A low body mass index (BMI) indicative of being underweight as well as a weight loss of 2 kg or more over the course of 1 year were both independently associated with a higher mortality risk in the following year in patients with fibrotic interstitial lung disease (ILD). In contrast, being both overweight and obese appeared to be protective against mortality at the same 1-year endpoint, according to the results of an observational, retrospective cohort study.

Compared with patients with a normal BMI, patients who were underweight at a BMI of less than 18.5 kg/m² were over three times more likely to die at 1 year, at a hazard ratio of 3.19 (P < .001), senior author Christopher Ryerson, MD, University of British Columbia, Vancouver, and colleagues reported in the journal Chest.

In contrast, patients who were overweight with a BMI of 25-29 had roughly half the mortality risk as those who were underweight, at an HR of 0.52 (P < .001). Results were roughly similar among the patients with obesity with a BMI in excess of 30, among whom the HR for mortality at 1 year was 0.55 (P < .001), compared with those who were underweight.

“All patients with fibrotic ILD should still engage in exercise and eat an appropriate diet and it is still okay if you are obese and lose weight as a consequence of these lifestyle choices,” Dr. Ryerson told this news organization. “But physicians should be concerned about patients who have severe ILD and who start to lose weight unintentionally since this often represents end-stage fibrosis or some other major comorbidity such as cancer.”
 

Two large cohorts

Patients from two large cohorts, including the six-center Canadian Registry for Pulmonary Fibrosis (CARE-PF) and the ILD registry at the University of California, San Francisco, were enrolled in the study. A total of 1,786 patients were included from the CARE-PF registry, which served as the derivation cohort, while another 1,779 patients from the UCSF registry served as the validation cohort. In the CARE-PF cohort, 21% of all ILD patients experienced a weight loss of at least 1 kg in the first year of follow-up, including 31% of patients with idiopathic pulmonary fibrosis (IPF).

“Fewer patients experienced a weight loss of at least 1 kg during the first year of the study period in the UCSF cohort,” the authors noted, at only 12% of all ILD patients, some 14% of those with IPF losing at least 1 kg of weight over the course of the year. At 2 years’ follow-up, 35% of all ILD patients had lost at least 1 kg, as had 46% of all IPF patients. Looking at BMI, “a higher value was associated with decreased 1-year mortality in both cohorts on unadjusted analysis,” the investigators observed.

In the CARE-PF cohort, the HR for 1-year mortality was 0.96 per unit difference in BMI (P < .001), while in the UCSF cohort, the HR for 1-year mortality was exactly the same, at 0.96 per unit difference in BMI (P < .001). The authors then adjusted findings for the ILD-GAP index, which included gender, age, and physiology index. After adjusting for this index, the HR for 1-year mortality in the CARE-PF cohort was 0.93 per unit change in BMI (95% CI, 0.90-0.967; P < .001), while in the UCSF cohort, the HR was 0.96 per unit change in BMI (95% CI, 0.94-0.98; P = .001).

Indeed, each 1-kg change above a BMI of 30, adjusted for the ILD-GAP index, was associated with a reduced risk of mortality at 1 year in both cohorts, at an HR of 0.98 (P = .001) in the CARE-PF cohort and an HR of 0.98 (P < .001) in the UCSF cohort. In contrast, patients who experienced a BMI weight loss of 2 kg or more within 1 year had a 41% increased risk of death in the subsequent year after adjusting for the ILD-GAP index and baseline BMI category, at an HR of 1.41 (P = .04). “The absolute change in mortality is much smaller than this,” Dr. Ryerson acknowledged.

“However, the magnitude [in mortality risk] did impress us and this illustrates how weight loss is a frequent consequence of end-stage disease which is something that we have all observed clinically as well,” he added.

Mortality risk plateaued in patients with a greater weight loss, the investigators observed, and there was no association between weight and subsequent 1-year mortality in either cohort on unadjusted analysis.

On the other hand, being underweight was associated with between a 13% and 16% higher mortality risk at 1 year after adjusting for the ILD-GAP, at an HR of 0.84 per 10 kg (P = .001) in the CARE-PF cohort and an HR of 0.87 per 10 kg (P < .001) in the UCSF cohort. “Results were similar in the two studied cohorts, suggesting a robust and generalizable association of both low BMI and weight loss with mortality,” the authors emphasized.

“Together these studies highlight the potential link between obesity and ILD pathogenesis and further suggest the possibility that nutritional support may have a more specific and important role in the management of fibrotic ILD,” the authors wrote. Dr. Ryerson in turn noted that being able to determine mortality risk more accurately than current mortality risk prediction models are able to do is very helpful when dealing with what are sometimes life-and-death decisions.

He also said that having more insight into a patient’s prognosis can change how physicians manage patients with respect to either transplantation or palliation and potentially the need to be more aggressive with pharmacotherapy as well.
 

Addressing weight loss

Asked to comment on the findings, Elizabeth Volkmann, MD, associate professor of medicine, University of California, Los Angeles, said that this was a very important study and something that she feels does not get adequate attention in clinical practice.

“Weight loss and malnutrition occur in many patients with ILD due to various factors such as gastrointestinal side effects from antifibrotic therapies, decreased oral intake due to psychosocial issues including depression, and increased caloric requirements due to increased work of breathing,” she said in an interview. That said, weight loss and malnutrition are still often underaddressed during clinical encounters for patients with ILD where the focus is on lung health.

“This study illuminates the importance of addressing weight loss in all patients with ILD as it can contribute to heightened risk of mortality,” Dr. Volkmann reemphasized. Dr. Volkmann and colleagues themselves recently reported that radiographic progression of scleroderma lung disease over the course of 1-2 years is associated with an increased risk of long-term mortality, based on two independent studies of systemic sclerosis–interstitial lung disease with extensive follow-up.

Over 8 years of follow-up, patients in the Scleroderma Lung Study II who exhibited an increase of 2% or more in the QILD score – a score that reflects the sum of all abnormally classified scores, including those for fibrosis, ground glass opacity, and honeycombing – for the whole lung at 24 months had an almost fourfold increased risk in mortality, which was significant (P = .014).

The association of an increase in the QILD of at least 2% at 12 months was suggestive in its association with mortality in the SLS I cohort at 12 years of follow-up, a finding that suggests that radiographic progression measured at 2 years is a better predictor of long-term mortality than at 1 year, as the authors concluded.

The CARR-PF is funded by Boehringer Ingelheim. Dr. Ryerson reported receiving personal fees from Boehringer Ingelheim. Dr. Volkmann consults or has received speaker fees from Boehringer Ingelheim and has received grant support from Kadmon and Horizon Therapeutics.

A version of this article first appeared on Medscape.com.

A low body mass index (BMI) indicative of being underweight as well as a weight loss of 2 kg or more over the course of 1 year were both independently associated with a higher mortality risk in the following year in patients with fibrotic interstitial lung disease (ILD). In contrast, being both overweight and obese appeared to be protective against mortality at the same 1-year endpoint, according to the results of an observational, retrospective cohort study.

Compared with patients with a normal BMI, patients who were underweight at a BMI of less than 18.5 kg/m² were over three times more likely to die at 1 year, at a hazard ratio of 3.19 (P < .001), senior author Christopher Ryerson, MD, University of British Columbia, Vancouver, and colleagues reported in the journal Chest.

In contrast, patients who were overweight with a BMI of 25-29 had roughly half the mortality risk as those who were underweight, at an HR of 0.52 (P < .001). Results were roughly similar among the patients with obesity with a BMI in excess of 30, among whom the HR for mortality at 1 year was 0.55 (P < .001), compared with those who were underweight.

“All patients with fibrotic ILD should still engage in exercise and eat an appropriate diet and it is still okay if you are obese and lose weight as a consequence of these lifestyle choices,” Dr. Ryerson told this news organization. “But physicians should be concerned about patients who have severe ILD and who start to lose weight unintentionally since this often represents end-stage fibrosis or some other major comorbidity such as cancer.”
 

Two large cohorts

Patients from two large cohorts, including the six-center Canadian Registry for Pulmonary Fibrosis (CARE-PF) and the ILD registry at the University of California, San Francisco, were enrolled in the study. A total of 1,786 patients were included from the CARE-PF registry, which served as the derivation cohort, while another 1,779 patients from the UCSF registry served as the validation cohort. In the CARE-PF cohort, 21% of all ILD patients experienced a weight loss of at least 1 kg in the first year of follow-up, including 31% of patients with idiopathic pulmonary fibrosis (IPF).

“Fewer patients experienced a weight loss of at least 1 kg during the first year of the study period in the UCSF cohort,” the authors noted, at only 12% of all ILD patients, some 14% of those with IPF losing at least 1 kg of weight over the course of the year. At 2 years’ follow-up, 35% of all ILD patients had lost at least 1 kg, as had 46% of all IPF patients. Looking at BMI, “a higher value was associated with decreased 1-year mortality in both cohorts on unadjusted analysis,” the investigators observed.

In the CARE-PF cohort, the HR for 1-year mortality was 0.96 per unit difference in BMI (P < .001), while in the UCSF cohort, the HR for 1-year mortality was exactly the same, at 0.96 per unit difference in BMI (P < .001). The authors then adjusted findings for the ILD-GAP index, which included gender, age, and physiology index. After adjusting for this index, the HR for 1-year mortality in the CARE-PF cohort was 0.93 per unit change in BMI (95% CI, 0.90-0.967; P < .001), while in the UCSF cohort, the HR was 0.96 per unit change in BMI (95% CI, 0.94-0.98; P = .001).

Indeed, each 1-kg change above a BMI of 30, adjusted for the ILD-GAP index, was associated with a reduced risk of mortality at 1 year in both cohorts, at an HR of 0.98 (P = .001) in the CARE-PF cohort and an HR of 0.98 (P < .001) in the UCSF cohort. In contrast, patients who experienced a BMI weight loss of 2 kg or more within 1 year had a 41% increased risk of death in the subsequent year after adjusting for the ILD-GAP index and baseline BMI category, at an HR of 1.41 (P = .04). “The absolute change in mortality is much smaller than this,” Dr. Ryerson acknowledged.

“However, the magnitude [in mortality risk] did impress us and this illustrates how weight loss is a frequent consequence of end-stage disease which is something that we have all observed clinically as well,” he added.

Mortality risk plateaued in patients with a greater weight loss, the investigators observed, and there was no association between weight and subsequent 1-year mortality in either cohort on unadjusted analysis.

On the other hand, being underweight was associated with between a 13% and 16% higher mortality risk at 1 year after adjusting for the ILD-GAP, at an HR of 0.84 per 10 kg (P = .001) in the CARE-PF cohort and an HR of 0.87 per 10 kg (P < .001) in the UCSF cohort. “Results were similar in the two studied cohorts, suggesting a robust and generalizable association of both low BMI and weight loss with mortality,” the authors emphasized.

“Together these studies highlight the potential link between obesity and ILD pathogenesis and further suggest the possibility that nutritional support may have a more specific and important role in the management of fibrotic ILD,” the authors wrote. Dr. Ryerson in turn noted that being able to determine mortality risk more accurately than current mortality risk prediction models are able to do is very helpful when dealing with what are sometimes life-and-death decisions.

He also said that having more insight into a patient’s prognosis can change how physicians manage patients with respect to either transplantation or palliation and potentially the need to be more aggressive with pharmacotherapy as well.
 

Addressing weight loss

Asked to comment on the findings, Elizabeth Volkmann, MD, associate professor of medicine, University of California, Los Angeles, said that this was a very important study and something that she feels does not get adequate attention in clinical practice.

“Weight loss and malnutrition occur in many patients with ILD due to various factors such as gastrointestinal side effects from antifibrotic therapies, decreased oral intake due to psychosocial issues including depression, and increased caloric requirements due to increased work of breathing,” she said in an interview. That said, weight loss and malnutrition are still often underaddressed during clinical encounters for patients with ILD where the focus is on lung health.

“This study illuminates the importance of addressing weight loss in all patients with ILD as it can contribute to heightened risk of mortality,” Dr. Volkmann reemphasized. Dr. Volkmann and colleagues themselves recently reported that radiographic progression of scleroderma lung disease over the course of 1-2 years is associated with an increased risk of long-term mortality, based on two independent studies of systemic sclerosis–interstitial lung disease with extensive follow-up.

Over 8 years of follow-up, patients in the Scleroderma Lung Study II who exhibited an increase of 2% or more in the QILD score – a score that reflects the sum of all abnormally classified scores, including those for fibrosis, ground glass opacity, and honeycombing – for the whole lung at 24 months had an almost fourfold increased risk in mortality, which was significant (P = .014).

The association of an increase in the QILD of at least 2% at 12 months was suggestive in its association with mortality in the SLS I cohort at 12 years of follow-up, a finding that suggests that radiographic progression measured at 2 years is a better predictor of long-term mortality than at 1 year, as the authors concluded.

The CARR-PF is funded by Boehringer Ingelheim. Dr. Ryerson reported receiving personal fees from Boehringer Ingelheim. Dr. Volkmann consults or has received speaker fees from Boehringer Ingelheim and has received grant support from Kadmon and Horizon Therapeutics.

A version of this article first appeared on Medscape.com.

A low body mass index (BMI) indicative of being underweight as well as a weight loss of 2 kg or more over the course of 1 year were both independently associated with a higher mortality risk in the following year in patients with fibrotic interstitial lung disease (ILD). In contrast, being both overweight and obese appeared to be protective against mortality at the same 1-year endpoint, according to the results of an observational, retrospective cohort study.

Compared with patients with a normal BMI, patients who were underweight at a BMI of less than 18.5 kg/m² were over three times more likely to die at 1 year, at a hazard ratio of 3.19 (P < .001), senior author Christopher Ryerson, MD, University of British Columbia, Vancouver, and colleagues reported in the journal Chest.

In contrast, patients who were overweight with a BMI of 25-29 had roughly half the mortality risk as those who were underweight, at an HR of 0.52 (P < .001). Results were roughly similar among the patients with obesity with a BMI in excess of 30, among whom the HR for mortality at 1 year was 0.55 (P < .001), compared with those who were underweight.

“All patients with fibrotic ILD should still engage in exercise and eat an appropriate diet and it is still okay if you are obese and lose weight as a consequence of these lifestyle choices,” Dr. Ryerson told this news organization. “But physicians should be concerned about patients who have severe ILD and who start to lose weight unintentionally since this often represents end-stage fibrosis or some other major comorbidity such as cancer.”
 

Two large cohorts

Patients from two large cohorts, including the six-center Canadian Registry for Pulmonary Fibrosis (CARE-PF) and the ILD registry at the University of California, San Francisco, were enrolled in the study. A total of 1,786 patients were included from the CARE-PF registry, which served as the derivation cohort, while another 1,779 patients from the UCSF registry served as the validation cohort. In the CARE-PF cohort, 21% of all ILD patients experienced a weight loss of at least 1 kg in the first year of follow-up, including 31% of patients with idiopathic pulmonary fibrosis (IPF).

“Fewer patients experienced a weight loss of at least 1 kg during the first year of the study period in the UCSF cohort,” the authors noted, at only 12% of all ILD patients, some 14% of those with IPF losing at least 1 kg of weight over the course of the year. At 2 years’ follow-up, 35% of all ILD patients had lost at least 1 kg, as had 46% of all IPF patients. Looking at BMI, “a higher value was associated with decreased 1-year mortality in both cohorts on unadjusted analysis,” the investigators observed.

In the CARE-PF cohort, the HR for 1-year mortality was 0.96 per unit difference in BMI (P < .001), while in the UCSF cohort, the HR for 1-year mortality was exactly the same, at 0.96 per unit difference in BMI (P < .001). The authors then adjusted findings for the ILD-GAP index, which included gender, age, and physiology index. After adjusting for this index, the HR for 1-year mortality in the CARE-PF cohort was 0.93 per unit change in BMI (95% CI, 0.90-0.967; P < .001), while in the UCSF cohort, the HR was 0.96 per unit change in BMI (95% CI, 0.94-0.98; P = .001).

