Patients with moderate to severe atopic dermatitis who received the immunoglobulin G1 anti–interleukin-33 monoclonal antibody etokimab showed significant disease improvement 29 days after receiving a single systemic administration, according to results from a recent proof-of-concept, phase IIa study.

“Most of the focus for IL-33 pathway inhibition has been on the type 2 cytokine axis because of significant supporting genetic and functional data in both human and murine systems,” Yi-Ling Chen, a DPhil student at the University of Oxford (England), and colleagues wrote in Science Translational Medicine. “Our findings might also provide a further dimension to explain how etokimab, by inhibiting IL-33, could provide such a rapid and persistent clinical benefit as described in this report.”

In their study, 12 patients with moderate to severe AD received etokimab in a single intravenous dose of 300 mg. Prior to receiving etokimab, patients received a placebo dose and then underwent saline or house dust mite intraepidermal challenge, with researchers obtaining blister samples 1 day after challenge following placebo administration and again after patients received etokimab.

At 29 days, 83% of patients reached rapid and sustained clinical benefit under Eczema Area and Severity Index (EASI ) 50 and 33% in EASI 75, including peripheral eosinophil reduction. There also was significant reduction in skin neutrophil infiltration after patients received etokimab and then house dust mite challenge, compared with after they received placebo, .

“These findings open new therapeutic possible applications of etokimab to sterile neutrophilic disease as well as other inflammatory diseases with a clear neutrophilic involvement such as neutrophilic asthma,” the researchers said. “This first-in-class experimental medicine study has shown that in vivo in human tissue IL-33 has key upstream effects which broadly influence different and relevant inflammatory cascades and thus widen the potential of this treatment to a larger than anticipated group of diseases.

“Although excellent previous studies have demonstrated in vitro and in murine models that IL-33 is involved in neutrophil migration, the translation here to human tissue immunology shows that IL-33 plays a dominant role and effects are in part likely to be mediated instead by CXCR1,” concluded Ms. Chen and colleagues. “Therefore, specific IL-33 therapeutic intervention is not targeting a redundant system and is worthy of further investigation.”

This study was funded by AnaptysBio, which was responsible for the conception and design of the study. AnaptysBio also helped in part to analyze and interpret the data from the study, and approved it for submission. Dr. Ogg reported having served on an advisory board, as a consultant, or holds equity in Eli Lilly, Novartis, Janssen, Orbit Discovery, and UCB Pharma. Ms. Marquette and Dr. Londei reported being employees of AnaptysBio.

SOURCE: Chen Y-L et al. Sci Transl Med. 2019. doi: 10.1126/scitranslmed.aax2945.

Patients with moderate to severe atopic dermatitis who received the immunoglobulin G1 anti–interleukin-33 monoclonal antibody etokimab showed significant disease improvement 29 days after receiving a single systemic administration, according to results from a recent proof-of-concept, phase IIa study.

“Most of the focus for IL-33 pathway inhibition has been on the type 2 cytokine axis because of significant supporting genetic and functional data in both human and murine systems,” Yi-Ling Chen, a DPhil student at the University of Oxford (England), and colleagues wrote in Science Translational Medicine. “Our findings might also provide a further dimension to explain how etokimab, by inhibiting IL-33, could provide such a rapid and persistent clinical benefit as described in this report.”

In their study, 12 patients with moderate to severe AD received etokimab in a single intravenous dose of 300 mg. Prior to receiving etokimab, patients received a placebo dose and then underwent saline or house dust mite intraepidermal challenge, with researchers obtaining blister samples 1 day after challenge following placebo administration and again after patients received etokimab.

At 29 days, 83% of patients reached rapid and sustained clinical benefit under Eczema Area and Severity Index (EASI ) 50 and 33% in EASI 75, including peripheral eosinophil reduction. There also was significant reduction in skin neutrophil infiltration after patients received etokimab and then house dust mite challenge, compared with after they received placebo, .

“These findings open new therapeutic possible applications of etokimab to sterile neutrophilic disease as well as other inflammatory diseases with a clear neutrophilic involvement such as neutrophilic asthma,” the researchers said. “This first-in-class experimental medicine study has shown that in vivo in human tissue IL-33 has key upstream effects which broadly influence different and relevant inflammatory cascades and thus widen the potential of this treatment to a larger than anticipated group of diseases.

“Although excellent previous studies have demonstrated in vitro and in murine models that IL-33 is involved in neutrophil migration, the translation here to human tissue immunology shows that IL-33 plays a dominant role and effects are in part likely to be mediated instead by CXCR1,” concluded Ms. Chen and colleagues. “Therefore, specific IL-33 therapeutic intervention is not targeting a redundant system and is worthy of further investigation.”

This study was funded by AnaptysBio, which was responsible for the conception and design of the study. AnaptysBio also helped in part to analyze and interpret the data from the study, and approved it for submission. Dr. Ogg reported having served on an advisory board, as a consultant, or holds equity in Eli Lilly, Novartis, Janssen, Orbit Discovery, and UCB Pharma. Ms. Marquette and Dr. Londei reported being employees of AnaptysBio.

SOURCE: Chen Y-L et al. Sci Transl Med. 2019. doi: 10.1126/scitranslmed.aax2945.

Patients with moderate to severe atopic dermatitis who received the immunoglobulin G1 anti–interleukin-33 monoclonal antibody etokimab showed significant disease improvement 29 days after receiving a single systemic administration, according to results from a recent proof-of-concept, phase IIa study.

“Most of the focus for IL-33 pathway inhibition has been on the type 2 cytokine axis because of significant supporting genetic and functional data in both human and murine systems,” Yi-Ling Chen, a DPhil student at the University of Oxford (England), and colleagues wrote in Science Translational Medicine. “Our findings might also provide a further dimension to explain how etokimab, by inhibiting IL-33, could provide such a rapid and persistent clinical benefit as described in this report.”

In their study, 12 patients with moderate to severe AD received etokimab in a single intravenous dose of 300 mg. Prior to receiving etokimab, patients received a placebo dose and then underwent saline or house dust mite intraepidermal challenge, with researchers obtaining blister samples 1 day after challenge following placebo administration and again after patients received etokimab.

At 29 days, 83% of patients reached rapid and sustained clinical benefit under Eczema Area and Severity Index (EASI ) 50 and 33% in EASI 75, including peripheral eosinophil reduction. There also was significant reduction in skin neutrophil infiltration after patients received etokimab and then house dust mite challenge, compared with after they received placebo, .

“These findings open new therapeutic possible applications of etokimab to sterile neutrophilic disease as well as other inflammatory diseases with a clear neutrophilic involvement such as neutrophilic asthma,” the researchers said. “This first-in-class experimental medicine study has shown that in vivo in human tissue IL-33 has key upstream effects which broadly influence different and relevant inflammatory cascades and thus widen the potential of this treatment to a larger than anticipated group of diseases.

“Although excellent previous studies have demonstrated in vitro and in murine models that IL-33 is involved in neutrophil migration, the translation here to human tissue immunology shows that IL-33 plays a dominant role and effects are in part likely to be mediated instead by CXCR1,” concluded Ms. Chen and colleagues. “Therefore, specific IL-33 therapeutic intervention is not targeting a redundant system and is worthy of further investigation.”

This study was funded by AnaptysBio, which was responsible for the conception and design of the study. AnaptysBio also helped in part to analyze and interpret the data from the study, and approved it for submission. Dr. Ogg reported having served on an advisory board, as a consultant, or holds equity in Eli Lilly, Novartis, Janssen, Orbit Discovery, and UCB Pharma. Ms. Marquette and Dr. Londei reported being employees of AnaptysBio.

SOURCE: Chen Y-L et al. Sci Transl Med. 2019. doi: 10.1126/scitranslmed.aax2945.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

There is increasing evidence that exercise lowers the risk of developing cancer, improves survival after a cancer diagnosis, and helps ease related health outcomes. However, relatively few cancer patients meet current physical activity guidelines – often because it wasn’t recommended by their oncologist.

thinkstock

“Observed barriers to clinicians referring patients to exercise programming include lack of awareness of the potential value of exercise in cancer populations, uncertainty regarding the safety or suitability of exercise for a particular patient, lack of awareness regarding available programs to help facilitate exercise in cancer populations, need for education and skills development for making referrals, and a belief that referrals to exercise programming are not within the scope of practice for oncology clinicians,” Kathryn H. Schmitz, PhD, from Penn State University in Hershey and coauthors from the American College of Sports Medicine International Multidisciplinary Roundtable wrote in CA: A Cancer Journal for Clinicians.

Dr. Schmitz and colleagues proposed using the American College of Sports Medicine’s Exercise Is Medicine initiative to address this gap, with a focus on asking physicians to take an assess, revise, and refer approach to recommending exercise.

Noting that there is clear evidence that patients are more likely to exercise if their oncologist recommends that they do so, the authors said a clinician’s silence on the subject of exercise could be interpreted as “tacit approval to maintain inactivity.”

To assess a patient’s level of physical activity, the authors suggested asking patients how many days during the past week they had undertaken physical activity during which their heart beat faster or they breathed harder than normal for more than 30 minutes or how often they had undertaken activity to increase muscle strength.

If the patient can safely exercise without medical supervision, the authors recommend that clinicians advise patients to increase their physical activity to achieve current recommended levels. Clinicians can refer patients to community programs to help ramp up their activity.

