodies to malt and barley proteins.^10,11

It is important to distinguish between systemic ACD and oral allergy syndrome (OAS). Although the defining features and criteria for diagnosing OAS have not been officially established, OAS is an IgE-mediated immune reaction commonly described as itching, tingling, or swelling, usually confined to the oral cavity after recent consumption of foods such as raw fruits, vegetables, and nuts.¹² Oral allergy syndrome is treated with antihistamines and avoidance of known food allergens. In comparison, ACD is a type IV hypersensitivity, delayed cell-mediated reaction, commonly presenting with widespread rash.

Occupational contact dermatitis is common in bakers and food handlers and is more often irritant than allergic. Several relevant allergens have been identified in these groups^13,14 and do not include sorbitans; our patient tested positive to both SSO and SMO. Sorbitan sesquioleate and SMO have been increasingly recognized as contact allergens over the last several years, both as standalone allergens and as potential cross-reactors.¹ Sorbitan sesquioleate, SMO, and other sorbitol derivatives are found in cosmetics, topical and oral medications, topical emollients, produce, and other commercial products, including but not limited to topical clindamycin, topical metronidazole, topical ketoconazole, tazarotene cream 0.05% and 0.1%, toothpastes, acetaminophen maximum strength liquid, apples, berries, and sucrose-free cakes and cookies.^1,15,16

In 2014, a study evaluated 12 oral antihistamines as potential sources for systemic contact allergens; 55% of these 12 oral antihistamine preparations included at least 1 of 10 allergen groups specifically identified. The sorbitans and sorbitol derivatives group ranked highest among the group of allergens found listed in these oral medications.¹⁷

Most patients found to have a contact allergy to the products containing SSO, SMO, or sorbitol derivatives reported notable improvement with discontinuation and change to sorbitol-free product use.^1,18 It should be noted that SSO is added as an emulsifier to many of the fragrances used for patch testing. A positive patch test to fragrance mix without concomitant sorbitan testing may incorrectly diagnose the allergen.¹⁹

Patients with atopic dermatitis, particularly those with a filaggrin mutation, are at increased risk for ACD to sorbitans due to a compromised skin barrier and frequent use of topical steroids. In one study, 75% of patients (n=12) with a positive patch test to SSO were using a topical steroid emulsified with sorbitol or sorbitan derivatives.¹⁹

Conclusion

Sorbitan sesquioleate and SMO are increasingly relevant contact allergens. Sorbitol and related substances have been identified in numerous products and may be present in yeast-fermented and leavened goods. When patch testing is positive to SSO and SMO, the dermatologist should inquire about dietary habits with specific attention to beer and bread, in addition to inventorying other dietary preferences, prescription and over-the-counter medications, and personal care products. We suggest dietary considerations only if topical exposures have been eliminated and the rash has not improved.

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.