Indeed, each 1-kg change above a BMI of 30, adjusted for the ILD-GAP index, was associated with a reduced risk of mortality at 1 year in both cohorts, at an HR of 0.98 (P = .001) in the CARE-PF cohort and an HR of 0.98 (P < .001) in the UCSF cohort. In contrast, patients who experienced a BMI weight loss of 2 kg or more within 1 year had a 41% increased risk of death in the subsequent year after adjusting for the ILD-GAP index and baseline BMI category, at an HR of 1.41 (P = .04). “The absolute change in mortality is much smaller than this,” Dr. Ryerson acknowledged.

“However, the magnitude [in mortality risk] did impress us and this illustrates how weight loss is a frequent consequence of end-stage disease which is something that we have all observed clinically as well,” he added.

Mortality risk plateaued in patients with a greater weight loss, the investigators observed, and there was no association between weight and subsequent 1-year mortality in either cohort on unadjusted analysis.

On the other hand, being underweight was associated with between a 13% and 16% higher mortality risk at 1 year after adjusting for the ILD-GAP, at an HR of 0.84 per 10 kg (P = .001) in the CARE-PF cohort and an HR of 0.87 per 10 kg (P < .001) in the UCSF cohort. “Results were similar in the two studied cohorts, suggesting a robust and generalizable association of both low BMI and weight loss with mortality,” the authors emphasized.

“Together these studies highlight the potential link between obesity and ILD pathogenesis and further suggest the possibility that nutritional support may have a more specific and important role in the management of fibrotic ILD,” the authors wrote. Dr. Ryerson in turn noted that being able to determine mortality risk more accurately than current mortality risk prediction models are able to do is very helpful when dealing with what are sometimes life-and-death decisions.

He also said that having more insight into a patient’s prognosis can change how physicians manage patients with respect to either transplantation or palliation and potentially the need to be more aggressive with pharmacotherapy as well.
 

Addressing weight loss

Asked to comment on the findings, Elizabeth Volkmann, MD, associate professor of medicine, University of California, Los Angeles, said that this was a very important study and something that she feels does not get adequate attention in clinical practice.

“Weight loss and malnutrition occur in many patients with ILD due to various factors such as gastrointestinal side effects from antifibrotic therapies, decreased oral intake due to psychosocial issues including depression, and increased caloric requirements due to increased work of breathing,” she said in an interview. That said, weight loss and malnutrition are still often underaddressed during clinical encounters for patients with ILD where the focus is on lung health.

“This study illuminates the importance of addressing weight loss in all patients with ILD as it can contribute to heightened risk of mortality,” Dr. Volkmann reemphasized. Dr. Volkmann and colleagues themselves recently reported that radiographic progression of scleroderma lung disease over the course of 1-2 years is associated with an increased risk of long-term mortality, based on two independent studies of systemic sclerosis–interstitial lung disease with extensive follow-up.

Over 8 years of follow-up, patients in the Scleroderma Lung Study II who exhibited an increase of 2% or more in the QILD score – a score that reflects the sum of all abnormally classified scores, including those for fibrosis, ground glass opacity, and honeycombing – for the whole lung at 24 months had an almost fourfold increased risk in mortality, which was significant (P = .014).

The association of an increase in the QILD of at least 2% at 12 months was suggestive in its association with mortality in the SLS I cohort at 12 years of follow-up, a finding that suggests that radiographic progression measured at 2 years is a better predictor of long-term mortality than at 1 year, as the authors concluded.

The CARR-PF is funded by Boehringer Ingelheim. Dr. Ryerson reported receiving personal fees from Boehringer Ingelheim. Dr. Volkmann consults or has received speaker fees from Boehringer Ingelheim and has received grant support from Kadmon and Horizon Therapeutics.

A version of this article first appeared on Medscape.com.

A wide range of treatments are being used to manage patients with palmoplantar pustulosis (PPP) and generalized pustular psoriasis (GPP), according to the results of two case series that evaluated the characteristics and course of the disease in patients diagnosed with PPP or GPP.

“These case series confirm the rarity of both generalized pustular psoriasis and palmoplantar pustulosis (PPP) and highlight the persistence of symptoms over time and the lack of effective treatment options available to patients,” Megan H. Noe, MD, MPH, MSCE, first author of both case series and assistant professor of dermatology, Harvard Medical School, and a dermatologist at Brigham and Women’s Hospital, both in Boston, said in an interview. In both studies, she added, “more than 20 different therapies were utilized, demonstrating a lack of consensus regarding effective treatment.”
 

The two case series were published in JAMA Dermatology.

Palmoplantar pustulosis

In the case series of 197 patients with PPP , data were obtained from a retrospective review at 20 academic dermatology practices in the United States between January 2007 and December 2018. The patients were mostly women (73.6%) who were White (60.9%), with a mean age of 53 years; 38.1% were current smokers, and 27.4% were former smokers, and the mean follow-up time was 22.1 months. About half (48.2%) of patients who presented to their respective centers had skin pain, 19.8% had problems using their hands and feet, 12.7% had arthralgias, and 2% had myalgias. Clinicians who examined these patients found pustules on the palms (80.2%), soles (76.7%), and both palms and soles (59.9%); some nail unit involvement was reported in 10.2%.

Patients were treated with a variety of topical therapies, systemic steroids, systemic anti-infectives, and systemic psoriasis therapies, Dr. Noe and colleagues said. The most common initial treatments included a topical steroid (84.8%), with the vast majority of clinicians using a high-potency topical steroid (153 of 167 patients; 91.6%), or topical therapy only (64.5%).

Other initial treatments used were other types of topical medications in 34 of the patients in the series (17.3%), such as a vitamin D analogue in 27 patients (79.4%); oral systemic treatments such as acitretin in 27 patients (13.7%) or methotrexate in 22 patients (11.2%); narrowband UVB phototherapy in 15 patients (7.7%); systemic steroids in 10 patients (5.1%); or systemic antibiotics in 9 patients (4.6%). Less commonly used were biologic agents like adalimumab, used in 6 patients (3.1%).

The researchers also examined health care utilization in 128 patients and found that 82% had at least one follow-up visit, 31.3% required two to three follow-up visits, and 18.8% had five or more follow-up visits. When adjusted to account for age and sex, there was a decreased risk of requiring five or more healthcare visits per year for women (odds ratio, 0.49; 95% confidence interval, 0.25-0.95)

Generalized pustular psoriasis

Dr. Noe and colleagues also evaluated 95 patients with GPP in a retrospective longitudinal case series of patients treated at 20 academic dermatology practices in the United States between January 2007 and December 2018. As in the PPP group, most patients in the GPP case series were women (70.5%), and over half were White (53.7%); the mean age was 50.3 years old, and the mean follow-up time was 19.8 months. A majority of patients with GPP were never-smokers (52.6%) or former smokers (20%). When patients with GPP initially presented to the study sites, 36.8% were admitted as inpatients, 9.5% presented in the emergency department, and 53.7% presented in an outpatient or ambulatory dermatology setting.

GPP commonly appeared on the trunk and extremities, but was “also reported on the scalp, face, genitals, nail unit, and mucous membranes in a minority of patients,” the researchers said. Overall, 62.1% of patients had skin pain, 26.2% had joint pain, 16.8% reported tachycardia, and 9.5% reported fever. Hypertension, depression, diabetes, chronic kidney disease, and hypothyroidism were common comorbidities of GPP, the researchers noted.

Clinicians reported treating GPP with topical steroids (86.3%) and topical treatments alone (32.3%). Oral systemic treatments such as acitretin (24.2%), cyclosporine (22.1%), and methotrexate (13.7%) were also used, as well as systemic steroids (20%). Other treatments used were narrowband UVB phototherapy (5.3%) and biologic agents like adalimumab (4.2%) and infliximab (4.2%).

For 53 patients with follow-up data of at least 6 months, 19 (35.8%) had been hospitalized because of their symptoms, and 8 patients were hospitalized for further GPP-specific concerns. Patients with GPP had a median 3.2 dermatology visits per year and a maximum of 18 visits. A model that was adjusted for age and sex showed women were at a decreased risk for being admitted to the hospital or emergency department in the follow-up period (odds ratio, 0.19; 95% confidence interval, 0.04-0.83).

PPP and GPP in practice

Sylvia Hsu, MD, professor and chair of the department of dermatology at Temple University, Philadelphia, who was not involved with the research, noted that most dermatologists will see few, if any, cases of PPP and GPP in a year. At her center, she estimated that she sees about one PPP case per week, and one or two cases of GPP a year. In general, she said that her clinical experience matched what was found by the authors of both case series.

For patients with PPP, “I would say the average dermatologist would probably start out with a superpotent topical steroid like clobetasol or halobetasol ointment,” Dr. Hsu said.

If they are not of childbearing age, she added, she would also prescribe acitretin, which she avoids giving to patients of childbearing age because of its teratogenicity. “Acitretin has the reputation that it doesn’t work well or fast for psoriasis. It doesn’t work well or fast for plaque-type psoriasis, but it works well and fast for pustular psoriasis,” she said.

In place of acitretin, Dr. Hsu recommended cyclosporine for a patient of childbearing age as a short-term solution to resolve symptoms before transitioning them to another therapy. “A woman of childbearing age, you put on cyclosporine, you’ve got to transition to something else,” she said. “And so many times you wean them off, the pustular psoriasis comes back because the topical steroid doesn’t work that well.”

One possible option is the interluekin-23 inhibitor guselkumab (approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis and psoriatic arthritis) but cost and effectiveness can be a factor. Although studies have shown efficacy, biologics as treatments for PPP are “hit or miss,” Dr. Hsu said.

Regarding use of systemic therapies, Dr. Hsu cautioned against using them to treat plaque-type psoriasis. “We always learn, don’t use a systemic steroid like prednisone to treat psoriasis because it helps, but it comes back with a vengeance,” she said. “Sometimes when you treat plaque-type psoriasis with prednisone, it could come back with a vengeance, and it can come back as generalized pustular psoriasis.”

For patients with GPP, “you need a quick fix” because of the painful symptoms associated with the disease, Dr. Hsu said. In this case, she recommended cyclosporine and said she would avoid prescribing topical medications. “You’re going to have to give an oral drug because usually when we’re seeing somebody with GPP, they’re either a hospital consult or they just walked in the door,” she said. After prescribing cyclosporine, you would transition to another treatment like a biologic “as quickly as you can” with the knowledge that the biologic “may or may not work.”

New treatment options needed

Commenting on both case series in a related editorial, Edward W. Cowen, MD, MHSc, senior clinician and head of the dermatology consultation service in the dermatology branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md., said that “much of the clinical presentation of pustular disease remains a mystery,” including why tobacco use is a risk factor for developing pustular psoriasis, and why tumor necrosis factor inhibitors “induce pustular disease in a small number of patients” with psoriasis vulgaris.

“Most importantly, we still do not know if localized and generalized pustular psoriasis all truly represent different variants of the same disease process, and if not, which biologic treatment represents the best option for a given clinical variant,” he wrote.

Dr. Cowen noted that the multi-institutional approach to collecting the retrospective data in these case series could be used as a “basic framework to build on for future clinical trials for rare skin diseases such as pustular psoriasis.”

In the interview, Dr. Noe said that she hoped that the “Pustular Psoriasis in the US Research Group” she and her coauthors created for the case series could help with the development of prospective clinical trials. “For pustular psoriasis and other rare diseases in dermatology, multi-institutional collaborations are necessary to conduct prospective research,” she said.

“While not directly studied in our research, I think it is important to consider the negative impact on quality of life, experienced by patients with pustular psoriasis. In our study, many patients experienced exacerbations of their disease over time, and it is important to consider the impact this has on patients,” she said in the interview. “Continued research on pustular psoriasis is necessary to decrease the negative impact of these diseases on the lives of our patients.”

The case series were funded in part by an institutional grant from Boehringer Ingelheim. The authors report relationships with various pharmaceutical and biopharmaceutical companies, technology companies, medical publishing companies, medical journals, and medical societies with connections to the topic area in the form of serving in roles as a chief medical editor, consultant, data safety monitoring board member, deputy editor, principal investigator, research investigator, scientific adviser, or speaker; or having received grants, honoraria, personal fees, or research funding. Dr. Cowen has no disclosures. Dr. Hsu reports serving on a Boehringer Ingelheim advisory board for a product being evaluated as a potential treatment for GPP.

A wide range of treatments are being used to manage patients with palmoplantar pustulosis (PPP) and generalized pustular psoriasis (GPP), according to the results of two case series that evaluated the characteristics and course of the disease in patients diagnosed with PPP or GPP.

“These case series confirm the rarity of both generalized pustular psoriasis and palmoplantar pustulosis (PPP) and highlight the persistence of symptoms over time and the lack of effective treatment options available to patients,” Megan H. Noe, MD, MPH, MSCE, first author of both case series and assistant professor of dermatology, Harvard Medical School, and a dermatologist at Brigham and Women’s Hospital, both in Boston, said in an interview. In both studies, she added, “more than 20 different therapies were utilized, demonstrating a lack of consensus regarding effective treatment.”
 

The two case series were published in JAMA Dermatology.

Palmoplantar pustulosis

In the case series of 197 patients with PPP , data were obtained from a retrospective review at 20 academic dermatology practices in the United States between January 2007 and December 2018. The patients were mostly women (73.6%) who were White (60.9%), with a mean age of 53 years; 38.1% were current smokers, and 27.4% were former smokers, and the mean follow-up time was 22.1 months. About half (48.2%) of patients who presented to their respective centers had skin pain, 19.8% had problems using their hands and feet, 12.7% had arthralgias, and 2% had myalgias. Clinicians who examined these patients found pustules on the palms (80.2%), soles (76.7%), and both palms and soles (59.9%); some nail unit involvement was reported in 10.2%.

Patients were treated with a variety of topical therapies, systemic steroids, systemic anti-infectives, and systemic psoriasis therapies, Dr. Noe and colleagues said. The most common initial treatments included a topical steroid (84.8%), with the vast majority of clinicians using a high-potency topical steroid (153 of 167 patients; 91.6%), or topical therapy only (64.5%).

Other initial treatments used were other types of topical medications in 34 of the patients in the series (17.3%), such as a vitamin D analogue in 27 patients (79.4%); oral systemic treatments such as acitretin in 27 patients (13.7%) or methotrexate in 22 patients (11.2%); narrowband UVB phototherapy in 15 patients (7.7%); systemic steroids in 10 patients (5.1%); or systemic antibiotics in 9 patients (4.6%). Less commonly used were biologic agents like adalimumab, used in 6 patients (3.1%).

The researchers also examined health care utilization in 128 patients and found that 82% had at least one follow-up visit, 31.3% required two to three follow-up visits, and 18.8% had five or more follow-up visits. When adjusted to account for age and sex, there was a decreased risk of requiring five or more healthcare visits per year for women (odds ratio, 0.49; 95% confidence interval, 0.25-0.95)

Generalized pustular psoriasis

Dr. Noe and colleagues also evaluated 95 patients with GPP in a retrospective longitudinal case series of patients treated at 20 academic dermatology practices in the United States between January 2007 and December 2018. As in the PPP group, most patients in the GPP case series were women (70.5%), and over half were White (53.7%); the mean age was 50.3 years old, and the mean follow-up time was 19.8 months. A majority of patients with GPP were never-smokers (52.6%) or former smokers (20%). When patients with GPP initially presented to the study sites, 36.8% were admitted as inpatients, 9.5% presented in the emergency department, and 53.7% presented in an outpatient or ambulatory dermatology setting.

GPP commonly appeared on the trunk and extremities, but was “also reported on the scalp, face, genitals, nail unit, and mucous membranes in a minority of patients,” the researchers said. Overall, 62.1% of patients had skin pain, 26.2% had joint pain, 16.8% reported tachycardia, and 9.5% reported fever. Hypertension, depression, diabetes, chronic kidney disease, and hypothyroidism were common comorbidities of GPP, the researchers noted.

Clinicians reported treating GPP with topical steroids (86.3%) and topical treatments alone (32.3%). Oral systemic treatments such as acitretin (24.2%), cyclosporine (22.1%), and methotrexate (13.7%) were also used, as well as systemic steroids (20%). Other treatments used were narrowband UVB phototherapy (5.3%) and biologic agents like adalimumab (4.2%) and infliximab (4.2%).