However, for patients who may not be able to exercise safely on their own, the authors recommend referring them to an outpatient rehabiliation professional.

“Referral to appropriate and effective programs and follow-up with an assessment of progress (or lack thereof) at subsequent visits can serve as key transition points to change a patient’s behavior and affect their tolerance of or recovery from treatment,” they wrote.

The authors stressed that oncology clinicians were not expected to prescribe specific levels of exercise or to perform extensive screening and triage of patients based on their fitness.

“Oncology clinicians, however, play a vital role in telling the patient that it is important to exercise and pointing patients in the right direction to make that happen,” they wrote.

The American College of Sports Medicine International Multidisciplinary Roundtable was funded by the American College of Sports Medicine, the American Cancer Society, and other groups. Four authors declared grant support for participating in the study. One declared private industry funding unrelated to the study. No other conflicts of interest were declared.

hematologynews@mdedge.com

SOURCE: Schmitz K et al. CA Cancer J Clin. 2019 Oct 16. doi: 10.3322/caac.21579.

There is increasing evidence that exercise lowers the risk of developing cancer, improves survival after a cancer diagnosis, and helps ease related health outcomes. However, relatively few cancer patients meet current physical activity guidelines – often because it wasn’t recommended by their oncologist.

thinkstock

“Observed barriers to clinicians referring patients to exercise programming include lack of awareness of the potential value of exercise in cancer populations, uncertainty regarding the safety or suitability of exercise for a particular patient, lack of awareness regarding available programs to help facilitate exercise in cancer populations, need for education and skills development for making referrals, and a belief that referrals to exercise programming are not within the scope of practice for oncology clinicians,” Kathryn H. Schmitz, PhD, from Penn State University in Hershey and coauthors from the American College of Sports Medicine International Multidisciplinary Roundtable wrote in CA: A Cancer Journal for Clinicians.

Dr. Schmitz and colleagues proposed using the American College of Sports Medicine’s Exercise Is Medicine initiative to address this gap, with a focus on asking physicians to take an assess, revise, and refer approach to recommending exercise.

Noting that there is clear evidence that patients are more likely to exercise if their oncologist recommends that they do so, the authors said a clinician’s silence on the subject of exercise could be interpreted as “tacit approval to maintain inactivity.”

To assess a patient’s level of physical activity, the authors suggested asking patients how many days during the past week they had undertaken physical activity during which their heart beat faster or they breathed harder than normal for more than 30 minutes or how often they had undertaken activity to increase muscle strength.

If the patient can safely exercise without medical supervision, the authors recommend that clinicians advise patients to increase their physical activity to achieve current recommended levels. Clinicians can refer patients to community programs to help ramp up their activity.

However, for patients who may not be able to exercise safely on their own, the authors recommend referring them to an outpatient rehabiliation professional.

“Referral to appropriate and effective programs and follow-up with an assessment of progress (or lack thereof) at subsequent visits can serve as key transition points to change a patient’s behavior and affect their tolerance of or recovery from treatment,” they wrote.

The authors stressed that oncology clinicians were not expected to prescribe specific levels of exercise or to perform extensive screening and triage of patients based on their fitness.

“Oncology clinicians, however, play a vital role in telling the patient that it is important to exercise and pointing patients in the right direction to make that happen,” they wrote.

The American College of Sports Medicine International Multidisciplinary Roundtable was funded by the American College of Sports Medicine, the American Cancer Society, and other groups. Four authors declared grant support for participating in the study. One declared private industry funding unrelated to the study. No other conflicts of interest were declared.

hematologynews@mdedge.com

SOURCE: Schmitz K et al. CA Cancer J Clin. 2019 Oct 16. doi: 10.3322/caac.21579.

There is increasing evidence that exercise lowers the risk of developing cancer, improves survival after a cancer diagnosis, and helps ease related health outcomes. However, relatively few cancer patients meet current physical activity guidelines – often because it wasn’t recommended by their oncologist.

thinkstock

“Observed barriers to clinicians referring patients to exercise programming include lack of awareness of the potential value of exercise in cancer populations, uncertainty regarding the safety or suitability of exercise for a particular patient, lack of awareness regarding available programs to help facilitate exercise in cancer populations, need for education and skills development for making referrals, and a belief that referrals to exercise programming are not within the scope of practice for oncology clinicians,” Kathryn H. Schmitz, PhD, from Penn State University in Hershey and coauthors from the American College of Sports Medicine International Multidisciplinary Roundtable wrote in CA: A Cancer Journal for Clinicians.

Dr. Schmitz and colleagues proposed using the American College of Sports Medicine’s Exercise Is Medicine initiative to address this gap, with a focus on asking physicians to take an assess, revise, and refer approach to recommending exercise.

Noting that there is clear evidence that patients are more likely to exercise if their oncologist recommends that they do so, the authors said a clinician’s silence on the subject of exercise could be interpreted as “tacit approval to maintain inactivity.”

To assess a patient’s level of physical activity, the authors suggested asking patients how many days during the past week they had undertaken physical activity during which their heart beat faster or they breathed harder than normal for more than 30 minutes or how often they had undertaken activity to increase muscle strength.

If the patient can safely exercise without medical supervision, the authors recommend that clinicians advise patients to increase their physical activity to achieve current recommended levels. Clinicians can refer patients to community programs to help ramp up their activity.

However, for patients who may not be able to exercise safely on their own, the authors recommend referring them to an outpatient rehabiliation professional.

“Referral to appropriate and effective programs and follow-up with an assessment of progress (or lack thereof) at subsequent visits can serve as key transition points to change a patient’s behavior and affect their tolerance of or recovery from treatment,” they wrote.

The authors stressed that oncology clinicians were not expected to prescribe specific levels of exercise or to perform extensive screening and triage of patients based on their fitness.

“Oncology clinicians, however, play a vital role in telling the patient that it is important to exercise and pointing patients in the right direction to make that happen,” they wrote.

The American College of Sports Medicine International Multidisciplinary Roundtable was funded by the American College of Sports Medicine, the American Cancer Society, and other groups. Four authors declared grant support for participating in the study. One declared private industry funding unrelated to the study. No other conflicts of interest were declared.

hematologynews@mdedge.com

SOURCE: Schmitz K et al. CA Cancer J Clin. 2019 Oct 16. doi: 10.3322/caac.21579.

MADRID – Do you ask your acne patients if they use cannabis? And if they say yes, do you suggest they consider giving it up? Dermatologist Delphine Kerob, MD, believes you should.

Bruce Jancin/MDedge News

In a late-breaker session at the annual congress of the European Academy of Dermatology and Venereology, she presented highlights of a massive international, industry-sponsored survey aimed at identifying novel external and internal factors that influence acne. One of the biggest surprises in this first-of-its-kind study was the finding of an association between cannabis use and acne: 21.1% of patients with physician-diagnosed acne were users, compared with 16.6% of controls without acne.

“I think as dermatologists we should ask these kinds of questions when we manage our patients because this may influence the course of their acne,” observed Dr. Kerob, who is the international medical director for Vichy Laboratories in Paris. The survey was sponsored by the company.

This was an Internet-based survey of 2,826 acne patients and 3,853 age- and sex-matched controls without acne. It was conducted in Canada, France, Germany, Italy, Brazil, and Russia.

The survey comprehensively addressed for the first time what lead investigator Brigitte Dreno, MD, PhD, professor and head of dermatology at Nantes (France) University Hospital and EADV Scientific Programming Committee Chair, has previously called the “acne exposome.” The exposome is essentially everything in a patient’s external and internal environment – other than genetics – that influences the occurrence and severity of the disease (J Eur Acad Dermatol Venereol. 2018 May;32[5]:812-9).

The survey probed the six major categories of exposome factors as defined by Dr. Dreno and coauthors: nutrition, air pollution, lifestyle and psychological factors, medications, skin care products, and climate. Here are the highlights:
 

Lifestyle and psychological factors. While cannabis use emerged as a novel factor linked to increased likelihood of acne, tobacco use was not – a surprising finding because other investigators had previously identified it as an acne trigger.

Feeling burdened by psychological stress was reported by 51% of acne patients and 29% of controls, for an adjusted 1.79-fold increased risk of acne.

Air pollution. Acne patients were significantly more likely to report exposure to solvent vapors, crude oil, tars, frying oil vapors, and living near an airport or close to factories with chimneys. Dr. Kerob noted that these findings are consistent with other investigators’ study of 189 residents of heavily polluted Mexico City or more pristine Cuernavaca, Mexico, with less pollution. The Mexico City cohort demonstrated an increased sebum excretion rate, lower levels of the antioxidants vitamin E and squalene in their sebum, and a less cohesive stratum corneum, along with a higher prevalence of atopic skin and facial seborrheic changes (Int J Cosmet Sci. 2015 Jun;37[3]:329-38).

Nutrition. This is a hot topic that acne patients have many questions about. Myths abound, as detailed by an expert panel including Dr. Dreno in an article entitled, “Acne and Nutrition: Hypotheses, Myths and Facts” (J Eur Acad Dermatol Venereol. 2018 Oct;32[10]:1631-7).

Dr. Kerob reported that the survey showed consumption of dairy products, probiotics, chocolate, cakes and other sweets, soft drinks, fruit juice, and whey protein were each associated with a significantly increased likelihood of acne .

Fifty-seven percent of acne patients indicated they consumed high-alcohol distilled spirits, compared with 43% of controls.