For 53 patients with follow-up data of at least 6 months, 19 (35.8%) had been hospitalized because of their symptoms, and 8 patients were hospitalized for further GPP-specific concerns. Patients with GPP had a median 3.2 dermatology visits per year and a maximum of 18 visits. A model that was adjusted for age and sex showed women were at a decreased risk for being admitted to the hospital or emergency department in the follow-up period (odds ratio, 0.19; 95% confidence interval, 0.04-0.83).

PPP and GPP in practice

Sylvia Hsu, MD, professor and chair of the department of dermatology at Temple University, Philadelphia, who was not involved with the research, noted that most dermatologists will see few, if any, cases of PPP and GPP in a year. At her center, she estimated that she sees about one PPP case per week, and one or two cases of GPP a year. In general, she said that her clinical experience matched what was found by the authors of both case series.

For patients with PPP, “I would say the average dermatologist would probably start out with a superpotent topical steroid like clobetasol or halobetasol ointment,” Dr. Hsu said.

If they are not of childbearing age, she added, she would also prescribe acitretin, which she avoids giving to patients of childbearing age because of its teratogenicity. “Acitretin has the reputation that it doesn’t work well or fast for psoriasis. It doesn’t work well or fast for plaque-type psoriasis, but it works well and fast for pustular psoriasis,” she said.

In place of acitretin, Dr. Hsu recommended cyclosporine for a patient of childbearing age as a short-term solution to resolve symptoms before transitioning them to another therapy. “A woman of childbearing age, you put on cyclosporine, you’ve got to transition to something else,” she said. “And so many times you wean them off, the pustular psoriasis comes back because the topical steroid doesn’t work that well.”

One possible option is the interluekin-23 inhibitor guselkumab (approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis and psoriatic arthritis) but cost and effectiveness can be a factor. Although studies have shown efficacy, biologics as treatments for PPP are “hit or miss,” Dr. Hsu said.

Regarding use of systemic therapies, Dr. Hsu cautioned against using them to treat plaque-type psoriasis. “We always learn, don’t use a systemic steroid like prednisone to treat psoriasis because it helps, but it comes back with a vengeance,” she said. “Sometimes when you treat plaque-type psoriasis with prednisone, it could come back with a vengeance, and it can come back as generalized pustular psoriasis.”

For patients with GPP, “you need a quick fix” because of the painful symptoms associated with the disease, Dr. Hsu said. In this case, she recommended cyclosporine and said she would avoid prescribing topical medications. “You’re going to have to give an oral drug because usually when we’re seeing somebody with GPP, they’re either a hospital consult or they just walked in the door,” she said. After prescribing cyclosporine, you would transition to another treatment like a biologic “as quickly as you can” with the knowledge that the biologic “may or may not work.”

New treatment options needed

Commenting on both case series in a related editorial, Edward W. Cowen, MD, MHSc, senior clinician and head of the dermatology consultation service in the dermatology branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md., said that “much of the clinical presentation of pustular disease remains a mystery,” including why tobacco use is a risk factor for developing pustular psoriasis, and why tumor necrosis factor inhibitors “induce pustular disease in a small number of patients” with psoriasis vulgaris.

“Most importantly, we still do not know if localized and generalized pustular psoriasis all truly represent different variants of the same disease process, and if not, which biologic treatment represents the best option for a given clinical variant,” he wrote.

Dr. Cowen noted that the multi-institutional approach to collecting the retrospective data in these case series could be used as a “basic framework to build on for future clinical trials for rare skin diseases such as pustular psoriasis.”

In the interview, Dr. Noe said that she hoped that the “Pustular Psoriasis in the US Research Group” she and her coauthors created for the case series could help with the development of prospective clinical trials. “For pustular psoriasis and other rare diseases in dermatology, multi-institutional collaborations are necessary to conduct prospective research,” she said.

“While not directly studied in our research, I think it is important to consider the negative impact on quality of life, experienced by patients with pustular psoriasis. In our study, many patients experienced exacerbations of their disease over time, and it is important to consider the impact this has on patients,” she said in the interview. “Continued research on pustular psoriasis is necessary to decrease the negative impact of these diseases on the lives of our patients.”

The case series were funded in part by an institutional grant from Boehringer Ingelheim. The authors report relationships with various pharmaceutical and biopharmaceutical companies, technology companies, medical publishing companies, medical journals, and medical societies with connections to the topic area in the form of serving in roles as a chief medical editor, consultant, data safety monitoring board member, deputy editor, principal investigator, research investigator, scientific adviser, or speaker; or having received grants, honoraria, personal fees, or research funding. Dr. Cowen has no disclosures. Dr. Hsu reports serving on a Boehringer Ingelheim advisory board for a product being evaluated as a potential treatment for GPP.

A wide range of treatments are being used to manage patients with palmoplantar pustulosis (PPP) and generalized pustular psoriasis (GPP), according to the results of two case series that evaluated the characteristics and course of the disease in patients diagnosed with PPP or GPP.

“These case series confirm the rarity of both generalized pustular psoriasis and palmoplantar pustulosis (PPP) and highlight the persistence of symptoms over time and the lack of effective treatment options available to patients,” Megan H. Noe, MD, MPH, MSCE, first author of both case series and assistant professor of dermatology, Harvard Medical School, and a dermatologist at Brigham and Women’s Hospital, both in Boston, said in an interview. In both studies, she added, “more than 20 different therapies were utilized, demonstrating a lack of consensus regarding effective treatment.”
 

The two case series were published in JAMA Dermatology.

Palmoplantar pustulosis

In the case series of 197 patients with PPP , data were obtained from a retrospective review at 20 academic dermatology practices in the United States between January 2007 and December 2018. The patients were mostly women (73.6%) who were White (60.9%), with a mean age of 53 years; 38.1% were current smokers, and 27.4% were former smokers, and the mean follow-up time was 22.1 months. About half (48.2%) of patients who presented to their respective centers had skin pain, 19.8% had problems using their hands and feet, 12.7% had arthralgias, and 2% had myalgias. Clinicians who examined these patients found pustules on the palms (80.2%), soles (76.7%), and both palms and soles (59.9%); some nail unit involvement was reported in 10.2%.

Patients were treated with a variety of topical therapies, systemic steroids, systemic anti-infectives, and systemic psoriasis therapies, Dr. Noe and colleagues said. The most common initial treatments included a topical steroid (84.8%), with the vast majority of clinicians using a high-potency topical steroid (153 of 167 patients; 91.6%), or topical therapy only (64.5%).

Other initial treatments used were other types of topical medications in 34 of the patients in the series (17.3%), such as a vitamin D analogue in 27 patients (79.4%); oral systemic treatments such as acitretin in 27 patients (13.7%) or methotrexate in 22 patients (11.2%); narrowband UVB phototherapy in 15 patients (7.7%); systemic steroids in 10 patients (5.1%); or systemic antibiotics in 9 patients (4.6%). Less commonly used were biologic agents like adalimumab, used in 6 patients (3.1%).

The researchers also examined health care utilization in 128 patients and found that 82% had at least one follow-up visit, 31.3% required two to three follow-up visits, and 18.8% had five or more follow-up visits. When adjusted to account for age and sex, there was a decreased risk of requiring five or more healthcare visits per year for women (odds ratio, 0.49; 95% confidence interval, 0.25-0.95)

Generalized pustular psoriasis

Dr. Noe and colleagues also evaluated 95 patients with GPP in a retrospective longitudinal case series of patients treated at 20 academic dermatology practices in the United States between January 2007 and December 2018. As in the PPP group, most patients in the GPP case series were women (70.5%), and over half were White (53.7%); the mean age was 50.3 years old, and the mean follow-up time was 19.8 months. A majority of patients with GPP were never-smokers (52.6%) or former smokers (20%). When patients with GPP initially presented to the study sites, 36.8% were admitted as inpatients, 9.5% presented in the emergency department, and 53.7% presented in an outpatient or ambulatory dermatology setting.

GPP commonly appeared on the trunk and extremities, but was “also reported on the scalp, face, genitals, nail unit, and mucous membranes in a minority of patients,” the researchers said. Overall, 62.1% of patients had skin pain, 26.2% had joint pain, 16.8% reported tachycardia, and 9.5% reported fever. Hypertension, depression, diabetes, chronic kidney disease, and hypothyroidism were common comorbidities of GPP, the researchers noted.

Clinicians reported treating GPP with topical steroids (86.3%) and topical treatments alone (32.3%). Oral systemic treatments such as acitretin (24.2%), cyclosporine (22.1%), and methotrexate (13.7%) were also used, as well as systemic steroids (20%). Other treatments used were narrowband UVB phototherapy (5.3%) and biologic agents like adalimumab (4.2%) and infliximab (4.2%).

For 53 patients with follow-up data of at least 6 months, 19 (35.8%) had been hospitalized because of their symptoms, and 8 patients were hospitalized for further GPP-specific concerns. Patients with GPP had a median 3.2 dermatology visits per year and a maximum of 18 visits. A model that was adjusted for age and sex showed women were at a decreased risk for being admitted to the hospital or emergency department in the follow-up period (odds ratio, 0.19; 95% confidence interval, 0.04-0.83).

PPP and GPP in practice

Sylvia Hsu, MD, professor and chair of the department of dermatology at Temple University, Philadelphia, who was not involved with the research, noted that most dermatologists will see few, if any, cases of PPP and GPP in a year. At her center, she estimated that she sees about one PPP case per week, and one or two cases of GPP a year. In general, she said that her clinical experience matched what was found by the authors of both case series.

For patients with PPP, “I would say the average dermatologist would probably start out with a superpotent topical steroid like clobetasol or halobetasol ointment,” Dr. Hsu said.

If they are not of childbearing age, she added, she would also prescribe acitretin, which she avoids giving to patients of childbearing age because of its teratogenicity. “Acitretin has the reputation that it doesn’t work well or fast for psoriasis. It doesn’t work well or fast for plaque-type psoriasis, but it works well and fast for pustular psoriasis,” she said.

In place of acitretin, Dr. Hsu recommended cyclosporine for a patient of childbearing age as a short-term solution to resolve symptoms before transitioning them to another therapy. “A woman of childbearing age, you put on cyclosporine, you’ve got to transition to something else,” she said. “And so many times you wean them off, the pustular psoriasis comes back because the topical steroid doesn’t work that well.”

One possible option is the interluekin-23 inhibitor guselkumab (approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis and psoriatic arthritis) but cost and effectiveness can be a factor. Although studies have shown efficacy, biologics as treatments for PPP are “hit or miss,” Dr. Hsu said.

Regarding use of systemic therapies, Dr. Hsu cautioned against using them to treat plaque-type psoriasis. “We always learn, don’t use a systemic steroid like prednisone to treat psoriasis because it helps, but it comes back with a vengeance,” she said. “Sometimes when you treat plaque-type psoriasis with prednisone, it could come back with a vengeance, and it can come back as generalized pustular psoriasis.”

For patients with GPP, “you need a quick fix” because of the painful symptoms associated with the disease, Dr. Hsu said. In this case, she recommended cyclosporine and said she would avoid prescribing topical medications. “You’re going to have to give an oral drug because usually when we’re seeing somebody with GPP, they’re either a hospital consult or they just walked in the door,” she said. After prescribing cyclosporine, you would transition to another treatment like a biologic “as quickly as you can” with the knowledge that the biologic “may or may not work.”

New treatment options needed

Commenting on both case series in a related editorial, Edward W. Cowen, MD, MHSc, senior clinician and head of the dermatology consultation service in the dermatology branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md., said that “much of the clinical presentation of pustular disease remains a mystery,” including why tobacco use is a risk factor for developing pustular psoriasis, and why tumor necrosis factor inhibitors “induce pustular disease in a small number of patients” with psoriasis vulgaris.

“Most importantly, we still do not know if localized and generalized pustular psoriasis all truly represent different variants of the same disease process, and if not, which biologic treatment represents the best option for a given clinical variant,” he wrote.

Dr. Cowen noted that the multi-institutional approach to collecting the retrospective data in these case series could be used as a “basic framework to build on for future clinical trials for rare skin diseases such as pustular psoriasis.”

In the interview, Dr. Noe said that she hoped that the “Pustular Psoriasis in the US Research Group” she and her coauthors created for the case series could help with the development of prospective clinical trials. “For pustular psoriasis and other rare diseases in dermatology, multi-institutional collaborations are necessary to conduct prospective research,” she said.

“While not directly studied in our research, I think it is important to consider the negative impact on quality of life, experienced by patients with pustular psoriasis. In our study, many patients experienced exacerbations of their disease over time, and it is important to consider the impact this has on patients,” she said in the interview. “Continued research on pustular psoriasis is necessary to decrease the negative impact of these diseases on the lives of our patients.”

The case series were funded in part by an institutional grant from Boehringer Ingelheim. The authors report relationships with various pharmaceutical and biopharmaceutical companies, technology companies, medical publishing companies, medical journals, and medical societies with connections to the topic area in the form of serving in roles as a chief medical editor, consultant, data safety monitoring board member, deputy editor, principal investigator, research investigator, scientific adviser, or speaker; or having received grants, honoraria, personal fees, or research funding. Dr. Cowen has no disclosures. Dr. Hsu reports serving on a Boehringer Ingelheim advisory board for a product being evaluated as a potential treatment for GPP.

A COVID-19 outbreak has occurred at one of the most remote places on earth – the Princess Elisabeth Polar Station in Antarctica.

Two-thirds of the 25 workers have tested positive at the station, despite all of them being fully vaccinated and going through several testing stages before being allowed entrance, the Belgium publication Le Soir reported.

So far, all the cases are mild at the station, which is owned by Belgium and operated by a private group: the International Polar Foundation.

The first case was discovered Dec. 14 among a group that arrived a week earlier in Antarctica, Le Soir reported. The first three people to test positive evacuated Dec. 23, Le Soir said, but the virus continued to spread among the remaining workers at the base.

Le Soir, citing a virologist, said the Omicron variant probably caused the outbreak, because the crew made its last stop in South Africa before arriving in Antarctica.

New arrivals to the station have been put on hold until the outbreak is brought under control, and one of the missions planned for the base has been postponed, Le Soir said.

“The situation isn’t dramatic,” Joseph Cheek, a project manager for the International Polar Foundation, told the BBC. “While it has been an inconvenience to have to quarantine certain members of the staff who caught the virus, it hasn’t significantly affected our work at the station overall.”

The BBC said there was another COVID outbreak in Antarctica about a year ago at the Bernardo O’Higgins research station operated by Chile.

A version of this article first appeared on WebMD.com.

A COVID-19 outbreak has occurred at one of the most remote places on earth – the Princess Elisabeth Polar Station in Antarctica.

Two-thirds of the 25 workers have tested positive at the station, despite all of them being fully vaccinated and going through several testing stages before being allowed entrance, the Belgium publication Le Soir reported.

So far, all the cases are mild at the station, which is owned by Belgium and operated by a private group: the International Polar Foundation.

The first case was discovered Dec. 14 among a group that arrived a week earlier in Antarctica, Le Soir reported. The first three people to test positive evacuated Dec. 23, Le Soir said, but the virus continued to spread among the remaining workers at the base.

Le Soir, citing a virologist, said the Omicron variant probably caused the outbreak, because the crew made its last stop in South Africa before arriving in Antarctica.

New arrivals to the station have been put on hold until the outbreak is brought under control, and one of the missions planned for the base has been postponed, Le Soir said.

“The situation isn’t dramatic,” Joseph Cheek, a project manager for the International Polar Foundation, told the BBC. “While it has been an inconvenience to have to quarantine certain members of the staff who caught the virus, it hasn’t significantly affected our work at the station overall.”

The BBC said there was another COVID outbreak in Antarctica about a year ago at the Bernardo O’Higgins research station operated by Chile.

A version of this article first appeared on WebMD.com.

A COVID-19 outbreak has occurred at one of the most remote places on earth – the Princess Elisabeth Polar Station in Antarctica.

Two-thirds of the 25 workers have tested positive at the station, despite all of them being fully vaccinated and going through several testing stages before being allowed entrance, the Belgium publication Le Soir reported.

So far, all the cases are mild at the station, which is owned by Belgium and operated by a private group: the International Polar Foundation.

The first case was discovered Dec. 14 among a group that arrived a week earlier in Antarctica, Le Soir reported. The first three people to test positive evacuated Dec. 23, Le Soir said, but the virus continued to spread among the remaining workers at the base.

Le Soir, citing a virologist, said the Omicron variant probably caused the outbreak, because the crew made its last stop in South Africa before arriving in Antarctica.

New arrivals to the station have been put on hold until the outbreak is brought under control, and one of the missions planned for the base has been postponed, Le Soir said.

“The situation isn’t dramatic,” Joseph Cheek, a project manager for the International Polar Foundation, told the BBC. “While it has been an inconvenience to have to quarantine certain members of the staff who caught the virus, it hasn’t significantly affected our work at the station overall.”

The BBC said there was another COVID outbreak in Antarctica about a year ago at the Bernardo O’Higgins research station operated by Chile.

A version of this article first appeared on WebMD.com.

Researchers have known for some time that depression is associated with Alzheimer’s disease (AD), but a causal link has been elusive. Now, using newly available data, they have uncovered genetic evidence of a causal role for depression in AD.

As depression typically affects those in early or midlife and dementia often occurs in later life, “it’s fascinating to see a connection between the two brain illnesses that manifest in different time windows,” coinvestigator Aliza P. Wingo, MD, associate professor of psychiatry and behavioral science, Emory University, Atlanta, said in an interview.

“If we can treat the depression early on, we may help reduce risk for dementia for our patients later in life,” Dr. Wingo said.

The findings were published online Dec. 16, 2021, in Biological Psychiatry.

Postmortem data

The investigators, who are all from the Emory University Center for Neurodegenerative Disease, wanted to clarify the genetic basis underlying the association between the established link between depression and dementia risk.

They used data from the largest and most recent genomewide association studies (GWAS). These included a 2019 analysis of depression among 807,553 individuals and a 2019 study of AD among 455,258 individuals, all of European ancestry. For sensitivity analyses, they used results from two additional AD GWAS.

The researchers also accessed postmortem brain samples from participants in the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). These participants were cognitively normal at enrollment, underwent annual clinical evaluations, and agreed to donate their brains.

They also assessed brain samples donated by participants in the Banner Sun Health Research Institute longitudinal study of healthy aging, Alzheimer’s, and Parkinson’s disease.

The brain samples allowed researchers to use deep brain proteomic data to help determine molecular links between depression and AD.

After quality control, the analysis included 8,356 proteins in 391 ROS/MAP participants and 7,854 proteins in 196 Banner participants.

Results showed a small but significant positive genetic correlation between depression and AD, suggesting the two conditions have a shared genetic basis.

The investigators also applied a framework called “Mendelian randomization” to determine causality between depression and AD.

After assessing the effect of 115 independent single-nucleotide polymorphisms (SNPs) from the GWAS of depression, they uncovered significant evidence “that the SNPs cause depression, which in turn cause AD,” said Dr. Wingo.
 

One-way relationship

The researchers conducted the same analysis on 61 significant SNPs from the GWAS of AD but did not find evidence to conclude AD causes depression.

“We found genetic evidence supporting a causal role of depression in AD but not vice versa,” Dr. Wingo said.

In addition, the investigators identified 75 brain transcripts (messenger RNA) and 28 brain proteins regulated by the depression-predisposing genetic variants. Of these, 46 brain transcripts and seven proteins were significantly associated with at least one AD feature – for example, beta-amyloid, tau tangles, and cognitive trajectory.

“These findings support the notion that the depression risk variants contribute to AD via regulating expression of their corresponding transcripts in the brain,” the investigators wrote.

It is only recently that large enough studies have allowed researchers sufficient power to reach these conclusions, coinvestigator Thomas Wingo, MD, said in an interview.

These additional “insights” into the relationship between depression and AD might “motivate” clinicians more to screen for and treat depressive symptoms, Dr. Aliza Wingo noted.

The new results also have implications for developing therapeutics to treat depression, she said. “If we target the genes, the brain proteins, that are shared risk between depression and AD, the medications that target that gene might mitigate risk for AD later on.”

However, the investigators advised caution. “A lot of this is still unknown,” said Dr. Thomas Wingo.

For example, it is not clear whether successfully treating depression mitigates the eventual risk of dementia, which is “a very important topic of inquiry and one we continue to work on,” he said, adding that a significant number of patients do not respond well to existing antidepressants such as SSRIs.
 

Need for further research

Commenting on the findings, Claire Sexton, DPhil, director of scientific programs and outreach, Alzheimer’s Association, said the study contributes to the debate about whether depression increases risk for AD, whether AD increases risk for depression, or both.

“These newly published findings strengthen our understanding of the role of depression as a risk factor for Alzheimer’s dementia,” said Dr. Sexton, who was not involved with the research.

While experts do not yet fully understand the impact of treating depression on dementia risk, “the findings emphasize the importance of assessing mental health status, particularly depression, and getting it properly diagnosed and treated in a timely manner,” she said.

However, she agreed more research in this area is needed. “Importantly, these findings need replication in broader, more diverse study populations,” Dr. Sexton said.

A study funded by the Alzheimer’s Association may provide more information on the link between depression and AD. It will investigate whether machine learning, an advanced computer science technique, can better predict cognitive decline, compared with traditional methods.

Over a period of 6 months, researchers will collect smartphone conversations from 225 older adults with dementia, mild cognitive impairment, or no cognitive impairment. They will also have data from cognitive tests, brain scans, and biomarkers such as cerebrospinal fluid samples to study brain changes associated with AD.

The novel method of analysis should be able to identify subtle differences in speech quality to indicate which depressive symptoms an individual might be experiencing.

“The study could help us further understand the potential impact of depression in the risk of developing dementia,” said Dr. Sexton.

Dr. Aliza Wingo and Dr. Thomas Wingo reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Researchers have known for some time that depression is associated with Alzheimer’s disease (AD), but a causal link has been elusive. Now, using newly available data, they have uncovered genetic evidence of a causal role for depression in AD.

As depression typically affects those in early or midlife and dementia often occurs in later life, “it’s fascinating to see a connection between the two brain illnesses that manifest in different time windows,” coinvestigator Aliza P. Wingo, MD, associate professor of psychiatry and behavioral science, Emory University, Atlanta, said in an interview.

“If we can treat the depression early on, we may help reduce risk for dementia for our patients later in life,” Dr. Wingo said.

The findings were published online Dec. 16, 2021, in Biological Psychiatry.

Postmortem data

The investigators, who are all from the Emory University Center for Neurodegenerative Disease, wanted to clarify the genetic basis underlying the association between the established link between depression and dementia risk.

They used data from the largest and most recent genomewide association studies (GWAS). These included a 2019 analysis of depression among 807,553 individuals and a 2019 study of AD among 455,258 individuals, all of European ancestry. For sensitivity analyses, they used results from two additional AD GWAS.

The researchers also accessed postmortem brain samples from participants in the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). These participants were cognitively normal at enrollment, underwent annual clinical evaluations, and agreed to donate their brains.

They also assessed brain samples donated by participants in the Banner Sun Health Research Institute longitudinal study of healthy aging, Alzheimer’s, and Parkinson’s disease.

The brain samples allowed researchers to use deep brain proteomic data to help determine molecular links between depression and AD.

After quality control, the analysis included 8,356 proteins in 391 ROS/MAP participants and 7,854 proteins in 196 Banner participants.

Results showed a small but significant positive genetic correlation between depression and AD, suggesting the two conditions have a shared genetic basis.

The investigators also applied a framework called “Mendelian randomization” to determine causality between depression and AD.

After assessing the effect of 115 independent single-nucleotide polymorphisms (SNPs) from the GWAS of depression, they uncovered significant evidence “that the SNPs cause depression, which in turn cause AD,” said Dr. Wingo.
 

One-way relationship

The researchers conducted the same analysis on 61 significant SNPs from the GWAS of AD but did not find evidence to conclude AD causes depression.

“We found genetic evidence supporting a causal role of depression in AD but not vice versa,” Dr. Wingo said.

In addition, the investigators identified 75 brain transcripts (messenger RNA) and 28 brain proteins regulated by the depression-predisposing genetic variants. Of these, 46 brain transcripts and seven proteins were significantly associated with at least one AD feature – for example, beta-amyloid, tau tangles, and cognitive trajectory.

“These findings support the notion that the depression risk variants contribute to AD via regulating expression of their corresponding transcripts in the brain,” the investigators wrote.

It is only recently that large enough studies have allowed researchers sufficient power to reach these conclusions, coinvestigator Thomas Wingo, MD, said in an interview.

These additional “insights” into the relationship between depression and AD might “motivate” clinicians more to screen for and treat depressive symptoms, Dr. Aliza Wingo noted.

The new results also have implications for developing therapeutics to treat depression, she said. “If we target the genes, the brain proteins, that are shared risk between depression and AD, the medications that target that gene might mitigate risk for AD later on.”

However, the investigators advised caution. “A lot of this is still unknown,” said Dr. Thomas Wingo.

For example, it is not clear whether successfully treating depression mitigates the eventual risk of dementia, which is “a very important topic of inquiry and one we continue to work on,” he said, adding that a significant number of patients do not respond well to existing antidepressants such as SSRIs.
 

Need for further research

Commenting on the findings, Claire Sexton, DPhil, director of scientific programs and outreach, Alzheimer’s Association, said the study contributes to the debate about whether depression increases risk for AD, whether AD increases risk for depression, or both.

“These newly published findings strengthen our understanding of the role of depression as a risk factor for Alzheimer’s dementia,” said Dr. Sexton, who was not involved with the research.

While experts do not yet fully understand the impact of treating depression on dementia risk, “the findings emphasize the importance of assessing mental health status, particularly depression, and getting it properly diagnosed and treated in a timely manner,” she said.

However, she agreed more research in this area is needed. “Importantly, these findings need replication in broader, more diverse study populations,” Dr. Sexton said.

A study funded by the Alzheimer’s Association may provide more information on the link between depression and AD. It will investigate whether machine learning, an advanced computer science technique, can better predict cognitive decline, compared with traditional methods.

Over a period of 6 months, researchers will collect smartphone conversations from 225 older adults with dementia, mild cognitive impairment, or no cognitive impairment. They will also have data from cognitive tests, brain scans, and biomarkers such as cerebrospinal fluid samples to study brain changes associated with AD.

The novel method of analysis should be able to identify subtle differences in speech quality to indicate which depressive symptoms an individual might be experiencing.

“The study could help us further understand the potential impact of depression in the risk of developing dementia,” said Dr. Sexton.

Dr. Aliza Wingo and Dr. Thomas Wingo reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Researchers have known for some time that depression is associated with Alzheimer’s disease (AD), but a causal link has been elusive. Now, using newly available data, they have uncovered genetic evidence of a causal role for depression in AD.

As depression typically affects those in early or midlife and dementia often occurs in later life, “it’s fascinating to see a connection between the two brain illnesses that manifest in different time windows,” coinvestigator Aliza P. Wingo, MD, associate professor of psychiatry and behavioral science, Emory University, Atlanta, said in an interview.

“If we can treat the depression early on, we may help reduce risk for dementia for our patients later in life,” Dr. Wingo said.

The findings were published online Dec. 16, 2021, in Biological Psychiatry.

Postmortem data

The investigators, who are all from the Emory University Center for Neurodegenerative Disease, wanted to clarify the genetic basis underlying the association between the established link between depression and dementia risk.

They used data from the largest and most recent genomewide association studies (GWAS). These included a 2019 analysis of depression among 807,553 individuals and a 2019 study of AD among 455,258 individuals, all of European ancestry. For sensitivity analyses, they used results from two additional AD GWAS.

The researchers also accessed postmortem brain samples from participants in the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). These participants were cognitively normal at enrollment, underwent annual clinical evaluations, and agreed to donate their brains.

They also assessed brain samples donated by participants in the Banner Sun Health Research Institute longitudinal study of healthy aging, Alzheimer’s, and Parkinson’s disease.

The brain samples allowed researchers to use deep brain proteomic data to help determine molecular links between depression and AD.

After quality control, the analysis included 8,356 proteins in 391 ROS/MAP participants and 7,854 proteins in 196 Banner participants.

Results showed a small but significant positive genetic correlation between depression and AD, suggesting the two conditions have a shared genetic basis.

The investigators also applied a framework called “Mendelian randomization” to determine causality between depression and AD.

After assessing the effect of 115 independent single-nucleotide polymorphisms (SNPs) from the GWAS of depression, they uncovered significant evidence “that the SNPs cause depression, which in turn cause AD,” said Dr. Wingo.
 

One-way relationship

The researchers conducted the same analysis on 61 significant SNPs from the GWAS of AD but did not find evidence to conclude AD causes depression.

“We found genetic evidence supporting a causal role of depression in AD but not vice versa,” Dr. Wingo said.

In addition, the investigators identified 75 brain transcripts (messenger RNA) and 28 brain proteins regulated by the depression-predisposing genetic variants. Of these, 46 brain transcripts and seven proteins were significantly associated with at least one AD feature – for example, beta-amyloid, tau tangles, and cognitive trajectory.

“These findings support the notion that the depression risk variants contribute to AD via regulating expression of their corresponding transcripts in the brain,” the investigators wrote.

It is only recently that large enough studies have allowed researchers sufficient power to reach these conclusions, coinvestigator Thomas Wingo, MD, said in an interview.

These additional “insights” into the relationship between depression and AD might “motivate” clinicians more to screen for and treat depressive symptoms, Dr. Aliza Wingo noted.

The new results also have implications for developing therapeutics to treat depression, she said. “If we target the genes, the brain proteins, that are shared risk between depression and AD, the medications that target that gene might mitigate risk for AD later on.”

However, the investigators advised caution. “A lot of this is still unknown,” said Dr. Thomas Wingo.

For example, it is not clear whether successfully treating depression mitigates the eventual risk of dementia, which is “a very important topic of inquiry and one we continue to work on,” he said, adding that a significant number of patients do not respond well to existing antidepressants such as SSRIs.
 

Need for further research

Commenting on the findings, Claire Sexton, DPhil, director of scientific programs and outreach, Alzheimer’s Association, said the study contributes to the debate about whether depression increases risk for AD, whether AD increases risk for depression, or both.

“These newly published findings strengthen our understanding of the role of depression as a risk factor for Alzheimer’s dementia,” said Dr. Sexton, who was not involved with the research.

While experts do not yet fully understand the impact of treating depression on dementia risk, “the findings emphasize the importance of assessing mental health status, particularly depression, and getting it properly diagnosed and treated in a timely manner,” she said.

However, she agreed more research in this area is needed. “Importantly, these findings need replication in broader, more diverse study populations,” Dr. Sexton said.

A study funded by the Alzheimer’s Association may provide more information on the link between depression and AD. It will investigate whether machine learning, an advanced computer science technique, can better predict cognitive decline, compared with traditional methods.

Over a period of 6 months, researchers will collect smartphone conversations from 225 older adults with dementia, mild cognitive impairment, or no cognitive impairment. They will also have data from cognitive tests, brain scans, and biomarkers such as cerebrospinal fluid samples to study brain changes associated with AD.

The novel method of analysis should be able to identify subtle differences in speech quality to indicate which depressive symptoms an individual might be experiencing.

“The study could help us further understand the potential impact of depression in the risk of developing dementia,” said Dr. Sexton.

Dr. Aliza Wingo and Dr. Thomas Wingo reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

“I am capable and ready to begin.”

Sounds trite, doesn’t it? What slush pile did that come from?

Actually, it was the closing sentence of the 1988 “personal statement” I wrote for my medical school applications. (I applied to something like 25 schools, maybe more.) Come to think of it, I suspect my father came up with that line.

Have you read your personal statement since you became an attending? It’s like a letter from an alternate universe, where you weren’t a doctor, weren’t sure you’d ever be one, and were trying very hard to sound confident in the face of an uncertain future.

Mine began in a melodramatic way, emphasizing what I’d seen as an emergency department volunteer. When I wrote it I thought I’d be an ED doc, and never imagined that years later I’d be doing something entirely different – and loving it.

Having the opportunity to go back and talk to our younger selves is a common trope in movies, but in real life reading something like this is as close as it gets. But it’s still neat. It brings back not who you are, but who you were. Reminds you why you wanted to be a doctor, when you were younger, probably more naive, and felt medicine was a calling, not a job.

Do you still feel that way, after years of paperwork, insurance games, a mortgage, a family, defensive medicine, your own health changes, and all the other things life and the often-jaded medical field bring?