“We know that on our sebaceous glands, as well as on keratinocytes, we have receptors that will be activated by the impact of some nutrients,” she commented.

Among these receptors on sebaceous glands are the insulin growth factor–1 receptor, the leptin receptor, histamine receptors, receptors for substance P, peroxisome proliferator-activated receptors alpha, beta, and gamma, and androgen receptors, she added.

Medications. For Dr. Kerob, another surprise study finding was that 11.9% of acne patients had used an anabolic steroid- or testosterone-based hormonal drug within the previous 12 months, compared with 3.2% of controls without acne.

Cosmetic factors. The use of facial scrubs, harsh cleansers, and dermarollers was significantly more common among the acne patients.

Climate. Acne patients were more likely to live in hot and/or humid locations. For example, 24.6% of the acne group lived in a hot climate, versus 17.1% of controls.

“We think that identifying and reducing the impact of the exposome is very important for an adequate and holistic acne disease management,” the researcher concluded.

However, Eric Simpson, MD, rose from the audience to comment that he finds this plethora of associations to be of little use in advising his acne patients in clinical practice. For example, does cannabis use cause acne, or are acne patients more likely to be cannabis users as a means of coping with the social stigma surrounding their skin disease?

“I’d just caution about confounding association with causation. Let’s look at trials of removing that association to see if it actually improves acne before we make strong recommendations in the clinic,” urged Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.

“You’re perfectly right, there,” Dr. Kerob replied. “The methodology of our study can’t separate cause from effect. But as dermatologists, if we have patients with acne that’s resistant to treatment, we need to see if there are other factors that could worsen acne outcome. And we have patients asking us questions all the time about nutrition – now we have some answers that we can provide to those patients.”

The study was sponsored by Vichy Laboratories, and Dr. Kerob is an employee of the company.
 

bjancin@mdedge.com

MADRID – Do you ask your acne patients if they use cannabis? And if they say yes, do you suggest they consider giving it up? Dermatologist Delphine Kerob, MD, believes you should.

Bruce Jancin/MDedge News

In a late-breaker session at the annual congress of the European Academy of Dermatology and Venereology, she presented highlights of a massive international, industry-sponsored survey aimed at identifying novel external and internal factors that influence acne. One of the biggest surprises in this first-of-its-kind study was the finding of an association between cannabis use and acne: 21.1% of patients with physician-diagnosed acne were users, compared with 16.6% of controls without acne.

“I think as dermatologists we should ask these kinds of questions when we manage our patients because this may influence the course of their acne,” observed Dr. Kerob, who is the international medical director for Vichy Laboratories in Paris. The survey was sponsored by the company.

This was an Internet-based survey of 2,826 acne patients and 3,853 age- and sex-matched controls without acne. It was conducted in Canada, France, Germany, Italy, Brazil, and Russia.

The survey comprehensively addressed for the first time what lead investigator Brigitte Dreno, MD, PhD, professor and head of dermatology at Nantes (France) University Hospital and EADV Scientific Programming Committee Chair, has previously called the “acne exposome.” The exposome is essentially everything in a patient’s external and internal environment – other than genetics – that influences the occurrence and severity of the disease (J Eur Acad Dermatol Venereol. 2018 May;32[5]:812-9).

The survey probed the six major categories of exposome factors as defined by Dr. Dreno and coauthors: nutrition, air pollution, lifestyle and psychological factors, medications, skin care products, and climate. Here are the highlights:
 

Lifestyle and psychological factors. While cannabis use emerged as a novel factor linked to increased likelihood of acne, tobacco use was not – a surprising finding because other investigators had previously identified it as an acne trigger.

Feeling burdened by psychological stress was reported by 51% of acne patients and 29% of controls, for an adjusted 1.79-fold increased risk of acne.

Air pollution. Acne patients were significantly more likely to report exposure to solvent vapors, crude oil, tars, frying oil vapors, and living near an airport or close to factories with chimneys. Dr. Kerob noted that these findings are consistent with other investigators’ study of 189 residents of heavily polluted Mexico City or more pristine Cuernavaca, Mexico, with less pollution. The Mexico City cohort demonstrated an increased sebum excretion rate, lower levels of the antioxidants vitamin E and squalene in their sebum, and a less cohesive stratum corneum, along with a higher prevalence of atopic skin and facial seborrheic changes (Int J Cosmet Sci. 2015 Jun;37[3]:329-38).

Nutrition. This is a hot topic that acne patients have many questions about. Myths abound, as detailed by an expert panel including Dr. Dreno in an article entitled, “Acne and Nutrition: Hypotheses, Myths and Facts” (J Eur Acad Dermatol Venereol. 2018 Oct;32[10]:1631-7).

Dr. Kerob reported that the survey showed consumption of dairy products, probiotics, chocolate, cakes and other sweets, soft drinks, fruit juice, and whey protein were each associated with a significantly increased likelihood of acne .

Fifty-seven percent of acne patients indicated they consumed high-alcohol distilled spirits, compared with 43% of controls.

“We know that on our sebaceous glands, as well as on keratinocytes, we have receptors that will be activated by the impact of some nutrients,” she commented.

Among these receptors on sebaceous glands are the insulin growth factor–1 receptor, the leptin receptor, histamine receptors, receptors for substance P, peroxisome proliferator-activated receptors alpha, beta, and gamma, and androgen receptors, she added.

Medications. For Dr. Kerob, another surprise study finding was that 11.9% of acne patients had used an anabolic steroid- or testosterone-based hormonal drug within the previous 12 months, compared with 3.2% of controls without acne.

Cosmetic factors. The use of facial scrubs, harsh cleansers, and dermarollers was significantly more common among the acne patients.

Climate. Acne patients were more likely to live in hot and/or humid locations. For example, 24.6% of the acne group lived in a hot climate, versus 17.1% of controls.

“We think that identifying and reducing the impact of the exposome is very important for an adequate and holistic acne disease management,” the researcher concluded.

However, Eric Simpson, MD, rose from the audience to comment that he finds this plethora of associations to be of little use in advising his acne patients in clinical practice. For example, does cannabis use cause acne, or are acne patients more likely to be cannabis users as a means of coping with the social stigma surrounding their skin disease?

“I’d just caution about confounding association with causation. Let’s look at trials of removing that association to see if it actually improves acne before we make strong recommendations in the clinic,” urged Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.

“You’re perfectly right, there,” Dr. Kerob replied. “The methodology of our study can’t separate cause from effect. But as dermatologists, if we have patients with acne that’s resistant to treatment, we need to see if there are other factors that could worsen acne outcome. And we have patients asking us questions all the time about nutrition – now we have some answers that we can provide to those patients.”

The study was sponsored by Vichy Laboratories, and Dr. Kerob is an employee of the company.
 

bjancin@mdedge.com

MADRID – Do you ask your acne patients if they use cannabis? And if they say yes, do you suggest they consider giving it up? Dermatologist Delphine Kerob, MD, believes you should.

Bruce Jancin/MDedge News

In a late-breaker session at the annual congress of the European Academy of Dermatology and Venereology, she presented highlights of a massive international, industry-sponsored survey aimed at identifying novel external and internal factors that influence acne. One of the biggest surprises in this first-of-its-kind study was the finding of an association between cannabis use and acne: 21.1% of patients with physician-diagnosed acne were users, compared with 16.6% of controls without acne.

“I think as dermatologists we should ask these kinds of questions when we manage our patients because this may influence the course of their acne,” observed Dr. Kerob, who is the international medical director for Vichy Laboratories in Paris. The survey was sponsored by the company.

This was an Internet-based survey of 2,826 acne patients and 3,853 age- and sex-matched controls without acne. It was conducted in Canada, France, Germany, Italy, Brazil, and Russia.

The survey comprehensively addressed for the first time what lead investigator Brigitte Dreno, MD, PhD, professor and head of dermatology at Nantes (France) University Hospital and EADV Scientific Programming Committee Chair, has previously called the “acne exposome.” The exposome is essentially everything in a patient’s external and internal environment – other than genetics – that influences the occurrence and severity of the disease (J Eur Acad Dermatol Venereol. 2018 May;32[5]:812-9).

The survey probed the six major categories of exposome factors as defined by Dr. Dreno and coauthors: nutrition, air pollution, lifestyle and psychological factors, medications, skin care products, and climate. Here are the highlights:
 

Lifestyle and psychological factors. While cannabis use emerged as a novel factor linked to increased likelihood of acne, tobacco use was not – a surprising finding because other investigators had previously identified it as an acne trigger.

Feeling burdened by psychological stress was reported by 51% of acne patients and 29% of controls, for an adjusted 1.79-fold increased risk of acne.

Air pollution. Acne patients were significantly more likely to report exposure to solvent vapors, crude oil, tars, frying oil vapors, and living near an airport or close to factories with chimneys. Dr. Kerob noted that these findings are consistent with other investigators’ study of 189 residents of heavily polluted Mexico City or more pristine Cuernavaca, Mexico, with less pollution. The Mexico City cohort demonstrated an increased sebum excretion rate, lower levels of the antioxidants vitamin E and squalene in their sebum, and a less cohesive stratum corneum, along with a higher prevalence of atopic skin and facial seborrheic changes (Int J Cosmet Sci. 2015 Jun;37[3]:329-38).