I hope the answer is still yes.

On my first day at Creighton Medical School, our dean – the late William L. Pancoe, PhD – gave us a “go get ‘em!” speech. His main theme was that we should “wear sneakers and hit the ground running” on day 1, because otherwise we’d never catch up. But he also told us to remember and hold on to the feeling we had when we got our first medical school acceptance letter. That feeling of relief, joy, the realization that we’d been given a chance to make our dream come true. He told us that feeling might be all that would get us through the long nights of studying, the occasional failures, the self-doubts, and all the other things in the 4 years to come.

Dean Pancoe, you were absolutely right. Today I’m older than you were when you gave us that speech. My only additions would be:

1. Don’t just hold onto that feeling for medical school, but for life.

2. Always keep one copy of your personal statement (even if in your picture you were wearing hideous 1980s-style glasses, like mine). Keep it in your work desk, not in the bottom of a filing cabinet or scrapbook. Read it at least once a year. It’ll take maybe 2 minutes. You have that much time to spare.

Because it’s not just the young who can learn from the wisdom of the old. The older can learn, and be reminded of, many good things from the young. Even if that younger person is you.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

“I am capable and ready to begin.”

Sounds trite, doesn’t it? What slush pile did that come from?

Actually, it was the closing sentence of the 1988 “personal statement” I wrote for my medical school applications. (I applied to something like 25 schools, maybe more.) Come to think of it, I suspect my father came up with that line.

Have you read your personal statement since you became an attending? It’s like a letter from an alternate universe, where you weren’t a doctor, weren’t sure you’d ever be one, and were trying very hard to sound confident in the face of an uncertain future.

Mine began in a melodramatic way, emphasizing what I’d seen as an emergency department volunteer. When I wrote it I thought I’d be an ED doc, and never imagined that years later I’d be doing something entirely different – and loving it.

Having the opportunity to go back and talk to our younger selves is a common trope in movies, but in real life reading something like this is as close as it gets. But it’s still neat. It brings back not who you are, but who you were. Reminds you why you wanted to be a doctor, when you were younger, probably more naive, and felt medicine was a calling, not a job.

Do you still feel that way, after years of paperwork, insurance games, a mortgage, a family, defensive medicine, your own health changes, and all the other things life and the often-jaded medical field bring?

I hope the answer is still yes.

On my first day at Creighton Medical School, our dean – the late William L. Pancoe, PhD – gave us a “go get ‘em!” speech. His main theme was that we should “wear sneakers and hit the ground running” on day 1, because otherwise we’d never catch up. But he also told us to remember and hold on to the feeling we had when we got our first medical school acceptance letter. That feeling of relief, joy, the realization that we’d been given a chance to make our dream come true. He told us that feeling might be all that would get us through the long nights of studying, the occasional failures, the self-doubts, and all the other things in the 4 years to come.

Dean Pancoe, you were absolutely right. Today I’m older than you were when you gave us that speech. My only additions would be:

1. Don’t just hold onto that feeling for medical school, but for life.

2. Always keep one copy of your personal statement (even if in your picture you were wearing hideous 1980s-style glasses, like mine). Keep it in your work desk, not in the bottom of a filing cabinet or scrapbook. Read it at least once a year. It’ll take maybe 2 minutes. You have that much time to spare.

Because it’s not just the young who can learn from the wisdom of the old. The older can learn, and be reminded of, many good things from the young. Even if that younger person is you.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

“I am capable and ready to begin.”

Sounds trite, doesn’t it? What slush pile did that come from?

Actually, it was the closing sentence of the 1988 “personal statement” I wrote for my medical school applications. (I applied to something like 25 schools, maybe more.) Come to think of it, I suspect my father came up with that line.

Have you read your personal statement since you became an attending? It’s like a letter from an alternate universe, where you weren’t a doctor, weren’t sure you’d ever be one, and were trying very hard to sound confident in the face of an uncertain future.

Mine began in a melodramatic way, emphasizing what I’d seen as an emergency department volunteer. When I wrote it I thought I’d be an ED doc, and never imagined that years later I’d be doing something entirely different – and loving it.

Having the opportunity to go back and talk to our younger selves is a common trope in movies, but in real life reading something like this is as close as it gets. But it’s still neat. It brings back not who you are, but who you were. Reminds you why you wanted to be a doctor, when you were younger, probably more naive, and felt medicine was a calling, not a job.

Do you still feel that way, after years of paperwork, insurance games, a mortgage, a family, defensive medicine, your own health changes, and all the other things life and the often-jaded medical field bring?

I hope the answer is still yes.

On my first day at Creighton Medical School, our dean – the late William L. Pancoe, PhD – gave us a “go get ‘em!” speech. His main theme was that we should “wear sneakers and hit the ground running” on day 1, because otherwise we’d never catch up. But he also told us to remember and hold on to the feeling we had when we got our first medical school acceptance letter. That feeling of relief, joy, the realization that we’d been given a chance to make our dream come true. He told us that feeling might be all that would get us through the long nights of studying, the occasional failures, the self-doubts, and all the other things in the 4 years to come.

Dean Pancoe, you were absolutely right. Today I’m older than you were when you gave us that speech. My only additions would be:

1. Don’t just hold onto that feeling for medical school, but for life.

2. Always keep one copy of your personal statement (even if in your picture you were wearing hideous 1980s-style glasses, like mine). Keep it in your work desk, not in the bottom of a filing cabinet or scrapbook. Read it at least once a year. It’ll take maybe 2 minutes. You have that much time to spare.

Because it’s not just the young who can learn from the wisdom of the old. The older can learn, and be reminded of, many good things from the young. Even if that younger person is you.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

New research offers more insight into potentially dangerous racial disparities in cesarean deliveries: In first-time live births, healthy African-American and Hispanic mothers were 21% and 26% more likely than White mothers, respectively, to deliver by cesarean section despite being low risk. The higher number of cesareans appeared to boost their risk of morbidity.

“A 20% increased odds of cesarean among otherwise healthy, low-risk, nulliparous individuals at term – with limited medical or obstetric explanation – is a significant concern, especially when considering that cesarean is the most common surgical procedure in the U.S.,” said study author Michelle P. Debbink, MD, PhD, an assistant professor with the department of obstetrics and gynecology at the University of Utah, in an interview.

Dr. Debbink and colleagues launched the study, published in the Jan. 2022 issue of Obstetrics & Gynecology, to better understand the racial gap in cesarean sections, which are considered riskier than vaginal deliveries. “Several studies have shown that Black women undergo cesarean more frequently than non-Hispanic White women. Numerous studies also show that Hispanic/Latina women undergo cesarean more frequently than White women, although these data are a bit more mixed,” she said. “What we don’t know, however, is why these differences occur and whether there are clues in the data which can point us toward interventions to close the gap.”

One theory, she said, is that Black and Hispanic women have more comorbidities and therefore more cesareans. To test that idea, the researchers found a cohort of healthy women in a randomized trial that studied the induction of labor.

For the study, they focused on 5,759 women (24.3% Black, 30% Hispanic, 46.6% White). Major differences between the groups included maternal age (average = 21 for Black, 22 for Hispanic, and 26 for White, P < .001), private insurance (17% for Black and Hispanic, 75% for White; P < .001), and full or part-time employment (37% for Black, 31% for Hispanic, and 71% for White; P < .001).

A total of 1,158 of the women (20.1%) underwent cesarean deliveries, accounting for 23% of deliveries by Black women, 22.8% of those by Hispanic women, and 17.6% of those by White women (P < .001). Black women were 21% more likely than White women to give birth via cesarean (adjusted relative risk = 1.21, 95% CI: 1.03-1.42) and Hispanic women were 26% more likely (aRR = 1.26, 95% CI: 1.08-1.46).

The study doesn’t explore why Black and Hispanic women have more cesarean deliveries. However, Dr. Debbink said, “we hypothesize that the difference likely stems more from differing treatment of Black or Hispanic individuals during labor.” It’s unlikely, she said, that these women are more likely to prefer cesarean sections. For one thing, she said, other research hasn’t shown a difference in preferences by race.

The researchers also analyzed maternal morbidity, defined as “transfusion of 4 or more units of red blood cells, any transfusion of other products, postpartum infection, intensive care unit admission, hysterectomy, venous thromboembolism, or maternal death.”

The study found that while few women (2.3%) suffered from morbidity, Black (aRR = 2.05, 95% CI: 1.21-3.47) and Hispanic (aRR = 1.92, 95% CI: 1.17-3.14) women were more likely to suffer from it than White women.

The researchers report that “cesarean birth accounted for an estimated 15.8% (95% CI: 2.1%-48.7%) and 16.5% (95% CI: 4.0%-44.0%) of excess maternal morbidity among non-Hispanic Black and Hispanic people, respectively.”

“Both endometritis and wound complications are much more common among individuals with cesarean, and blood clots, hysterectomy, and ICU admission are also more common after cesarean compared with vaginal delivery,” Dr. Debbink said.

The message of the study, she said, is that the health care system “perpetuates gaps in cesarean delivery for Black and Hispanic individuals compared to White individuals” even in low-risk, first-time live births. “We do not yet know exactly what the right levers are to address this gap, but it is important that we ob-gyns examine our practice patterns and our hospitals’ practice patterns to ensure equity for all our patients.”

Rebecca Delafield, PhD, an assistant professor of Native Hawaiian Health at the University of Hawaii, praised the study as “well-conducted” in an interview. “I agree with the assessment that while the cesarean delivery accounts for a modest proportion of excess morbidity in this study, the impact at the population level is significant,” said Dr. Delafield, who studies health disparities and didn’t take part in the study. “Delivery is complex and the causes of disparities observed are likely multifactorial, therefore research such as this is necessary and compelling.”

She added: “It is becoming increasingly evident that studies investigating racial/ethnic disparities in cesarean delivery and other maternal health outcomes must look beyond maternal behavioral or medical risk factors – e.g., obesity or hypertension – and consider the contribution of a broader set of factors, including societal prejudices.”

The study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences. One study author reports funding from GlaxoSmithKline, Pfizer, Moderna, and UpToDate (contributor) and from the Centers for Disease Control and Prevention (via her institution). Dr. Debbink, the other authors, and Dr. Delafield report no disclosures.

New research offers more insight into potentially dangerous racial disparities in cesarean deliveries: In first-time live births, healthy African-American and Hispanic mothers were 21% and 26% more likely than White mothers, respectively, to deliver by cesarean section despite being low risk. The higher number of cesareans appeared to boost their risk of morbidity.

“A 20% increased odds of cesarean among otherwise healthy, low-risk, nulliparous individuals at term – with limited medical or obstetric explanation – is a significant concern, especially when considering that cesarean is the most common surgical procedure in the U.S.,” said study author Michelle P. Debbink, MD, PhD, an assistant professor with the department of obstetrics and gynecology at the University of Utah, in an interview.

Dr. Debbink and colleagues launched the study, published in the Jan. 2022 issue of Obstetrics & Gynecology, to better understand the racial gap in cesarean sections, which are considered riskier than vaginal deliveries. “Several studies have shown that Black women undergo cesarean more frequently than non-Hispanic White women. Numerous studies also show that Hispanic/Latina women undergo cesarean more frequently than White women, although these data are a bit more mixed,” she said. “What we don’t know, however, is why these differences occur and whether there are clues in the data which can point us toward interventions to close the gap.”

One theory, she said, is that Black and Hispanic women have more comorbidities and therefore more cesareans. To test that idea, the researchers found a cohort of healthy women in a randomized trial that studied the induction of labor.

For the study, they focused on 5,759 women (24.3% Black, 30% Hispanic, 46.6% White). Major differences between the groups included maternal age (average = 21 for Black, 22 for Hispanic, and 26 for White, P < .001), private insurance (17% for Black and Hispanic, 75% for White; P < .001), and full or part-time employment (37% for Black, 31% for Hispanic, and 71% for White; P < .001).

A total of 1,158 of the women (20.1%) underwent cesarean deliveries, accounting for 23% of deliveries by Black women, 22.8% of those by Hispanic women, and 17.6% of those by White women (P < .001). Black women were 21% more likely than White women to give birth via cesarean (adjusted relative risk = 1.21, 95% CI: 1.03-1.42) and Hispanic women were 26% more likely (aRR = 1.26, 95% CI: 1.08-1.46).

The study doesn’t explore why Black and Hispanic women have more cesarean deliveries. However, Dr. Debbink said, “we hypothesize that the difference likely stems more from differing treatment of Black or Hispanic individuals during labor.” It’s unlikely, she said, that these women are more likely to prefer cesarean sections. For one thing, she said, other research hasn’t shown a difference in preferences by race.

The researchers also analyzed maternal morbidity, defined as “transfusion of 4 or more units of red blood cells, any transfusion of other products, postpartum infection, intensive care unit admission, hysterectomy, venous thromboembolism, or maternal death.”

The study found that while few women (2.3%) suffered from morbidity, Black (aRR = 2.05, 95% CI: 1.21-3.47) and Hispanic (aRR = 1.92, 95% CI: 1.17-3.14) women were more likely to suffer from it than White women.

The researchers report that “cesarean birth accounted for an estimated 15.8% (95% CI: 2.1%-48.7%) and 16.5% (95% CI: 4.0%-44.0%) of excess maternal morbidity among non-Hispanic Black and Hispanic people, respectively.”

“Both endometritis and wound complications are much more common among individuals with cesarean, and blood clots, hysterectomy, and ICU admission are also more common after cesarean compared with vaginal delivery,” Dr. Debbink said.

The message of the study, she said, is that the health care system “perpetuates gaps in cesarean delivery for Black and Hispanic individuals compared to White individuals” even in low-risk, first-time live births. “We do not yet know exactly what the right levers are to address this gap, but it is important that we ob-gyns examine our practice patterns and our hospitals’ practice patterns to ensure equity for all our patients.”

Rebecca Delafield, PhD, an assistant professor of Native Hawaiian Health at the University of Hawaii, praised the study as “well-conducted” in an interview. “I agree with the assessment that while the cesarean delivery accounts for a modest proportion of excess morbidity in this study, the impact at the population level is significant,” said Dr. Delafield, who studies health disparities and didn’t take part in the study. “Delivery is complex and the causes of disparities observed are likely multifactorial, therefore research such as this is necessary and compelling.”

She added: “It is becoming increasingly evident that studies investigating racial/ethnic disparities in cesarean delivery and other maternal health outcomes must look beyond maternal behavioral or medical risk factors – e.g., obesity or hypertension – and consider the contribution of a broader set of factors, including societal prejudices.”

The study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences. One study author reports funding from GlaxoSmithKline, Pfizer, Moderna, and UpToDate (contributor) and from the Centers for Disease Control and Prevention (via her institution). Dr. Debbink, the other authors, and Dr. Delafield report no disclosures.

New research offers more insight into potentially dangerous racial disparities in cesarean deliveries: In first-time live births, healthy African-American and Hispanic mothers were 21% and 26% more likely than White mothers, respectively, to deliver by cesarean section despite being low risk. The higher number of cesareans appeared to boost their risk of morbidity.

“A 20% increased odds of cesarean among otherwise healthy, low-risk, nulliparous individuals at term – with limited medical or obstetric explanation – is a significant concern, especially when considering that cesarean is the most common surgical procedure in the U.S.,” said study author Michelle P. Debbink, MD, PhD, an assistant professor with the department of obstetrics and gynecology at the University of Utah, in an interview.

Dr. Debbink and colleagues launched the study, published in the Jan. 2022 issue of Obstetrics & Gynecology, to better understand the racial gap in cesarean sections, which are considered riskier than vaginal deliveries. “Several studies have shown that Black women undergo cesarean more frequently than non-Hispanic White women. Numerous studies also show that Hispanic/Latina women undergo cesarean more frequently than White women, although these data are a bit more mixed,” she said. “What we don’t know, however, is why these differences occur and whether there are clues in the data which can point us toward interventions to close the gap.”

One theory, she said, is that Black and Hispanic women have more comorbidities and therefore more cesareans. To test that idea, the researchers found a cohort of healthy women in a randomized trial that studied the induction of labor.

For the study, they focused on 5,759 women (24.3% Black, 30% Hispanic, 46.6% White). Major differences between the groups included maternal age (average = 21 for Black, 22 for Hispanic, and 26 for White, P < .001), private insurance (17% for Black and Hispanic, 75% for White; P < .001), and full or part-time employment (37% for Black, 31% for Hispanic, and 71% for White; P < .001).

A total of 1,158 of the women (20.1%) underwent cesarean deliveries, accounting for 23% of deliveries by Black women, 22.8% of those by Hispanic women, and 17.6% of those by White women (P < .001). Black women were 21% more likely than White women to give birth via cesarean (adjusted relative risk = 1.21, 95% CI: 1.03-1.42) and Hispanic women were 26% more likely (aRR = 1.26, 95% CI: 1.08-1.46).

The study doesn’t explore why Black and Hispanic women have more cesarean deliveries. However, Dr. Debbink said, “we hypothesize that the difference likely stems more from differing treatment of Black or Hispanic individuals during labor.” It’s unlikely, she said, that these women are more likely to prefer cesarean sections. For one thing, she said, other research hasn’t shown a difference in preferences by race.

The researchers also analyzed maternal morbidity, defined as “transfusion of 4 or more units of red blood cells, any transfusion of other products, postpartum infection, intensive care unit admission, hysterectomy, venous thromboembolism, or maternal death.”

The study found that while few women (2.3%) suffered from morbidity, Black (aRR = 2.05, 95% CI: 1.21-3.47) and Hispanic (aRR = 1.92, 95% CI: 1.17-3.14) women were more likely to suffer from it than White women.

The researchers report that “cesarean birth accounted for an estimated 15.8% (95% CI: 2.1%-48.7%) and 16.5% (95% CI: 4.0%-44.0%) of excess maternal morbidity among non-Hispanic Black and Hispanic people, respectively.”

“Both endometritis and wound complications are much more common among individuals with cesarean, and blood clots, hysterectomy, and ICU admission are also more common after cesarean compared with vaginal delivery,” Dr. Debbink said.

The message of the study, she said, is that the health care system “perpetuates gaps in cesarean delivery for Black and Hispanic individuals compared to White individuals” even in low-risk, first-time live births. “We do not yet know exactly what the right levers are to address this gap, but it is important that we ob-gyns examine our practice patterns and our hospitals’ practice patterns to ensure equity for all our patients.”

Rebecca Delafield, PhD, an assistant professor of Native Hawaiian Health at the University of Hawaii, praised the study as “well-conducted” in an interview. “I agree with the assessment that while the cesarean delivery accounts for a modest proportion of excess morbidity in this study, the impact at the population level is significant,” said Dr. Delafield, who studies health disparities and didn’t take part in the study. “Delivery is complex and the causes of disparities observed are likely multifactorial, therefore research such as this is necessary and compelling.”

She added: “It is becoming increasingly evident that studies investigating racial/ethnic disparities in cesarean delivery and other maternal health outcomes must look beyond maternal behavioral or medical risk factors – e.g., obesity or hypertension – and consider the contribution of a broader set of factors, including societal prejudices.”

The study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences. One study author reports funding from GlaxoSmithKline, Pfizer, Moderna, and UpToDate (contributor) and from the Centers for Disease Control and Prevention (via her institution). Dr. Debbink, the other authors, and Dr. Delafield report no disclosures.

Atopic dermatitis (AD) may be especially active and severe among older adults, and it may be associated with increased risk of comorbid conditions common in later stages of life, including osteoporosis, dementia, and cardiovascular disease.

During the Revolutionizing Atopic Dermatitis virtual symposium, Katrina Abuabara, MD, highlighted the epidemiology and burden of AD among older adults. She began by noting that the disease peaks in infancy and older adulthood. In an analysis that she and her colleagues made of physician-diagnosed AD among more than 8.6 million patients in the United Kingdom between 1994 and 2013, the mean prevalence in a given year was 12.3% among those aged 0-17 years, 5.1% among those age 18-74 years, and 8.7% among those age 75 and older.

“We saw what we expected in early infancy with very high rates of active disease,” said Dr. Abuabara, associate professor of dermatology and epidemiology at the University of California, San Francisco. “We also saw a second peak in older adulthood. This was more surprising to us because the disease hadn’t been as well studied in this population.” Researchers who analyzed data from the Global Burden of Disease Study, which evaluates disease-related morbidity and mortality worldwide, found a somewhat attenuated peak but a similar trend around the world. Its authors ranked AD as 15th among all nonfatal diseases.

In a separate analysis, Dr. Abuabara and colleagues evaluated records of more than 9.1 million primary care patients in the United Kingdom between 1994 and 2013, and who were followed for an average of 6 years. They examined AD activity and found that, based on doctor visits and prescriptions, AD appeared to be active in 48% of those aged 0-17 years, compared with 42% of those aged 18-74 years, and 60% of those aged 75 years and older. “Also, when we looked at the distribution of active disease in older adults, we saw that those who were older had more severe disease,” she said. When they evaluated the prevalence of AD by sociodemographic factors, AD increased with age among older adults (adjusted odd ratio, 1.06), while it decreased by 14% annually among children. In addition, female older adults had about three-fourths the odds of prevalent disease as their male counterparts (aOR, 0.73).

“We also looked at rural and urban differences and found that across ages it was more common in urban as compared to rural populations,” she said. “As for socioeconomic status, it tends to be more common among those of higher socioeconomic status in children and in the older adult group.”

In a study that drew from medical records of 3.85 million primary care patients in the United Kingdom, AD was more common in Asian and Black ethnic groups than in people of White ethnicity. In addition, higher socioeconomic status was associated with a greater incidence of eczema in infants aged younger than 2 years, but the reverse was seen for all other age groups.

To identify subtypes of atopic eczema based on patterns of disease activity through mid-adulthood, Dr. Abuabara and colleagues evaluated members of two population-based birth cohorts: the 1958 National Childhood Development Study and the 1970 British Cohort Study. The patients were classified into one of four patters of disease activity followed to age 50: rare/none, increasing, decreasing, and high. “We found that there was the early-onset decreasing subgroup, which tend to have a lower probability of AD over time,” Dr. Abuabara said. “We also found that there was a small subgroup that had a constant high probability of AD over time. But we were surprised to find a subgroup with increasing probability over time. This was a fairly sizable subgroup.”

In an earlier study, she and her colleagues examined whether there were differences based on whether people had adult-onset or childhood-onset disease in the same two cohorts of U.K. patients. Those with childhood-onset disease had stronger associations with known genetic risk factors and they tended to be of higher socioeconomic status. “They also tended to have more asthma and other allergic comorbidities,” Dr. Abuabara said. “On the other hand, the adult-onset group [after age 23] were more likely to be female, more likely to be smokers, and tended to have lower childhood socioeconomic status.”

According to the best available evidence, she continued, there is good data on higher relative risk of osteoporosis/fractures and dementia specifically among older adults with AD, and good data on associations with cardiometabolic disease and atopic disease among adults overall, as well as data showing that AD does not seem to be associated with cancer overall. In a study conducted by Jonathan I. Silverberg, MD, PhD, MPH, and Mohammed S. Shaheen, JD, the researchers used physician-diagnosed AD to investigate the associations of osteopenia and osteoporosis in two large U.S. databases: the 2006-2012 Nationwide Emergency Department Sample (NEDS) database and 2002-2012 National Inpatient Sample (NIS). Among patients aged 50 years and older, AD was associated with a higher odds of osteoporosis in NEDS (aOR, 1.31) and NIS (aOR, 1.25) and osteopenia in NEDS (aOR, 1.86).

In a separate matched cohort study, Dr. Abuabara and colleagues used U.K. primary care patient data to evaluate the association between AD and fracture and whether fracture risk varies with AD severity. Overall, they observed a 10% increase in fracture risk among people with AD, compared with those without, especially those of the hip, spine, pelvis, and wrist. “We found that there was a dose-response effect,” she said. “Those with more severe eczema had a much higher risk of fractures. When we looked at different age groups, we found a similar increased risk in the oldest adults as in younger adults.”

In a longitudinal cohort study of primary care medical records from more than 1.1 million individuals in the United Kingdom, AD was associated with an increased risk of vascular dementia (hazard ratio, 1.88), Alzheimer’s disease (HR, 1.69, and other/unspecified dementia (HR, 1.48; .269). “We found a nice dose response, where people with more severe AD had higher rates of dementia,” Dr. Abuabara said. Results from a more recent, smaller study of patients in Taiwan also found an increased risk between AD and the risk of dementia, but not a dose-response effect, likely because of a much smaller sample size.

Mounting research suggests that the risk for cardiovascular disease is also elevated in patients with AD. “There is some variability in the literature, but I think it’s important that when we’re talking about atopic dermatitis to think about the heterogeneity of the disease,” Dr. Abuabara said. In a meta-analysis and systematic review of 19 studies on the topic, she and her colleagues found that AD was associated with an increased risk of myocardial infarction (relative risk, 1.12), stroke (RR, 1.10), ischemic stroke (RR, 1.17), angina (RR, 1.18), and heart failure (RR, 1.26). “For all the different [cardiovascular disease] outcomes there was increasing risk with increasing disease severity,” she said.

She reported that UCSF receives research funding from Pfizer and Cosmetique Active International. She also receives consulting fees from Target RWE.

[email protected]

Atopic dermatitis (AD) may be especially active and severe among older adults, and it may be associated with increased risk of comorbid conditions common in later stages of life, including osteoporosis, dementia, and cardiovascular disease.

During the Revolutionizing Atopic Dermatitis virtual symposium, Katrina Abuabara, MD, highlighted the epidemiology and burden of AD among older adults. She began by noting that the disease peaks in infancy and older adulthood. In an analysis that she and her colleagues made of physician-diagnosed AD among more than 8.6 million patients in the United Kingdom between 1994 and 2013, the mean prevalence in a given year was 12.3% among those aged 0-17 years, 5.1% among those age 18-74 years, and 8.7% among those age 75 and older.

“We saw what we expected in early infancy with very high rates of active disease,” said Dr. Abuabara, associate professor of dermatology and epidemiology at the University of California, San Francisco. “We also saw a second peak in older adulthood. This was more surprising to us because the disease hadn’t been as well studied in this population.” Researchers who analyzed data from the Global Burden of Disease Study, which evaluates disease-related morbidity and mortality worldwide, found a somewhat attenuated peak but a similar trend around the world. Its authors ranked AD as 15th among all nonfatal diseases.

In a separate analysis, Dr. Abuabara and colleagues evaluated records of more than 9.1 million primary care patients in the United Kingdom between 1994 and 2013, and who were followed for an average of 6 years. They examined AD activity and found that, based on doctor visits and prescriptions, AD appeared to be active in 48% of those aged 0-17 years, compared with 42% of those aged 18-74 years, and 60% of those aged 75 years and older. “Also, when we looked at the distribution of active disease in older adults, we saw that those who were older had more severe disease,” she said. When they evaluated the prevalence of AD by sociodemographic factors, AD increased with age among older adults (adjusted odd ratio, 1.06), while it decreased by 14% annually among children. In addition, female older adults had about three-fourths the odds of prevalent disease as their male counterparts (aOR, 0.73).

“We also looked at rural and urban differences and found that across ages it was more common in urban as compared to rural populations,” she said. “As for socioeconomic status, it tends to be more common among those of higher socioeconomic status in children and in the older adult group.”

In a study that drew from medical records of 3.85 million primary care patients in the United Kingdom, AD was more common in Asian and Black ethnic groups than in people of White ethnicity. In addition, higher socioeconomic status was associated with a greater incidence of eczema in infants aged younger than 2 years, but the reverse was seen for all other age groups.

To identify subtypes of atopic eczema based on patterns of disease activity through mid-adulthood, Dr. Abuabara and colleagues evaluated members of two population-based birth cohorts: the 1958 National Childhood Development Study and the 1970 British Cohort Study. The patients were classified into one of four patters of disease activity followed to age 50: rare/none, increasing, decreasing, and high. “We found that there was the early-onset decreasing subgroup, which tend to have a lower probability of AD over time,” Dr. Abuabara said. “We also found that there was a small subgroup that had a constant high probability of AD over time. But we were surprised to find a subgroup with increasing probability over time. This was a fairly sizable subgroup.”

In an earlier study, she and her colleagues examined whether there were differences based on whether people had adult-onset or childhood-onset disease in the same two cohorts of U.K. patients. Those with childhood-onset disease had stronger associations with known genetic risk factors and they tended to be of higher socioeconomic status. “They also tended to have more asthma and other allergic comorbidities,” Dr. Abuabara said. “On the other hand, the adult-onset group [after age 23] were more likely to be female, more likely to be smokers, and tended to have lower childhood socioeconomic status.”

According to the best available evidence, she continued, there is good data on higher relative risk of osteoporosis/fractures and dementia specifically among older adults with AD, and good data on associations with cardiometabolic disease and atopic disease among adults overall, as well as data showing that AD does not seem to be associated with cancer overall. In a study conducted by Jonathan I. Silverberg, MD, PhD, MPH, and Mohammed S. Shaheen, JD, the researchers used physician-diagnosed AD to investigate the associations of osteopenia and osteoporosis in two large U.S. databases: the 2006-2012 Nationwide Emergency Department Sample (NEDS) database and 2002-2012 National Inpatient Sample (NIS). Among patients aged 50 years and older, AD was associated with a higher odds of osteoporosis in NEDS (aOR, 1.31) and NIS (aOR, 1.25) and osteopenia in NEDS (aOR, 1.86).

In a separate matched cohort study, Dr. Abuabara and colleagues used U.K. primary care patient data to evaluate the association between AD and fracture and whether fracture risk varies with AD severity. Overall, they observed a 10% increase in fracture risk among people with AD, compared with those without, especially those of the hip, spine, pelvis, and wrist. “We found that there was a dose-response effect,” she said. “Those with more severe eczema had a much higher risk of fractures. When we looked at different age groups, we found a similar increased risk in the oldest adults as in younger adults.”

In a longitudinal cohort study of primary care medical records from more than 1.1 million individuals in the United Kingdom, AD was associated with an increased risk of vascular dementia (hazard ratio, 1.88), Alzheimer’s disease (HR, 1.69, and other/unspecified dementia (HR, 1.48; .269). “We found a nice dose response, where people with more severe AD had higher rates of dementia,” Dr. Abuabara said. Results from a more recent, smaller study of patients in Taiwan also found an increased risk between AD and the risk of dementia, but not a dose-response effect, likely because of a much smaller sample size.

Mounting research suggests that the risk for cardiovascular disease is also elevated in patients with AD. “There is some variability in the literature, but I think it’s important that when we’re talking about atopic dermatitis to think about the heterogeneity of the disease,” Dr. Abuabara said. In a meta-analysis and systematic review of 19 studies on the topic, she and her colleagues found that AD was associated with an increased risk of myocardial infarction (relative risk, 1.12), stroke (RR, 1.10), ischemic stroke (RR, 1.17), angina (RR, 1.18), and heart failure (RR, 1.26). “For all the different [cardiovascular disease] outcomes there was increasing risk with increasing disease severity,” she said.

She reported that UCSF receives research funding from Pfizer and Cosmetique Active International. She also receives consulting fees from Target RWE.

[email protected]

Atopic dermatitis (AD) may be especially active and severe among older adults, and it may be associated with increased risk of comorbid conditions common in later stages of life, including osteoporosis, dementia, and cardiovascular disease.

During the Revolutionizing Atopic Dermatitis virtual symposium, Katrina Abuabara, MD, highlighted the epidemiology and burden of AD among older adults. She began by noting that the disease peaks in infancy and older adulthood. In an analysis that she and her colleagues made of physician-diagnosed AD among more than 8.6 million patients in the United Kingdom between 1994 and 2013, the mean prevalence in a given year was 12.3% among those aged 0-17 years, 5.1% among those age 18-74 years, and 8.7% among those age 75 and older.

“We saw what we expected in early infancy with very high rates of active disease,” said Dr. Abuabara, associate professor of dermatology and epidemiology at the University of California, San Francisco. “We also saw a second peak in older adulthood. This was more surprising to us because the disease hadn’t been as well studied in this population.” Researchers who analyzed data from the Global Burden of Disease Study, which evaluates disease-related morbidity and mortality worldwide, found a somewhat attenuated peak but a similar trend around the world. Its authors ranked AD as 15th among all nonfatal diseases.