Nutrition. This is a hot topic that acne patients have many questions about. Myths abound, as detailed by an expert panel including Dr. Dreno in an article entitled, “Acne and Nutrition: Hypotheses, Myths and Facts” (J Eur Acad Dermatol Venereol. 2018 Oct;32[10]:1631-7).

Dr. Kerob reported that the survey showed consumption of dairy products, probiotics, chocolate, cakes and other sweets, soft drinks, fruit juice, and whey protein were each associated with a significantly increased likelihood of acne .

Fifty-seven percent of acne patients indicated they consumed high-alcohol distilled spirits, compared with 43% of controls.

“We know that on our sebaceous glands, as well as on keratinocytes, we have receptors that will be activated by the impact of some nutrients,” she commented.

Among these receptors on sebaceous glands are the insulin growth factor–1 receptor, the leptin receptor, histamine receptors, receptors for substance P, peroxisome proliferator-activated receptors alpha, beta, and gamma, and androgen receptors, she added.

Medications. For Dr. Kerob, another surprise study finding was that 11.9% of acne patients had used an anabolic steroid- or testosterone-based hormonal drug within the previous 12 months, compared with 3.2% of controls without acne.

Cosmetic factors. The use of facial scrubs, harsh cleansers, and dermarollers was significantly more common among the acne patients.

Climate. Acne patients were more likely to live in hot and/or humid locations. For example, 24.6% of the acne group lived in a hot climate, versus 17.1% of controls.

“We think that identifying and reducing the impact of the exposome is very important for an adequate and holistic acne disease management,” the researcher concluded.

However, Eric Simpson, MD, rose from the audience to comment that he finds this plethora of associations to be of little use in advising his acne patients in clinical practice. For example, does cannabis use cause acne, or are acne patients more likely to be cannabis users as a means of coping with the social stigma surrounding their skin disease?

“I’d just caution about confounding association with causation. Let’s look at trials of removing that association to see if it actually improves acne before we make strong recommendations in the clinic,” urged Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.

“You’re perfectly right, there,” Dr. Kerob replied. “The methodology of our study can’t separate cause from effect. But as dermatologists, if we have patients with acne that’s resistant to treatment, we need to see if there are other factors that could worsen acne outcome. And we have patients asking us questions all the time about nutrition – now we have some answers that we can provide to those patients.”

The study was sponsored by Vichy Laboratories, and Dr. Kerob is an employee of the company.
 

bjancin@mdedge.com

Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.

Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.

Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.

“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.

“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.

The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.

Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).

Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.

On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.

The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).

Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.

Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.

SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.

Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.

Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.

Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.

“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.

“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.

The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.

Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).

Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.

On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.

The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).

Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.

Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.

SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.

Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.

Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.

Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.

“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.

“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.

The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.

Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).

Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.

On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.

The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).

Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.

Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.

SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.

MADRID – No hint of increased cancer risk emerged with up to 10 years of topical tacrolimus use for treatment of atopic dermatitis (AD) in children participating in the large, prospective, observational APPLES study, Regina Folster-Holst, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

With nearly 45,000 person-years of follow-up in APPLES (A Prospective Pediatric Longitudinal Evaluation Study), there were no lymphomas and just a single case of skin cancer. That’s highly reassuring, since those were the two types of malignancies singled out as being of particular concern in the boxed warnings for the topical calcineurin inhibitors tacrolimus and pimecrolimus mandated by U.S. and European regulatory agencies in 2005, noted Dr. Folster-Holst, professor of dermatology at Christian Albrechts University of Kiel (Germany).

APPLES included 7,954 children with moderate or severe AD who were a median of 6 years old at enrollment in the study, conducted at 314 sites in the United States, Canada, and seven European countries. This was a naturalistic study in which patients used the topical calcineurin inhibitor as needed, with no restrictions.

A total of six cancers were diagnosed in six individuals during 44,629 person-years of prospective follow-up: one case each of chronic myeloid leukemia, alveolar rhabdomyosarcoma, malignant paraganglioma, carcinoid tumor of the appendix, spinal cord neoplasm, and Spitzoid melanoma. None of those malignancies are classically associated with immunosuppressive therapy.

The primary outcome in APPLES was the standardized incidence ratio of observed cancers to the expected number based upon extrapolation from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, as well as national cancer registries in the other countries where the study was carried out. The expected number of cancers was 5.95, yielding a standardized incidence ratio of 1.01.

Only 27% of patients completed the study. Investigators had anticipated a substantial attrition rate and recalculated their statistics based upon a range of hypothetically increased cancer rates among the dropouts. Even if the cancer rate was 2.5-fold higher in dropouts than in those who remained in the study – a far-fetched possibility – the standardized incidence ratio would not be significantly affected, according to Dr. Folster-Holst.

The new APPLES findings were preceded by a favorable report on long-term use of topical pimecrolimus from the Pediatric Eczema Elective Registry (PEER). The study included 7,457 pimecrolimus-using children with AD followed for 26,792 person-years. The standardized incidence ratio for all cancers was not significantly increased at 1.2. The investigators concluded “it seems unlikely” that topical pimecrolimus as generally used for treatment of AD is associated with an increased risk of malignancy (JAMA Dermatol. 2015 Jun;151[6]:594-9).

The boxed warnings for the topical calcineurin inhibitors have been the source of enormous frustration for dermatologists. The warnings were ordered because of regulatory concern about an increased risk of malignancy in organ transplant recipients on systemic calcineurin inhibitors for immunosuppression, even though the topical agents – unlike the systemic versions – are used intermittently, their systemic absorption is low to nil, and no plausible mechanism by which they could cause cancer has been put forth. Many physicians believe these drugs are probably safer than topical corticosteroids, so the first question put to Dr. Folster-Holst from the audience was, When will the boxed warnings be removed?

“That’s a good question,” she replied. “Patients and parents are afraid. But I think we have now a good argument to move forward with topically applied calcineurin inhibitors.”

Dr. Folster-Holst reported having no financial conflicts of interest regarding the APPLES study, funded by LEO Pharma.

bjancin@mdedge.com

MADRID – No hint of increased cancer risk emerged with up to 10 years of topical tacrolimus use for treatment of atopic dermatitis (AD) in children participating in the large, prospective, observational APPLES study, Regina Folster-Holst, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

With nearly 45,000 person-years of follow-up in APPLES (A Prospective Pediatric Longitudinal Evaluation Study), there were no lymphomas and just a single case of skin cancer. That’s highly reassuring, since those were the two types of malignancies singled out as being of particular concern in the boxed warnings for the topical calcineurin inhibitors tacrolimus and pimecrolimus mandated by U.S. and European regulatory agencies in 2005, noted Dr. Folster-Holst, professor of dermatology at Christian Albrechts University of Kiel (Germany).

APPLES included 7,954 children with moderate or severe AD who were a median of 6 years old at enrollment in the study, conducted at 314 sites in the United States, Canada, and seven European countries. This was a naturalistic study in which patients used the topical calcineurin inhibitor as needed, with no restrictions.

A total of six cancers were diagnosed in six individuals during 44,629 person-years of prospective follow-up: one case each of chronic myeloid leukemia, alveolar rhabdomyosarcoma, malignant paraganglioma, carcinoid tumor of the appendix, spinal cord neoplasm, and Spitzoid melanoma. None of those malignancies are classically associated with immunosuppressive therapy.

The primary outcome in APPLES was the standardized incidence ratio of observed cancers to the expected number based upon extrapolation from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, as well as national cancer registries in the other countries where the study was carried out. The expected number of cancers was 5.95, yielding a standardized incidence ratio of 1.01.

Only 27% of patients completed the study. Investigators had anticipated a substantial attrition rate and recalculated their statistics based upon a range of hypothetically increased cancer rates among the dropouts. Even if the cancer rate was 2.5-fold higher in dropouts than in those who remained in the study – a far-fetched possibility – the standardized incidence ratio would not be significantly affected, according to Dr. Folster-Holst.

The new APPLES findings were preceded by a favorable report on long-term use of topical pimecrolimus from the Pediatric Eczema Elective Registry (PEER). The study included 7,457 pimecrolimus-using children with AD followed for 26,792 person-years. The standardized incidence ratio for all cancers was not significantly increased at 1.2. The investigators concluded “it seems unlikely” that topical pimecrolimus as generally used for treatment of AD is associated with an increased risk of malignancy (JAMA Dermatol. 2015 Jun;151[6]:594-9).

The boxed warnings for the topical calcineurin inhibitors have been the source of enormous frustration for dermatologists. The warnings were ordered because of regulatory concern about an increased risk of malignancy in organ transplant recipients on systemic calcineurin inhibitors for immunosuppression, even though the topical agents – unlike the systemic versions – are used intermittently, their systemic absorption is low to nil, and no plausible mechanism by which they could cause cancer has been put forth. Many physicians believe these drugs are probably safer than topical corticosteroids, so the first question put to Dr. Folster-Holst from the audience was, When will the boxed warnings be removed?

“That’s a good question,” she replied. “Patients and parents are afraid. But I think we have now a good argument to move forward with topically applied calcineurin inhibitors.”

Dr. Folster-Holst reported having no financial conflicts of interest regarding the APPLES study, funded by LEO Pharma.

bjancin@mdedge.com

MADRID – No hint of increased cancer risk emerged with up to 10 years of topical tacrolimus use for treatment of atopic dermatitis (AD) in children participating in the large, prospective, observational APPLES study, Regina Folster-Holst, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

With nearly 45,000 person-years of follow-up in APPLES (A Prospective Pediatric Longitudinal Evaluation Study), there were no lymphomas and just a single case of skin cancer. That’s highly reassuring, since those were the two types of malignancies singled out as being of particular concern in the boxed warnings for the topical calcineurin inhibitors tacrolimus and pimecrolimus mandated by U.S. and European regulatory agencies in 2005, noted Dr. Folster-Holst, professor of dermatology at Christian Albrechts University of Kiel (Germany).

APPLES included 7,954 children with moderate or severe AD who were a median of 6 years old at enrollment in the study, conducted at 314 sites in the United States, Canada, and seven European countries. This was a naturalistic study in which patients used the topical calcineurin inhibitor as needed, with no restrictions.

A total of six cancers were diagnosed in six individuals during 44,629 person-years of prospective follow-up: one case each of chronic myeloid leukemia, alveolar rhabdomyosarcoma, malignant paraganglioma, carcinoid tumor of the appendix, spinal cord neoplasm, and Spitzoid melanoma. None of those malignancies are classically associated with immunosuppressive therapy.

The primary outcome in APPLES was the standardized incidence ratio of observed cancers to the expected number based upon extrapolation from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, as well as national cancer registries in the other countries where the study was carried out. The expected number of cancers was 5.95, yielding a standardized incidence ratio of 1.01.

Only 27% of patients completed the study. Investigators had anticipated a substantial attrition rate and recalculated their statistics based upon a range of hypothetically increased cancer rates among the dropouts. Even if the cancer rate was 2.5-fold higher in dropouts than in those who remained in the study – a far-fetched possibility – the standardized incidence ratio would not be significantly affected, according to Dr. Folster-Holst.

The new APPLES findings were preceded by a favorable report on long-term use of topical pimecrolimus from the Pediatric Eczema Elective Registry (PEER). The study included 7,457 pimecrolimus-using children with AD followed for 26,792 person-years. The standardized incidence ratio for all cancers was not significantly increased at 1.2. The investigators concluded “it seems unlikely” that topical pimecrolimus as generally used for treatment of AD is associated with an increased risk of malignancy (JAMA Dermatol. 2015 Jun;151[6]:594-9).

The boxed warnings for the topical calcineurin inhibitors have been the source of enormous frustration for dermatologists. The warnings were ordered because of regulatory concern about an increased risk of malignancy in organ transplant recipients on systemic calcineurin inhibitors for immunosuppression, even though the topical agents – unlike the systemic versions – are used intermittently, their systemic absorption is low to nil, and no plausible mechanism by which they could cause cancer has been put forth. Many physicians believe these drugs are probably safer than topical corticosteroids, so the first question put to Dr. Folster-Holst from the audience was, When will the boxed warnings be removed?

“That’s a good question,” she replied. “Patients and parents are afraid. But I think we have now a good argument to move forward with topically applied calcineurin inhibitors.”

Dr. Folster-Holst reported having no financial conflicts of interest regarding the APPLES study, funded by LEO Pharma.

bjancin@mdedge.com

SAN DIEGO – Research suggests that as many as 23% of patients with substance use disorder (SUD) also have ADHD, adding an extra layer of complexity to a difficult-to-treat condition. What to do?

“Treating the ADHD can be useful in reducing the severity of symptoms without worsening the substance use disorder. It shouldn’t be avoided,” said psychiatrist Larissa J. Mooney, MD, of the University of California, Los Angeles, and the Veterans Affairs Greater Los Angeles Healthcare System, in a presentation at the annual Psych Congress.

When ADHD is on board, “it’s a more complicated and challenging clinical course,” Dr. Mooney said. The duo of disorders is linked to higher rates of polysubstance abuse and other psychiatric conditions, such as anxiety, bipolar disorder, posttraumatic stress, and antisocial/borderline conditions (Eur Addict Res. 2018;24[1]:43-51).

“These individuals typically have more difficulty with [drug] abstinence, more health consequences, and reduced quality of life, and social and professional consequences,” she said. “Some studies have suggested that they may not respond to lower doses of medication for attention-deficit/hyperactivity disorder and may require doses in the higher range.”

Research has hinted that several drugs that might prove helpful in these patients by improving both conditions, Dr. Mooney said. These include up to 180 mg/day of methylphenidate (Ritalin), 60- and 80-mg doses of mixed amphetamine salts/extended release, atomoxetine (Strattera), and bupropion.

In regard to bupropion, she said, “I find it to be a good choice in my substance use disorder patients for their depression and concentration problems. I have a greater number of individuals at 450 milligrams per day and the XL formulation.”

Early research has suggested that guanfacine XR (Intuniv), which is used to treat children with ADHD, also might be helpful in adults, including those with SUD. “We need more research to show if this is helpful,” she said. “It’s a reasonable choice in terms of weighing pros and cons, because it’s not [a controlled substance].”

Still, some of those medications are stimulants, Dr. Mooney said, and their use in patients with SUD is controversial. There are concerns about misuse and diversion.

“We want to have some flexibility,” she said, but it’s important to think about risks and priorities. In certain cases, ADHD may be a secondary concern.

“Some patients have a severe substance use disorder that keeps landing them in the emergency room or causing them to be hospitalized,” she said. “I’m more worried about that than the impairment function from ADHD.”

If you do consider stimulants, she said, longer-acting formulations can be less risky because there’s less potential for diversion. “Also, think about their treatment plan: Is their functioning improving? Are they or showing up for appointments? These are factors that will say: ‘Oh, I’m on the right path with this medication.’ ”

Behavioral treatment also can be helpful in these patients, she said, although “some may not be willing or motivated to put in the time that it takes to do the behavioral work.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

SAN DIEGO – Research suggests that as many as 23% of patients with substance use disorder (SUD) also have ADHD, adding an extra layer of complexity to a difficult-to-treat condition. What to do?

“Treating the ADHD can be useful in reducing the severity of symptoms without worsening the substance use disorder. It shouldn’t be avoided,” said psychiatrist Larissa J. Mooney, MD, of the University of California, Los Angeles, and the Veterans Affairs Greater Los Angeles Healthcare System, in a presentation at the annual Psych Congress.

When ADHD is on board, “it’s a more complicated and challenging clinical course,” Dr. Mooney said. The duo of disorders is linked to higher rates of polysubstance abuse and other psychiatric conditions, such as anxiety, bipolar disorder, posttraumatic stress, and antisocial/borderline conditions (Eur Addict Res. 2018;24[1]:43-51).

“These individuals typically have more difficulty with [drug] abstinence, more health consequences, and reduced quality of life, and social and professional consequences,” she said. “Some studies have suggested that they may not respond to lower doses of medication for attention-deficit/hyperactivity disorder and may require doses in the higher range.”

Research has hinted that several drugs that might prove helpful in these patients by improving both conditions, Dr. Mooney said. These include up to 180 mg/day of methylphenidate (Ritalin), 60- and 80-mg doses of mixed amphetamine salts/extended release, atomoxetine (Strattera), and bupropion.

In regard to bupropion, she said, “I find it to be a good choice in my substance use disorder patients for their depression and concentration problems. I have a greater number of individuals at 450 milligrams per day and the XL formulation.”

Early research has suggested that guanfacine XR (Intuniv), which is used to treat children with ADHD, also might be helpful in adults, including those with SUD. “We need more research to show if this is helpful,” she said. “It’s a reasonable choice in terms of weighing pros and cons, because it’s not [a controlled substance].”

Still, some of those medications are stimulants, Dr. Mooney said, and their use in patients with SUD is controversial. There are concerns about misuse and diversion.

“We want to have some flexibility,” she said, but it’s important to think about risks and priorities. In certain cases, ADHD may be a secondary concern.

“Some patients have a severe substance use disorder that keeps landing them in the emergency room or causing them to be hospitalized,” she said. “I’m more worried about that than the impairment function from ADHD.”

If you do consider stimulants, she said, longer-acting formulations can be less risky because there’s less potential for diversion. “Also, think about their treatment plan: Is their functioning improving? Are they or showing up for appointments? These are factors that will say: ‘Oh, I’m on the right path with this medication.’ ”

Behavioral treatment also can be helpful in these patients, she said, although “some may not be willing or motivated to put in the time that it takes to do the behavioral work.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

SAN DIEGO – Research suggests that as many as 23% of patients with substance use disorder (SUD) also have ADHD, adding an extra layer of complexity to a difficult-to-treat condition. What to do?

“Treating the ADHD can be useful in reducing the severity of symptoms without worsening the substance use disorder. It shouldn’t be avoided,” said psychiatrist Larissa J. Mooney, MD, of the University of California, Los Angeles, and the Veterans Affairs Greater Los Angeles Healthcare System, in a presentation at the annual Psych Congress.

When ADHD is on board, “it’s a more complicated and challenging clinical course,” Dr. Mooney said. The duo of disorders is linked to higher rates of polysubstance abuse and other psychiatric conditions, such as anxiety, bipolar disorder, posttraumatic stress, and antisocial/borderline conditions (Eur Addict Res. 2018;24[1]:43-51).

“These individuals typically have more difficulty with [drug] abstinence, more health consequences, and reduced quality of life, and social and professional consequences,” she said. “Some studies have suggested that they may not respond to lower doses of medication for attention-deficit/hyperactivity disorder and may require doses in the higher range.”

Research has hinted that several drugs that might prove helpful in these patients by improving both conditions, Dr. Mooney said. These include up to 180 mg/day of methylphenidate (Ritalin), 60- and 80-mg doses of mixed amphetamine salts/extended release, atomoxetine (Strattera), and bupropion.