In a separate analysis, Dr. Abuabara and colleagues evaluated records of more than 9.1 million primary care patients in the United Kingdom between 1994 and 2013, and who were followed for an average of 6 years. They examined AD activity and found that, based on doctor visits and prescriptions, AD appeared to be active in 48% of those aged 0-17 years, compared with 42% of those aged 18-74 years, and 60% of those aged 75 years and older. “Also, when we looked at the distribution of active disease in older adults, we saw that those who were older had more severe disease,” she said. When they evaluated the prevalence of AD by sociodemographic factors, AD increased with age among older adults (adjusted odd ratio, 1.06), while it decreased by 14% annually among children. In addition, female older adults had about three-fourths the odds of prevalent disease as their male counterparts (aOR, 0.73).

“We also looked at rural and urban differences and found that across ages it was more common in urban as compared to rural populations,” she said. “As for socioeconomic status, it tends to be more common among those of higher socioeconomic status in children and in the older adult group.”

In a study that drew from medical records of 3.85 million primary care patients in the United Kingdom, AD was more common in Asian and Black ethnic groups than in people of White ethnicity. In addition, higher socioeconomic status was associated with a greater incidence of eczema in infants aged younger than 2 years, but the reverse was seen for all other age groups.

To identify subtypes of atopic eczema based on patterns of disease activity through mid-adulthood, Dr. Abuabara and colleagues evaluated members of two population-based birth cohorts: the 1958 National Childhood Development Study and the 1970 British Cohort Study. The patients were classified into one of four patters of disease activity followed to age 50: rare/none, increasing, decreasing, and high. “We found that there was the early-onset decreasing subgroup, which tend to have a lower probability of AD over time,” Dr. Abuabara said. “We also found that there was a small subgroup that had a constant high probability of AD over time. But we were surprised to find a subgroup with increasing probability over time. This was a fairly sizable subgroup.”

In an earlier study, she and her colleagues examined whether there were differences based on whether people had adult-onset or childhood-onset disease in the same two cohorts of U.K. patients. Those with childhood-onset disease had stronger associations with known genetic risk factors and they tended to be of higher socioeconomic status. “They also tended to have more asthma and other allergic comorbidities,” Dr. Abuabara said. “On the other hand, the adult-onset group [after age 23] were more likely to be female, more likely to be smokers, and tended to have lower childhood socioeconomic status.”

According to the best available evidence, she continued, there is good data on higher relative risk of osteoporosis/fractures and dementia specifically among older adults with AD, and good data on associations with cardiometabolic disease and atopic disease among adults overall, as well as data showing that AD does not seem to be associated with cancer overall. In a study conducted by Jonathan I. Silverberg, MD, PhD, MPH, and Mohammed S. Shaheen, JD, the researchers used physician-diagnosed AD to investigate the associations of osteopenia and osteoporosis in two large U.S. databases: the 2006-2012 Nationwide Emergency Department Sample (NEDS) database and 2002-2012 National Inpatient Sample (NIS). Among patients aged 50 years and older, AD was associated with a higher odds of osteoporosis in NEDS (aOR, 1.31) and NIS (aOR, 1.25) and osteopenia in NEDS (aOR, 1.86).

In a separate matched cohort study, Dr. Abuabara and colleagues used U.K. primary care patient data to evaluate the association between AD and fracture and whether fracture risk varies with AD severity. Overall, they observed a 10% increase in fracture risk among people with AD, compared with those without, especially those of the hip, spine, pelvis, and wrist. “We found that there was a dose-response effect,” she said. “Those with more severe eczema had a much higher risk of fractures. When we looked at different age groups, we found a similar increased risk in the oldest adults as in younger adults.”

In a longitudinal cohort study of primary care medical records from more than 1.1 million individuals in the United Kingdom, AD was associated with an increased risk of vascular dementia (hazard ratio, 1.88), Alzheimer’s disease (HR, 1.69, and other/unspecified dementia (HR, 1.48; .269). “We found a nice dose response, where people with more severe AD had higher rates of dementia,” Dr. Abuabara said. Results from a more recent, smaller study of patients in Taiwan also found an increased risk between AD and the risk of dementia, but not a dose-response effect, likely because of a much smaller sample size.

Mounting research suggests that the risk for cardiovascular disease is also elevated in patients with AD. “There is some variability in the literature, but I think it’s important that when we’re talking about atopic dermatitis to think about the heterogeneity of the disease,” Dr. Abuabara said. In a meta-analysis and systematic review of 19 studies on the topic, she and her colleagues found that AD was associated with an increased risk of myocardial infarction (relative risk, 1.12), stroke (RR, 1.10), ischemic stroke (RR, 1.17), angina (RR, 1.18), and heart failure (RR, 1.26). “For all the different [cardiovascular disease] outcomes there was increasing risk with increasing disease severity,” she said.

She reported that UCSF receives research funding from Pfizer and Cosmetique Active International. She also receives consulting fees from Target RWE.

[email protected]

A new meta-analysis suggests the risk for violence is higher in patients with schizophrenia, but some experts beg to differ, calling out study limitations and urging caution when interpreting the findings.

The study suggests patients with schizophrenia spectrum disorder (SSD) are 4.5 times more likely than individuals in the general population to perpetrate violence against others.

While the results showed comorbid substance misuse was associated with a significantly increased risk for violence in those with SSD, data on medication nonadherence, prior exposure to violence, childhood trauma, or other known risk factors were not included in the study.

“I think one of the main implications of this study is that prevention of violence outcomes really should be a focus for clinical services, because these are important outcomes to prevent and many of the factors that increase risk are modifiable, such as substance misuse and treatment adherence,” study coinvestigator Seena Fazel, MD, professor of forensic psychiatry at the University of Oxford (England), said in an interview.

Still, some experts urge caution when interpreting the findings, which they fear could perpetuate stigma against individuals with serious mental illness if not taken in the context of a study that shows association, not causation.

“While potential for violence is certainly a relevant consideration in assessing persons with schizophrenia spectrum disorder, it would be wrong to conclude from this study that schizophrenia spectrum disorders per se cause people to become violent,” said Ronald W. Pies, MD, professor emeritus of psychiatry at the State University of New York, Syracuse, who commented on the findings.

The findings were published online Dec. 22, 2021, in JAMA Psychiatry.
 

No causal link

The meta-analysis included 24 studies involving 51,309 individuals with SSD from 15 countries over 4 decades.

Risk for violence perpetrated by men with schizophrenia was 4.5 times higher (95% confidence interval, 3.6-5.6) than their counterparts in the general population. Among women, the rate was 10.2 times higher (95% CI, 7.1-14.6) versus those without SSD.

The odds of perpetrating sexual offenses (odds ratio, 5.1; 95% CI, 3.8-6.8) and homicide (OR, 17.7; 95% CI, 13.9-22.6) were also increased.

When restricting analysis to studies that used outcomes only from register-based sources, indicating a criminal arrest or conviction, absolute risks of violence perpetration ranged from 2.3% to 24.7% in men with SSD and from 0% to 5.4% in women up to a 35-year follow-up.

“That means that over a 35-year period most men are not going to be involved in these criminal register-based violent outcomes,” Dr. Fazel said. “And at least 90% of the women are not going to have any register-based violent outcomes.”

When accounting for substance use comorbidity, risk for violence perpetration dropped sharply. Those with no substance misuse were 3.5 times more likely than those in the general population to commit acts of violence versus 9.9 times in those with substance misuse comorbidity.

“In these subgroup studies of people with dual diagnoses of schizophrenia and substance misuse, the risk was increased 10-fold,” Dr. Fazel said. “If you look at people without substance misuse comorbidity, there remains a risk there of between three- to fourfold increase. It doesn’t explain the association completely.”

The investigators were quick to point out that this new study identifies an association between SSD and violence, and not causation.

“One important way to consider the association is to think of clinical services for people presenting with a schizophrenia spectrum disorder: Does the evidence suggest that violence is an important enough potential adverse outcome, for a minority of those individuals, such that support for this clinical need should be improved?” study investigator Daniel Whiting, BM BCh, a doctoral research fellow in psychiatry at the University of Oxford, said in an interview. “We highlight this as an implication of the findings.”

Whether the association would change if researchers controlled for substance misuse in both the study and control groups is unknown. Also unclear from this study is what impact other risk factors may have on increasing violent outcomes in individuals with SSD.
 

Education, treatment adherence important

Dr. Pies pointed out that, “notably, the risk for violence in the study population declined more than sixfold when comorbid substance abuse was excluded from the analysis.”

That aligns with an earlier study conducted in Sweden by Dr. Fazel, which showed that, after controlling for substance misuse, the rate of violent crime among individuals with schizophrenia was only slightly higher than in the general population.

“The fact is that people with schizophrenia who are compliant with proper medication do not commit violent acts any more than those in the general population,” Lynn DeLisi, MD, professor of psychiatry at Harvard Medical School, Boston, and founding editor of Schizophrenia Research, said in a comment.

Indeed, Dr. Fazel’s own research suggests treatment with antipsychotics cuts in half the risk for violent crime by patients with severe mental illness.

“The goal should be education of school officials, families, and primary care physicians to detect this illness early and treat it. Programs that make sure patients comply with medication once they begin it are equally important,” Dr. DeLisi said.

Treatment adherence is important, but the first step toward violence prevention is high-quality risk assessment, said Dr. Fazel. His research team has developed a web-based, free risk calculator shown to help clinicians evaluate the risk that a patient might become violent.

Dr. Pies agreed with the importance of comprehensive, clinical assessments of modifiable risk factors, including substance use, homelessness, medication adherence, and conflictual relationships.

This kind of assessment, “in my experience, is rarely carried out in most evaluations of persons with psychotic symptoms or SSD,” he said.
 

Perpetuating stigma?

Another concern raised by Dr. Pies and Dr. DeLisi is how the findings might perpetuate stigma toward individuals with serious mental illness. Results from a recently published study showed that, although attitudes toward those with major depression have improved in the United States over the past few decades, stigma toward those with schizophrenia has actually worsened.

The most effective approach to reducing stigma is to “face up to the evidence, then try and prevent the negative outcomes,” Dr. Fazel said.

“The conclusion of this paper is that it’s all pointing toward a strategy toward prevention by developing high-quality risk assessment and then developing high-quality treatment programs that include not just pharmacological treatments but psychosocial treatments and beyond,” he added. “We know that’s the way it works for other disorders as well.”

Although mental illness stigma is a serious problem, Dr. Pies noted, “the risk is not so much that studies of this sort are carried out and then covered in the media, but that they are decontextualized and reduced to ‘bumper sticker’ headlines.”

“The public needs context and perspective,” he said. “It needs to be informed that violent behavior is relatively rare among persons with psychiatric illness, including persons with schizophrenia and related disorders who do not also have a substance use disorder.”

Indeed, some studies have shown that individuals with mental illness are more often the victims of violence than the perpetrators.

“Frankly, the public is much more at risk from the neighborhood lout who drinks heavily and repeatedly starts bar fights than from the average patient with a schizophrenia spectrum disorder,” Dr. Pies said.

Dr. Fazel reported receiving funding from the Wellcome Trust. Dr. DeLisi and Dr. Pies disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new meta-analysis suggests the risk for violence is higher in patients with schizophrenia, but some experts beg to differ, calling out study limitations and urging caution when interpreting the findings.

The study suggests patients with schizophrenia spectrum disorder (SSD) are 4.5 times more likely than individuals in the general population to perpetrate violence against others.

While the results showed comorbid substance misuse was associated with a significantly increased risk for violence in those with SSD, data on medication nonadherence, prior exposure to violence, childhood trauma, or other known risk factors were not included in the study.

“I think one of the main implications of this study is that prevention of violence outcomes really should be a focus for clinical services, because these are important outcomes to prevent and many of the factors that increase risk are modifiable, such as substance misuse and treatment adherence,” study coinvestigator Seena Fazel, MD, professor of forensic psychiatry at the University of Oxford (England), said in an interview.

Still, some experts urge caution when interpreting the findings, which they fear could perpetuate stigma against individuals with serious mental illness if not taken in the context of a study that shows association, not causation.

“While potential for violence is certainly a relevant consideration in assessing persons with schizophrenia spectrum disorder, it would be wrong to conclude from this study that schizophrenia spectrum disorders per se cause people to become violent,” said Ronald W. Pies, MD, professor emeritus of psychiatry at the State University of New York, Syracuse, who commented on the findings.

The findings were published online Dec. 22, 2021, in JAMA Psychiatry.
 

No causal link

The meta-analysis included 24 studies involving 51,309 individuals with SSD from 15 countries over 4 decades.

Risk for violence perpetrated by men with schizophrenia was 4.5 times higher (95% confidence interval, 3.6-5.6) than their counterparts in the general population. Among women, the rate was 10.2 times higher (95% CI, 7.1-14.6) versus those without SSD.

The odds of perpetrating sexual offenses (odds ratio, 5.1; 95% CI, 3.8-6.8) and homicide (OR, 17.7; 95% CI, 13.9-22.6) were also increased.

When restricting analysis to studies that used outcomes only from register-based sources, indicating a criminal arrest or conviction, absolute risks of violence perpetration ranged from 2.3% to 24.7% in men with SSD and from 0% to 5.4% in women up to a 35-year follow-up.

“That means that over a 35-year period most men are not going to be involved in these criminal register-based violent outcomes,” Dr. Fazel said. “And at least 90% of the women are not going to have any register-based violent outcomes.”

When accounting for substance use comorbidity, risk for violence perpetration dropped sharply. Those with no substance misuse were 3.5 times more likely than those in the general population to commit acts of violence versus 9.9 times in those with substance misuse comorbidity.

“In these subgroup studies of people with dual diagnoses of schizophrenia and substance misuse, the risk was increased 10-fold,” Dr. Fazel said. “If you look at people without substance misuse comorbidity, there remains a risk there of between three- to fourfold increase. It doesn’t explain the association completely.”

The investigators were quick to point out that this new study identifies an association between SSD and violence, and not causation.

“One important way to consider the association is to think of clinical services for people presenting with a schizophrenia spectrum disorder: Does the evidence suggest that violence is an important enough potential adverse outcome, for a minority of those individuals, such that support for this clinical need should be improved?” study investigator Daniel Whiting, BM BCh, a doctoral research fellow in psychiatry at the University of Oxford, said in an interview. “We highlight this as an implication of the findings.”

Whether the association would change if researchers controlled for substance misuse in both the study and control groups is unknown. Also unclear from this study is what impact other risk factors may have on increasing violent outcomes in individuals with SSD.
 

Education, treatment adherence important

Dr. Pies pointed out that, “notably, the risk for violence in the study population declined more than sixfold when comorbid substance abuse was excluded from the analysis.”

That aligns with an earlier study conducted in Sweden by Dr. Fazel, which showed that, after controlling for substance misuse, the rate of violent crime among individuals with schizophrenia was only slightly higher than in the general population.

“The fact is that people with schizophrenia who are compliant with proper medication do not commit violent acts any more than those in the general population,” Lynn DeLisi, MD, professor of psychiatry at Harvard Medical School, Boston, and founding editor of Schizophrenia Research, said in a comment.

Indeed, Dr. Fazel’s own research suggests treatment with antipsychotics cuts in half the risk for violent crime by patients with severe mental illness.

“The goal should be education of school officials, families, and primary care physicians to detect this illness early and treat it. Programs that make sure patients comply with medication once they begin it are equally important,” Dr. DeLisi said.

Treatment adherence is important, but the first step toward violence prevention is high-quality risk assessment, said Dr. Fazel. His research team has developed a web-based, free risk calculator shown to help clinicians evaluate the risk that a patient might become violent.

Dr. Pies agreed with the importance of comprehensive, clinical assessments of modifiable risk factors, including substance use, homelessness, medication adherence, and conflictual relationships.

This kind of assessment, “in my experience, is rarely carried out in most evaluations of persons with psychotic symptoms or SSD,” he said.
 

Perpetuating stigma?

Another concern raised by Dr. Pies and Dr. DeLisi is how the findings might perpetuate stigma toward individuals with serious mental illness. Results from a recently published study showed that, although attitudes toward those with major depression have improved in the United States over the past few decades, stigma toward those with schizophrenia has actually worsened.