In regard to bupropion, she said, “I find it to be a good choice in my substance use disorder patients for their depression and concentration problems. I have a greater number of individuals at 450 milligrams per day and the XL formulation.”

Early research has suggested that guanfacine XR (Intuniv), which is used to treat children with ADHD, also might be helpful in adults, including those with SUD. “We need more research to show if this is helpful,” she said. “It’s a reasonable choice in terms of weighing pros and cons, because it’s not [a controlled substance].”

Still, some of those medications are stimulants, Dr. Mooney said, and their use in patients with SUD is controversial. There are concerns about misuse and diversion.

“We want to have some flexibility,” she said, but it’s important to think about risks and priorities. In certain cases, ADHD may be a secondary concern.

“Some patients have a severe substance use disorder that keeps landing them in the emergency room or causing them to be hospitalized,” she said. “I’m more worried about that than the impairment function from ADHD.”

If you do consider stimulants, she said, longer-acting formulations can be less risky because there’s less potential for diversion. “Also, think about their treatment plan: Is their functioning improving? Are they or showing up for appointments? These are factors that will say: ‘Oh, I’m on the right path with this medication.’ ”

Behavioral treatment also can be helpful in these patients, she said, although “some may not be willing or motivated to put in the time that it takes to do the behavioral work.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

The Batman characters have been cultural icons for generations – spanning more than three-quarters of a century. How many of us had Batman (or the Joker) on our school lunch box or watched reruns of Adam West’s campy televised rendition of Batman? The October release of “Joker” has been breaking contemporary box office records.

(Spoiler alert!) The Todd Phillips film associates mental illness with violent acts, spurring a slew of articles explaining that this association is uncommon and may promote stigmatization and public fear of people with obvious symptoms of mental illness. The protagonist, Arthur Fleck (Joaquin Phoenix), suffers from a condition in which his affect and facial expressions are not appropriate to his emotions or to the situation. He laughs uncontrollably when a situation is sad or upsetting. Sometimes he laughs and cries at the same time. As a result, he often is misunderstood, ridiculed, and victimized – like many people with obvious mental illness.

Arthur Fleck is a loner who has difficulty with relationships and self-esteem, and is beaten severely while at work as a clown. Shortly after the incident, he is given a gun by one of his coworkers. He keeps it with him even when working as a clown in a children’s hospital – where it is accidentally revealed, and he is subsequently fired. Still in his clown garb, he later uses the gun when he is mocked and assaulted on the subway by three Gotham City bankers.

In an unusual tone, his mental health worker reminds him early in the film that he is prescribed seven different psychotropic medications, helping to cement for the viewer that mental illness is the cause of Arthur’s problems and the Joker’s origin story. Then the funding for Arthur’s mental health treatment (even if it was not good treatment) was cut – a problem not just in Gotham.

While some of Arthur Fleck’s symptoms are consistent with real mental illness, the combination of symptoms is unusual. Although he is being treated with a variety of medications, it is unclear whether any of them are helping him or what exactly they are helping him with. (Ironically, once he is off of his medications, he becomes a better dresser and a better dancer.) He writes in a disorganized way in his journal; the only intelligible sentence that is focused on is, “The worst part about having mental illness is people expect you to behave as if you DONT.” A smiley face in the ‘O’ suggests that his affect is inappropriate even in his writing. Arthur’s condition of uncontrollable laughing and/or crying, associated with head trauma, appears more consistent with the neurologic condition pseudobulbar affect rather than a mental illness. In addition to pseudobulbar affect, Arthur demonstrates a constellation of symptoms of different kinds of mental illness, including erotomanic delusions, ideas of reference, and disorganized thinking. He also does not appear to take social cues, such as knowing when he is being mocked. He appears to believe that his neighbor is his girlfriend (as the viewer was similarly led to believe), eventually breaking into her apartment where he thought he belonged, much to her horror when she finds him there. Some of his symptoms may run in his family (whether it be his biological or adoptive family).

Wikimedia Commons

In the final scenes, Arthur Fleck (who is now the Joker) is apparently back in the white-walled Arkham State Hospital, with an implication that he has gotten away with the murders, either found incompetent or insane. This, too, has negative implications for the public viewing the film – and further perpetuates the misunderstanding that people with mental illness “get away” with their crimes. In reality, depending on the study, approximately one-quarter of those who pleaded insanity were found insane, and those facing jury trials (and public perception) are less likely to be found insane than those with bench trials. Public misinterpretations and outrage over the idea that a mentally unwell person might be found insane rather than guilty have existed for centuries, perhaps most memorably when John Hinckley Jr. attempted to assassinate former President Ronald Reagan, after identifying with a character in the film “Taxi Driver.” Let’s presume that Gotham has an insanity defense similar to other places in America. Then, in order to be found insane, Arthur’s pseudobulbar affect or his (unclear) mental illness would have either caused him not to know the nature and consequences of his acts, and/or to appreciate the wrongfulness of his acts (if we are fairly certain that Gotham is actually New York City). Neither of these appear to be true from the film. He knew that he was killing. No delusions or hallucinations made him think his acts were not wrong. Rather, he had an arguably rational motive – certainly the multitudes wearing clown masks in the subsequent uprisings against the powerful also believed his motive to be rational. He deliberately killed the bankers who mocked and beat him. He was also able to defer his killings until what he calculated was the right time to have the most impact – for example, on live television, or when he was alone with his mother in the hospital.

In closing, unrealistic portrayals of the link between mental illness, violence, and forensic hospitalization are seen on the silver screen in “Joker.” We hope that others who feign mental illness symptoms to evade criminal responsibility will emulate Joaquin Phoenix’s Joker as it will make it much easier for forensic psychiatrists to ferret out malingerers!
 

Dr. Hatters Friedman serves as the Phillip Resnick Professor of Forensic Psychiatry at Case Western Reserve University, Cleveland. She is also editor of Family Murder: Pathologies of Love and Hate (Washington, D.C.: American Psychiatric Association Publishing [2019]), which was written by the Group for the Advancement of Psychiatry’s Committee on Psychiatry & Law. Dr. Rosenbaum is a clinical and forensic psychiatrist in private practice in New York. She is an assistant clinical professor at New York University Langone Medical Center and on the faculty at Weill-Cornell Medical Center.

The Batman characters have been cultural icons for generations – spanning more than three-quarters of a century. How many of us had Batman (or the Joker) on our school lunch box or watched reruns of Adam West’s campy televised rendition of Batman? The October release of “Joker” has been breaking contemporary box office records.

(Spoiler alert!) The Todd Phillips film associates mental illness with violent acts, spurring a slew of articles explaining that this association is uncommon and may promote stigmatization and public fear of people with obvious symptoms of mental illness. The protagonist, Arthur Fleck (Joaquin Phoenix), suffers from a condition in which his affect and facial expressions are not appropriate to his emotions or to the situation. He laughs uncontrollably when a situation is sad or upsetting. Sometimes he laughs and cries at the same time. As a result, he often is misunderstood, ridiculed, and victimized – like many people with obvious mental illness.

Arthur Fleck is a loner who has difficulty with relationships and self-esteem, and is beaten severely while at work as a clown. Shortly after the incident, he is given a gun by one of his coworkers. He keeps it with him even when working as a clown in a children’s hospital – where it is accidentally revealed, and he is subsequently fired. Still in his clown garb, he later uses the gun when he is mocked and assaulted on the subway by three Gotham City bankers.

In an unusual tone, his mental health worker reminds him early in the film that he is prescribed seven different psychotropic medications, helping to cement for the viewer that mental illness is the cause of Arthur’s problems and the Joker’s origin story. Then the funding for Arthur’s mental health treatment (even if it was not good treatment) was cut – a problem not just in Gotham.

While some of Arthur Fleck’s symptoms are consistent with real mental illness, the combination of symptoms is unusual. Although he is being treated with a variety of medications, it is unclear whether any of them are helping him or what exactly they are helping him with. (Ironically, once he is off of his medications, he becomes a better dresser and a better dancer.) He writes in a disorganized way in his journal; the only intelligible sentence that is focused on is, “The worst part about having mental illness is people expect you to behave as if you DONT.” A smiley face in the ‘O’ suggests that his affect is inappropriate even in his writing. Arthur’s condition of uncontrollable laughing and/or crying, associated with head trauma, appears more consistent with the neurologic condition pseudobulbar affect rather than a mental illness. In addition to pseudobulbar affect, Arthur demonstrates a constellation of symptoms of different kinds of mental illness, including erotomanic delusions, ideas of reference, and disorganized thinking. He also does not appear to take social cues, such as knowing when he is being mocked. He appears to believe that his neighbor is his girlfriend (as the viewer was similarly led to believe), eventually breaking into her apartment where he thought he belonged, much to her horror when she finds him there. Some of his symptoms may run in his family (whether it be his biological or adoptive family).

Wikimedia Commons

In the final scenes, Arthur Fleck (who is now the Joker) is apparently back in the white-walled Arkham State Hospital, with an implication that he has gotten away with the murders, either found incompetent or insane. This, too, has negative implications for the public viewing the film – and further perpetuates the misunderstanding that people with mental illness “get away” with their crimes. In reality, depending on the study, approximately one-quarter of those who pleaded insanity were found insane, and those facing jury trials (and public perception) are less likely to be found insane than those with bench trials. Public misinterpretations and outrage over the idea that a mentally unwell person might be found insane rather than guilty have existed for centuries, perhaps most memorably when John Hinckley Jr. attempted to assassinate former President Ronald Reagan, after identifying with a character in the film “Taxi Driver.” Let’s presume that Gotham has an insanity defense similar to other places in America. Then, in order to be found insane, Arthur’s pseudobulbar affect or his (unclear) mental illness would have either caused him not to know the nature and consequences of his acts, and/or to appreciate the wrongfulness of his acts (if we are fairly certain that Gotham is actually New York City). Neither of these appear to be true from the film. He knew that he was killing. No delusions or hallucinations made him think his acts were not wrong. Rather, he had an arguably rational motive – certainly the multitudes wearing clown masks in the subsequent uprisings against the powerful also believed his motive to be rational. He deliberately killed the bankers who mocked and beat him. He was also able to defer his killings until what he calculated was the right time to have the most impact – for example, on live television, or when he was alone with his mother in the hospital.

In closing, unrealistic portrayals of the link between mental illness, violence, and forensic hospitalization are seen on the silver screen in “Joker.” We hope that others who feign mental illness symptoms to evade criminal responsibility will emulate Joaquin Phoenix’s Joker as it will make it much easier for forensic psychiatrists to ferret out malingerers!
 

Dr. Hatters Friedman serves as the Phillip Resnick Professor of Forensic Psychiatry at Case Western Reserve University, Cleveland. She is also editor of Family Murder: Pathologies of Love and Hate (Washington, D.C.: American Psychiatric Association Publishing [2019]), which was written by the Group for the Advancement of Psychiatry’s Committee on Psychiatry & Law. Dr. Rosenbaum is a clinical and forensic psychiatrist in private practice in New York. She is an assistant clinical professor at New York University Langone Medical Center and on the faculty at Weill-Cornell Medical Center.

The Batman characters have been cultural icons for generations – spanning more than three-quarters of a century. How many of us had Batman (or the Joker) on our school lunch box or watched reruns of Adam West’s campy televised rendition of Batman? The October release of “Joker” has been breaking contemporary box office records.

(Spoiler alert!) The Todd Phillips film associates mental illness with violent acts, spurring a slew of articles explaining that this association is uncommon and may promote stigmatization and public fear of people with obvious symptoms of mental illness. The protagonist, Arthur Fleck (Joaquin Phoenix), suffers from a condition in which his affect and facial expressions are not appropriate to his emotions or to the situation. He laughs uncontrollably when a situation is sad or upsetting. Sometimes he laughs and cries at the same time. As a result, he often is misunderstood, ridiculed, and victimized – like many people with obvious mental illness.

Arthur Fleck is a loner who has difficulty with relationships and self-esteem, and is beaten severely while at work as a clown. Shortly after the incident, he is given a gun by one of his coworkers. He keeps it with him even when working as a clown in a children’s hospital – where it is accidentally revealed, and he is subsequently fired. Still in his clown garb, he later uses the gun when he is mocked and assaulted on the subway by three Gotham City bankers.

In an unusual tone, his mental health worker reminds him early in the film that he is prescribed seven different psychotropic medications, helping to cement for the viewer that mental illness is the cause of Arthur’s problems and the Joker’s origin story. Then the funding for Arthur’s mental health treatment (even if it was not good treatment) was cut – a problem not just in Gotham.

While some of Arthur Fleck’s symptoms are consistent with real mental illness, the combination of symptoms is unusual. Although he is being treated with a variety of medications, it is unclear whether any of them are helping him or what exactly they are helping him with. (Ironically, once he is off of his medications, he becomes a better dresser and a better dancer.) He writes in a disorganized way in his journal; the only intelligible sentence that is focused on is, “The worst part about having mental illness is people expect you to behave as if you DONT.” A smiley face in the ‘O’ suggests that his affect is inappropriate even in his writing. Arthur’s condition of uncontrollable laughing and/or crying, associated with head trauma, appears more consistent with the neurologic condition pseudobulbar affect rather than a mental illness. In addition to pseudobulbar affect, Arthur demonstrates a constellation of symptoms of different kinds of mental illness, including erotomanic delusions, ideas of reference, and disorganized thinking. He also does not appear to take social cues, such as knowing when he is being mocked. He appears to believe that his neighbor is his girlfriend (as the viewer was similarly led to believe), eventually breaking into her apartment where he thought he belonged, much to her horror when she finds him there. Some of his symptoms may run in his family (whether it be his biological or adoptive family).

Wikimedia Commons

In the final scenes, Arthur Fleck (who is now the Joker) is apparently back in the white-walled Arkham State Hospital, with an implication that he has gotten away with the murders, either found incompetent or insane. This, too, has negative implications for the public viewing the film – and further perpetuates the misunderstanding that people with mental illness “get away” with their crimes. In reality, depending on the study, approximately one-quarter of those who pleaded insanity were found insane, and those facing jury trials (and public perception) are less likely to be found insane than those with bench trials. Public misinterpretations and outrage over the idea that a mentally unwell person might be found insane rather than guilty have existed for centuries, perhaps most memorably when John Hinckley Jr. attempted to assassinate former President Ronald Reagan, after identifying with a character in the film “Taxi Driver.” Let’s presume that Gotham has an insanity defense similar to other places in America. Then, in order to be found insane, Arthur’s pseudobulbar affect or his (unclear) mental illness would have either caused him not to know the nature and consequences of his acts, and/or to appreciate the wrongfulness of his acts (if we are fairly certain that Gotham is actually New York City). Neither of these appear to be true from the film. He knew that he was killing. No delusions or hallucinations made him think his acts were not wrong. Rather, he had an arguably rational motive – certainly the multitudes wearing clown masks in the subsequent uprisings against the powerful also believed his motive to be rational. He deliberately killed the bankers who mocked and beat him. He was also able to defer his killings until what he calculated was the right time to have the most impact – for example, on live television, or when he was alone with his mother in the hospital.

In closing, unrealistic portrayals of the link between mental illness, violence, and forensic hospitalization are seen on the silver screen in “Joker.” We hope that others who feign mental illness symptoms to evade criminal responsibility will emulate Joaquin Phoenix’s Joker as it will make it much easier for forensic psychiatrists to ferret out malingerers!
 

Dr. Hatters Friedman serves as the Phillip Resnick Professor of Forensic Psychiatry at Case Western Reserve University, Cleveland. She is also editor of Family Murder: Pathologies of Love and Hate (Washington, D.C.: American Psychiatric Association Publishing [2019]), which was written by the Group for the Advancement of Psychiatry’s Committee on Psychiatry & Law. Dr. Rosenbaum is a clinical and forensic psychiatrist in private practice in New York. She is an assistant clinical professor at New York University Langone Medical Center and on the faculty at Weill-Cornell Medical Center.

SAN FRANCISCO – A urine flow rate (UFR)–guided approach was superior to the left ventricular end-diastolic pressure (LVEDP)-guided hydration regimen in preventing contrast-induced acute kidney injury and acute pulmonary edema in high-risk patients.

The results come from a randomized, multicenter, investigator-initiated trial designed to compare two hydration strategies for reducing the risk of acute kidney injury that Carlo Briguori, MD, PhD, presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

Between July 15, 2015 and June 6, 2019, Dr. Briguori, chief of the laboratory of interventional cardiology at the Mediterranea Cardiocentro in Naples, Italy, and his colleagues enrolled 708 patients with an estimated glomerular filtration rate of 45 mL/min per 1.73 m^{2 or less} and/or with a Mehran’s score greater of at least 11 and/or a Gurm’s score greater than 7. Of these, 355 were assigned to LVEDP-guided hydration with normal saline, while 353 were assigned to UFR-guided hydration controlled by the RenalGuard system. Iobitridol, a low-osmolar, nonionic contrast agent, was administered in all cases.

The primary endpoint for the trial, known as Renal Insufficiency Following Contrast Media Administration Trial III (REMEDIAL III), was the composite of contrast-induced acute kidney injury (defined as a serum creatinine increase of at least 25% and/or at least 0.5 mg/dL from baseline to 48 hours) and/or acute pulmonary edema. That endpoint occurred in 5.7% of patients in the UFR-guided group and in 10.3% of patients in the LVEDP-guided group (relative risk, 0.56; P = .036). As for side effects, three patients in the UFR-guided group (0.8%) experienced complications related to Foley insertion, including one case of hematuria and two cases of pain on micturition. No patients developed a urinary tract infection, Dr. Briguori reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Hypokalemia occurred in 6.2% of patients in the UFR-guided group and 2.3% of patients in the LVEDP-guided group (RR, 2.70; P = .013), while potassium replacement was required in 5.1% of patients in the UFR-guided group, compared with 1.4% of LVEDP-guided patients (RR, 3.74; P = .009). Meanwhile, hypernatremia was observed in 1.2% of patients in both groups (P = 1.00).

“For the longest time, the interventional field has been trying to find ways to minimize acute kidney injury related to interventional procedures,” Juan F. Granada, MD, president and CEO of the Cardiovascular Research Foundation said in a media briefing. “We have a lot of data with multiple approaches with different results – mostly negative. This is important because, as procedures get more complex, longer, and contrast media is used, there is continuous interest in minimizing the potential kidney injury.”