The most effective approach to reducing stigma is to “face up to the evidence, then try and prevent the negative outcomes,” Dr. Fazel said.

“The conclusion of this paper is that it’s all pointing toward a strategy toward prevention by developing high-quality risk assessment and then developing high-quality treatment programs that include not just pharmacological treatments but psychosocial treatments and beyond,” he added. “We know that’s the way it works for other disorders as well.”

Although mental illness stigma is a serious problem, Dr. Pies noted, “the risk is not so much that studies of this sort are carried out and then covered in the media, but that they are decontextualized and reduced to ‘bumper sticker’ headlines.”

“The public needs context and perspective,” he said. “It needs to be informed that violent behavior is relatively rare among persons with psychiatric illness, including persons with schizophrenia and related disorders who do not also have a substance use disorder.”

Indeed, some studies have shown that individuals with mental illness are more often the victims of violence than the perpetrators.

“Frankly, the public is much more at risk from the neighborhood lout who drinks heavily and repeatedly starts bar fights than from the average patient with a schizophrenia spectrum disorder,” Dr. Pies said.

Dr. Fazel reported receiving funding from the Wellcome Trust. Dr. DeLisi and Dr. Pies disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new meta-analysis suggests the risk for violence is higher in patients with schizophrenia, but some experts beg to differ, calling out study limitations and urging caution when interpreting the findings.

The study suggests patients with schizophrenia spectrum disorder (SSD) are 4.5 times more likely than individuals in the general population to perpetrate violence against others.

While the results showed comorbid substance misuse was associated with a significantly increased risk for violence in those with SSD, data on medication nonadherence, prior exposure to violence, childhood trauma, or other known risk factors were not included in the study.

“I think one of the main implications of this study is that prevention of violence outcomes really should be a focus for clinical services, because these are important outcomes to prevent and many of the factors that increase risk are modifiable, such as substance misuse and treatment adherence,” study coinvestigator Seena Fazel, MD, professor of forensic psychiatry at the University of Oxford (England), said in an interview.

Still, some experts urge caution when interpreting the findings, which they fear could perpetuate stigma against individuals with serious mental illness if not taken in the context of a study that shows association, not causation.

“While potential for violence is certainly a relevant consideration in assessing persons with schizophrenia spectrum disorder, it would be wrong to conclude from this study that schizophrenia spectrum disorders per se cause people to become violent,” said Ronald W. Pies, MD, professor emeritus of psychiatry at the State University of New York, Syracuse, who commented on the findings.

The findings were published online Dec. 22, 2021, in JAMA Psychiatry.
 

No causal link

The meta-analysis included 24 studies involving 51,309 individuals with SSD from 15 countries over 4 decades.

Risk for violence perpetrated by men with schizophrenia was 4.5 times higher (95% confidence interval, 3.6-5.6) than their counterparts in the general population. Among women, the rate was 10.2 times higher (95% CI, 7.1-14.6) versus those without SSD.

The odds of perpetrating sexual offenses (odds ratio, 5.1; 95% CI, 3.8-6.8) and homicide (OR, 17.7; 95% CI, 13.9-22.6) were also increased.

When restricting analysis to studies that used outcomes only from register-based sources, indicating a criminal arrest or conviction, absolute risks of violence perpetration ranged from 2.3% to 24.7% in men with SSD and from 0% to 5.4% in women up to a 35-year follow-up.

“That means that over a 35-year period most men are not going to be involved in these criminal register-based violent outcomes,” Dr. Fazel said. “And at least 90% of the women are not going to have any register-based violent outcomes.”

When accounting for substance use comorbidity, risk for violence perpetration dropped sharply. Those with no substance misuse were 3.5 times more likely than those in the general population to commit acts of violence versus 9.9 times in those with substance misuse comorbidity.

“In these subgroup studies of people with dual diagnoses of schizophrenia and substance misuse, the risk was increased 10-fold,” Dr. Fazel said. “If you look at people without substance misuse comorbidity, there remains a risk there of between three- to fourfold increase. It doesn’t explain the association completely.”

The investigators were quick to point out that this new study identifies an association between SSD and violence, and not causation.

“One important way to consider the association is to think of clinical services for people presenting with a schizophrenia spectrum disorder: Does the evidence suggest that violence is an important enough potential adverse outcome, for a minority of those individuals, such that support for this clinical need should be improved?” study investigator Daniel Whiting, BM BCh, a doctoral research fellow in psychiatry at the University of Oxford, said in an interview. “We highlight this as an implication of the findings.”

Whether the association would change if researchers controlled for substance misuse in both the study and control groups is unknown. Also unclear from this study is what impact other risk factors may have on increasing violent outcomes in individuals with SSD.
 

Education, treatment adherence important

Dr. Pies pointed out that, “notably, the risk for violence in the study population declined more than sixfold when comorbid substance abuse was excluded from the analysis.”

That aligns with an earlier study conducted in Sweden by Dr. Fazel, which showed that, after controlling for substance misuse, the rate of violent crime among individuals with schizophrenia was only slightly higher than in the general population.

“The fact is that people with schizophrenia who are compliant with proper medication do not commit violent acts any more than those in the general population,” Lynn DeLisi, MD, professor of psychiatry at Harvard Medical School, Boston, and founding editor of Schizophrenia Research, said in a comment.

Indeed, Dr. Fazel’s own research suggests treatment with antipsychotics cuts in half the risk for violent crime by patients with severe mental illness.

“The goal should be education of school officials, families, and primary care physicians to detect this illness early and treat it. Programs that make sure patients comply with medication once they begin it are equally important,” Dr. DeLisi said.

Treatment adherence is important, but the first step toward violence prevention is high-quality risk assessment, said Dr. Fazel. His research team has developed a web-based, free risk calculator shown to help clinicians evaluate the risk that a patient might become violent.

Dr. Pies agreed with the importance of comprehensive, clinical assessments of modifiable risk factors, including substance use, homelessness, medication adherence, and conflictual relationships.

This kind of assessment, “in my experience, is rarely carried out in most evaluations of persons with psychotic symptoms or SSD,” he said.
 

Perpetuating stigma?

Another concern raised by Dr. Pies and Dr. DeLisi is how the findings might perpetuate stigma toward individuals with serious mental illness. Results from a recently published study showed that, although attitudes toward those with major depression have improved in the United States over the past few decades, stigma toward those with schizophrenia has actually worsened.

The most effective approach to reducing stigma is to “face up to the evidence, then try and prevent the negative outcomes,” Dr. Fazel said.

“The conclusion of this paper is that it’s all pointing toward a strategy toward prevention by developing high-quality risk assessment and then developing high-quality treatment programs that include not just pharmacological treatments but psychosocial treatments and beyond,” he added. “We know that’s the way it works for other disorders as well.”

Although mental illness stigma is a serious problem, Dr. Pies noted, “the risk is not so much that studies of this sort are carried out and then covered in the media, but that they are decontextualized and reduced to ‘bumper sticker’ headlines.”

“The public needs context and perspective,” he said. “It needs to be informed that violent behavior is relatively rare among persons with psychiatric illness, including persons with schizophrenia and related disorders who do not also have a substance use disorder.”

Indeed, some studies have shown that individuals with mental illness are more often the victims of violence than the perpetrators.

“Frankly, the public is much more at risk from the neighborhood lout who drinks heavily and repeatedly starts bar fights than from the average patient with a schizophrenia spectrum disorder,” Dr. Pies said.

Dr. Fazel reported receiving funding from the Wellcome Trust. Dr. DeLisi and Dr. Pies disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new analysis of cardiovascular adverse drug reactions for non–small cell lung cancer (NCSLC)–targeted therapies finds that ALK and ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than BRAF and EGFR inhibitors.

The findings are especially important because cardiovascular disease is known to be associated with NSCLC. Even before the start of therapy, 14%-22% of patients with stage I-IV NSCLC have heart failure and 26%-31% of patients have arrhythmias. No other study to date has described cardiovascular effects to this extent as a result of treatment.

The findings were published in the Journal of Thoracic Oncology.

Led by Joel W. Neal, MD, PhD, a medical oncologist at Stanford (Calif.) Health Care, researchers evaluated the association between NSCLC-targeted agents with arrhythmia and heart failure. Their findings are based on analysis of data from the World Health Organization pharmacovigilance database VigiBase. They found that of 98,765 adverse reactions, 61,383 occurred in patients treated with EGFR inhibitors, 15,540 were associated with ALK inhibitors, and 21,842 were associated with BRAF and MEK inhibitors. Arrhythmias occurred in 1,783 patients and 1,146 patients had heart failure.
 

The specifics

Strong associations with conduction disease and QT prolongation were found for ALK and ROS1 inhibitors, especially crizotinib. Of QT prolongation cases, 38.5% of patients on ceritinib and 18.4% of patients on crizotinib also had conduction disease and 7.9% of alectinib-associated conduction disease cases also had prolongation.

BRAF and MEK inhibitors had stronger associations with heart failure, while osimertinib, a third-generation EGFR tyrosine kinase inhibitor, was strongly associated with QT prolongation, supraventricular tachycardia, and heart failure.

ALK inhibitors were found to be 13 times more likely to lead to conduction disease and five times more likely to lead to lead to long QT syndrome as compared to all NSCLC-targeted therapies together. ALK inhibitor crizotinib had significantly higher odds of conduction disease, compared with all other targeted therapies, but of all ALK inhibitors, ceritinib and lorlatinib had the lowest odds of conduction disease. Crizotinib was 1.9 times more likely to lead to QT prolongation than other ALK inhibitors.

The EGFR inhibitor osimertinib was associated with 49 times more like to lead to long QT syndrome than other EGFR inhibitors and 6 times more likely as compared with all other targeted therapies. The EGFR inhibitor gefitinib was twice as likely than other EGFR inhibitors to lead to conduction disease. The third-generation EGFR inhibitor osimertinib had approximately two times higher odds of supraventricular tachycardia than other EGFR inhibitors.

Osimertinib was associated with 6.8 times higher chances of heart failure, compared with other EGFR inhibitors, and 3.6 times more than other targeted therapies. Dabrafenib and trametinib were associated with two to three times higher odds of heart failure as compared with other targeted therapies.

“There is a need for an understanding of the mechanisms underlying these toxicities and for additional studies to establish standardized guidelines for monitoring, particularly for osimertinib, crizotinib, and alectinib,” the authors wrote

The authors disclosed a number of paid advisory roles with various pharmaceutical companies.

A new analysis of cardiovascular adverse drug reactions for non–small cell lung cancer (NCSLC)–targeted therapies finds that ALK and ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than BRAF and EGFR inhibitors.

The findings are especially important because cardiovascular disease is known to be associated with NSCLC. Even before the start of therapy, 14%-22% of patients with stage I-IV NSCLC have heart failure and 26%-31% of patients have arrhythmias. No other study to date has described cardiovascular effects to this extent as a result of treatment.

The findings were published in the Journal of Thoracic Oncology.

Led by Joel W. Neal, MD, PhD, a medical oncologist at Stanford (Calif.) Health Care, researchers evaluated the association between NSCLC-targeted agents with arrhythmia and heart failure. Their findings are based on analysis of data from the World Health Organization pharmacovigilance database VigiBase. They found that of 98,765 adverse reactions, 61,383 occurred in patients treated with EGFR inhibitors, 15,540 were associated with ALK inhibitors, and 21,842 were associated with BRAF and MEK inhibitors. Arrhythmias occurred in 1,783 patients and 1,146 patients had heart failure.
 

The specifics

Strong associations with conduction disease and QT prolongation were found for ALK and ROS1 inhibitors, especially crizotinib. Of QT prolongation cases, 38.5% of patients on ceritinib and 18.4% of patients on crizotinib also had conduction disease and 7.9% of alectinib-associated conduction disease cases also had prolongation.

BRAF and MEK inhibitors had stronger associations with heart failure, while osimertinib, a third-generation EGFR tyrosine kinase inhibitor, was strongly associated with QT prolongation, supraventricular tachycardia, and heart failure.

ALK inhibitors were found to be 13 times more likely to lead to conduction disease and five times more likely to lead to lead to long QT syndrome as compared to all NSCLC-targeted therapies together. ALK inhibitor crizotinib had significantly higher odds of conduction disease, compared with all other targeted therapies, but of all ALK inhibitors, ceritinib and lorlatinib had the lowest odds of conduction disease. Crizotinib was 1.9 times more likely to lead to QT prolongation than other ALK inhibitors.

The EGFR inhibitor osimertinib was associated with 49 times more like to lead to long QT syndrome than other EGFR inhibitors and 6 times more likely as compared with all other targeted therapies. The EGFR inhibitor gefitinib was twice as likely than other EGFR inhibitors to lead to conduction disease. The third-generation EGFR inhibitor osimertinib had approximately two times higher odds of supraventricular tachycardia than other EGFR inhibitors.

Osimertinib was associated with 6.8 times higher chances of heart failure, compared with other EGFR inhibitors, and 3.6 times more than other targeted therapies. Dabrafenib and trametinib were associated with two to three times higher odds of heart failure as compared with other targeted therapies.

“There is a need for an understanding of the mechanisms underlying these toxicities and for additional studies to establish standardized guidelines for monitoring, particularly for osimertinib, crizotinib, and alectinib,” the authors wrote

The authors disclosed a number of paid advisory roles with various pharmaceutical companies.

A new analysis of cardiovascular adverse drug reactions for non–small cell lung cancer (NCSLC)–targeted therapies finds that ALK and ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than BRAF and EGFR inhibitors.

The findings are especially important because cardiovascular disease is known to be associated with NSCLC. Even before the start of therapy, 14%-22% of patients with stage I-IV NSCLC have heart failure and 26%-31% of patients have arrhythmias. No other study to date has described cardiovascular effects to this extent as a result of treatment.

The findings were published in the Journal of Thoracic Oncology.

Led by Joel W. Neal, MD, PhD, a medical oncologist at Stanford (Calif.) Health Care, researchers evaluated the association between NSCLC-targeted agents with arrhythmia and heart failure. Their findings are based on analysis of data from the World Health Organization pharmacovigilance database VigiBase. They found that of 98,765 adverse reactions, 61,383 occurred in patients treated with EGFR inhibitors, 15,540 were associated with ALK inhibitors, and 21,842 were associated with BRAF and MEK inhibitors. Arrhythmias occurred in 1,783 patients and 1,146 patients had heart failure.
 

The specifics

Strong associations with conduction disease and QT prolongation were found for ALK and ROS1 inhibitors, especially crizotinib. Of QT prolongation cases, 38.5% of patients on ceritinib and 18.4% of patients on crizotinib also had conduction disease and 7.9% of alectinib-associated conduction disease cases also had prolongation.

BRAF and MEK inhibitors had stronger associations with heart failure, while osimertinib, a third-generation EGFR tyrosine kinase inhibitor, was strongly associated with QT prolongation, supraventricular tachycardia, and heart failure.

ALK inhibitors were found to be 13 times more likely to lead to conduction disease and five times more likely to lead to lead to long QT syndrome as compared to all NSCLC-targeted therapies together. ALK inhibitor crizotinib had significantly higher odds of conduction disease, compared with all other targeted therapies, but of all ALK inhibitors, ceritinib and lorlatinib had the lowest odds of conduction disease. Crizotinib was 1.9 times more likely to lead to QT prolongation than other ALK inhibitors.

The EGFR inhibitor osimertinib was associated with 49 times more like to lead to long QT syndrome than other EGFR inhibitors and 6 times more likely as compared with all other targeted therapies. The EGFR inhibitor gefitinib was twice as likely than other EGFR inhibitors to lead to conduction disease. The third-generation EGFR inhibitor osimertinib had approximately two times higher odds of supraventricular tachycardia than other EGFR inhibitors.

Osimertinib was associated with 6.8 times higher chances of heart failure, compared with other EGFR inhibitors, and 3.6 times more than other targeted therapies. Dabrafenib and trametinib were associated with two to three times higher odds of heart failure as compared with other targeted therapies.

“There is a need for an understanding of the mechanisms underlying these toxicities and for additional studies to establish standardized guidelines for monitoring, particularly for osimertinib, crizotinib, and alectinib,” the authors wrote

The authors disclosed a number of paid advisory roles with various pharmaceutical companies.