A discussant at the briefing, Gary S. Mintz, MD, a senior medical adviser for the CRF, suggested a different approach to preventing contrast-induced nephropathy. “If you do imaging-guided zero-contrast percutaneous coronary intervention, you do not get contrast-induced nephropathy, period,” he said. “If you get rid of contrast, you get rid of contrast nephropathy. Anybody who has worked with patients who transition to dialysis understands that once you go on dialysis, your life changes for the worse no matter what you do. There has been no improvement in dialysis therapy in decades. But to me, the solution is to get rid of contrast, which can be done if you think differently and plan differently.”

For his part, Dr. Briguori said that he and his colleagues in REMEDIAL III “tried to use the least amount of contrast possible. The mean volume of contrast media in this trial was 70 mL, which is very low.”

The RenalGuard device (RenalGuard Solutions) is CE-marked for sale in Europe and is under investigation in the United States. The REMEDIAL III study was supported by an unrestricted grant from Guerbet (Villepinte, France) provided to the Mediterranea Cardiocentro. Dr. Briguori reported having no relevant disclosures.

dbrunk@mdedge.com

SOURCE: Briguori C. TCT 2019, Late Breaking Trials 4 Session.

SAN FRANCISCO – A urine flow rate (UFR)–guided approach was superior to the left ventricular end-diastolic pressure (LVEDP)-guided hydration regimen in preventing contrast-induced acute kidney injury and acute pulmonary edema in high-risk patients.

The results come from a randomized, multicenter, investigator-initiated trial designed to compare two hydration strategies for reducing the risk of acute kidney injury that Carlo Briguori, MD, PhD, presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

Between July 15, 2015 and June 6, 2019, Dr. Briguori, chief of the laboratory of interventional cardiology at the Mediterranea Cardiocentro in Naples, Italy, and his colleagues enrolled 708 patients with an estimated glomerular filtration rate of 45 mL/min per 1.73 m^{2 or less} and/or with a Mehran’s score greater of at least 11 and/or a Gurm’s score greater than 7. Of these, 355 were assigned to LVEDP-guided hydration with normal saline, while 353 were assigned to UFR-guided hydration controlled by the RenalGuard system. Iobitridol, a low-osmolar, nonionic contrast agent, was administered in all cases.

The primary endpoint for the trial, known as Renal Insufficiency Following Contrast Media Administration Trial III (REMEDIAL III), was the composite of contrast-induced acute kidney injury (defined as a serum creatinine increase of at least 25% and/or at least 0.5 mg/dL from baseline to 48 hours) and/or acute pulmonary edema. That endpoint occurred in 5.7% of patients in the UFR-guided group and in 10.3% of patients in the LVEDP-guided group (relative risk, 0.56; P = .036). As for side effects, three patients in the UFR-guided group (0.8%) experienced complications related to Foley insertion, including one case of hematuria and two cases of pain on micturition. No patients developed a urinary tract infection, Dr. Briguori reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Hypokalemia occurred in 6.2% of patients in the UFR-guided group and 2.3% of patients in the LVEDP-guided group (RR, 2.70; P = .013), while potassium replacement was required in 5.1% of patients in the UFR-guided group, compared with 1.4% of LVEDP-guided patients (RR, 3.74; P = .009). Meanwhile, hypernatremia was observed in 1.2% of patients in both groups (P = 1.00).

“For the longest time, the interventional field has been trying to find ways to minimize acute kidney injury related to interventional procedures,” Juan F. Granada, MD, president and CEO of the Cardiovascular Research Foundation said in a media briefing. “We have a lot of data with multiple approaches with different results – mostly negative. This is important because, as procedures get more complex, longer, and contrast media is used, there is continuous interest in minimizing the potential kidney injury.”

A discussant at the briefing, Gary S. Mintz, MD, a senior medical adviser for the CRF, suggested a different approach to preventing contrast-induced nephropathy. “If you do imaging-guided zero-contrast percutaneous coronary intervention, you do not get contrast-induced nephropathy, period,” he said. “If you get rid of contrast, you get rid of contrast nephropathy. Anybody who has worked with patients who transition to dialysis understands that once you go on dialysis, your life changes for the worse no matter what you do. There has been no improvement in dialysis therapy in decades. But to me, the solution is to get rid of contrast, which can be done if you think differently and plan differently.”

For his part, Dr. Briguori said that he and his colleagues in REMEDIAL III “tried to use the least amount of contrast possible. The mean volume of contrast media in this trial was 70 mL, which is very low.”

The RenalGuard device (RenalGuard Solutions) is CE-marked for sale in Europe and is under investigation in the United States. The REMEDIAL III study was supported by an unrestricted grant from Guerbet (Villepinte, France) provided to the Mediterranea Cardiocentro. Dr. Briguori reported having no relevant disclosures.

dbrunk@mdedge.com

SOURCE: Briguori C. TCT 2019, Late Breaking Trials 4 Session.

SAN FRANCISCO – A urine flow rate (UFR)–guided approach was superior to the left ventricular end-diastolic pressure (LVEDP)-guided hydration regimen in preventing contrast-induced acute kidney injury and acute pulmonary edema in high-risk patients.

The results come from a randomized, multicenter, investigator-initiated trial designed to compare two hydration strategies for reducing the risk of acute kidney injury that Carlo Briguori, MD, PhD, presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

Between July 15, 2015 and June 6, 2019, Dr. Briguori, chief of the laboratory of interventional cardiology at the Mediterranea Cardiocentro in Naples, Italy, and his colleagues enrolled 708 patients with an estimated glomerular filtration rate of 45 mL/min per 1.73 m^{2 or less} and/or with a Mehran’s score greater of at least 11 and/or a Gurm’s score greater than 7. Of these, 355 were assigned to LVEDP-guided hydration with normal saline, while 353 were assigned to UFR-guided hydration controlled by the RenalGuard system. Iobitridol, a low-osmolar, nonionic contrast agent, was administered in all cases.

The primary endpoint for the trial, known as Renal Insufficiency Following Contrast Media Administration Trial III (REMEDIAL III), was the composite of contrast-induced acute kidney injury (defined as a serum creatinine increase of at least 25% and/or at least 0.5 mg/dL from baseline to 48 hours) and/or acute pulmonary edema. That endpoint occurred in 5.7% of patients in the UFR-guided group and in 10.3% of patients in the LVEDP-guided group (relative risk, 0.56; P = .036). As for side effects, three patients in the UFR-guided group (0.8%) experienced complications related to Foley insertion, including one case of hematuria and two cases of pain on micturition. No patients developed a urinary tract infection, Dr. Briguori reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Hypokalemia occurred in 6.2% of patients in the UFR-guided group and 2.3% of patients in the LVEDP-guided group (RR, 2.70; P = .013), while potassium replacement was required in 5.1% of patients in the UFR-guided group, compared with 1.4% of LVEDP-guided patients (RR, 3.74; P = .009). Meanwhile, hypernatremia was observed in 1.2% of patients in both groups (P = 1.00).

“For the longest time, the interventional field has been trying to find ways to minimize acute kidney injury related to interventional procedures,” Juan F. Granada, MD, president and CEO of the Cardiovascular Research Foundation said in a media briefing. “We have a lot of data with multiple approaches with different results – mostly negative. This is important because, as procedures get more complex, longer, and contrast media is used, there is continuous interest in minimizing the potential kidney injury.”

A discussant at the briefing, Gary S. Mintz, MD, a senior medical adviser for the CRF, suggested a different approach to preventing contrast-induced nephropathy. “If you do imaging-guided zero-contrast percutaneous coronary intervention, you do not get contrast-induced nephropathy, period,” he said. “If you get rid of contrast, you get rid of contrast nephropathy. Anybody who has worked with patients who transition to dialysis understands that once you go on dialysis, your life changes for the worse no matter what you do. There has been no improvement in dialysis therapy in decades. But to me, the solution is to get rid of contrast, which can be done if you think differently and plan differently.”

For his part, Dr. Briguori said that he and his colleagues in REMEDIAL III “tried to use the least amount of contrast possible. The mean volume of contrast media in this trial was 70 mL, which is very low.”

The RenalGuard device (RenalGuard Solutions) is CE-marked for sale in Europe and is under investigation in the United States. The REMEDIAL III study was supported by an unrestricted grant from Guerbet (Villepinte, France) provided to the Mediterranea Cardiocentro. Dr. Briguori reported having no relevant disclosures.

dbrunk@mdedge.com

SOURCE: Briguori C. TCT 2019, Late Breaking Trials 4 Session.

COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.

Bruce Jancin/MDedge News

This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.

The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.

The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.

Dr. Horsager said that she found the relatively low prevalence of food addiction in the ADHD population to be surprising, since impulsivity has been shown to be associated with food addiction. But then again, the medications for ADHD tend to suppress appetite.

Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.

Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).

Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.

The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.

She reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.

Bruce Jancin/MDedge News

This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.

The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.

The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.

Dr. Horsager said that she found the relatively low prevalence of food addiction in the ADHD population to be surprising, since impulsivity has been shown to be associated with food addiction. But then again, the medications for ADHD tend to suppress appetite.

Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.

Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).

Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.

The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.

She reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.

Bruce Jancin/MDedge News

This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.

The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.

The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.

Dr. Horsager said that she found the relatively low prevalence of food addiction in the ADHD population to be surprising, since impulsivity has been shown to be associated with food addiction. But then again, the medications for ADHD tend to suppress appetite.

Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.

Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).

Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.

The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.

She reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com