Mixed Topics

Potentially life-threatening cutaneous adverse drug reactions (cADRs) are associated with commonly prescribed oral antibiotics, according to a large, population-based, nested case-control study of older adults, spanning two decades.

The findings, published online in JAMA, “underscore the importance of judicious prescribing, with preferential use of antibiotics associated with a lower risk when clinically appropriate,” noted senior author David Juurlink, MD, PhD, professor of medicine; pediatrics; and health policy, management and evaluation at the University of Toronto, and head of the Clinical Pharmacology and Toxicology Division at Sunnybrook Health Sciences Centre, also in Toronto, Ontario, Canada, and coauthors.

“We hope our study raises awareness about the importance of drug allergy and gains support for future studies to improve drug allergy care,” lead author Erika Lee, MD, clinical immunology and allergy lecturer at the University of Toronto’s Drug Allergy Clinic, Sunnybrook Health Sciences Centre, said in an interview. “It is important to recognize symptoms and signs of a severe drug rash and promptly stop culprit drugs to prevent worsening reaction.”

Serious cADRs are “a group of rare but potentially life-threatening drug hypersensitivity reactions involving the skin and, frequently, internal organs,” the authors wrote. “Typically delayed in onset, these reactions include drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) — the most severe cADR, which has a reported mortality of 20%-40%,” they noted.

Speculation Without Data

Although it has been speculated that some oral antibiotics are more likely than others to be associated with serious cADRs, there have been no population-based studies examining this, they added.

The study included adults aged 66 years or older and used administrative health databases in Ontario, spanning from April 1, 2002, to March 31, 2022. Data on antibiotic use were taken from the Ontario Drug Benefit database. The Canadian Institute for Health Information (CIHI) National Ambulatory Care Reporting System was used to obtain data on emergency department (ED) visits for cADRs, while the CIHI Discharge Abstract Database was used to identify hospitalizations for cADRs. Finally, demographic information and outpatient healthcare utilization data were obtained from the Registered Persons Database and the Ontario Health Insurance Plan database, respectively.

A cohort of 21,758 older adults (median age, 75 years; 64.1% women) who had an ED visit or hospitalization for serious cADRs within 60 days of receiving antibiotic therapy was matched by age and sex with 87,025 antibiotic-treated controls who did not have a cutaneous reaction.

The median duration of antibiotic prescription was 7 days among cases and controls, and among the cases, the median latency period between antibiotic prescriptions and hospital visits for cADRs was 14 days. Most of the case patients went to the ED only (86.9%), and the rest were hospitalized.

The most commonly prescribed antibiotic class was penicillins (28.9%), followed by cephalosporins (18.2%), fluoroquinolones (16.5%), macrolides (14.8%), nitrofurantoin (8.6%), and sulfonamides (6.2%). Less commonly used antibiotics (“other” antibiotics) accounted for 6.9%.

Macrolide antibiotics were used as the reference because they are rarely associated with serious cADRs, noted the authors, and the multivariable analysis, adjusted for risk factors associated with serious cADRs, including malignancy, chronic liver disease, chronic kidney disease, and HIV.

After multivariable adjustment, relative to macrolides, sulfonamides were most strongly associated with serious cADRs (adjusted odds ratio [aOR], 2.9) but so were all other antibiotic classes, including cephalosporins (aOR, 2.6), “other” antibiotics (aOR, 2.3), nitrofurantoin (aOR, 2.2), penicillins (aOR, 1.4), and fluoroquinolones (aOR,1.3).

In the secondary analysis, the crude rate of ED visits or hospitalizations for cADRs was highest for cephalosporins (4.92 per 1000 prescriptions), followed by sulfonamides (3.22 per 1000 prescriptions). Among hospitalized patients, the median length of stay was 6 days, with 9.6% requiring transfer to a critical care unit and 5.3% dying in the hospital.
 

Hospitalizations, ED Visits Not Studied Previously

“Notably, the rate of antibiotic-associated serious cADRs leading to an ED visit or hospitalization has not been previously studied,” noted the authors. “We found that at least two hospital encounters for serious cADRs ensued for every 1000 antibiotic prescriptions. This rate is considerably higher than suggested by studies that examine only SJS/TEN and drug reaction with eosinophilia and systemic symptoms.”

Dr. Lee also emphasized the previously unreported findings about nitrofurantoin. “It is surprising to find that nitrofurantoin, a commonly prescribed antibiotic for urinary tract infection, is also associated with an increased risk of severe drug rash,” she said in an interview.

“This finding highlights a potential novel risk at a population-based level and should be further explored in other populations to verify this association,” the authors wrote.

Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security in Baltimore, Maryland, and a spokesperson for the Infectious Diseases Society of America, who was not involved in the study, agreed that the nitrofurantoin finding was surprising, but he was not surprised that sulfonamides were high on the list.

“The study reinforces that antibiotics are not benign medications to be dispensed injudiciously,” he said in an interview. “Antibiotics have risks, including serious skin reactions, as well as the fostering of antibiotic resistance. Clinicians should always first ask themselves if their patient actually merits an antibiotic and then assess what is the safest antibiotic for the purpose, bearing in mind that certain antibiotics are more likely to result in adverse reactions than others.”

The study was supported by the Canadian Institutes of Health Research. The study was conducted at ICES, which is funded in part by an annual grant from the Ontario Ministry of Health and Long-Term Care. One coauthor reported receiving compensation from the British Journal of Dermatology as reviewer and section editor, the American Academy of Dermatology as guidelines writer, Canadian Dermatology Today as manuscript writer, and the National Eczema Association and the Canadian Agency for Drugs and Technologies in Health as consultant; as well as receiving research grants to the coauthor’s institution from the National Eczema Association, Eczema Society of Canada, Canadian Dermatology Foundation, Canadian Institutes of Health Research, US National Institutes of Health, and PSI Foundation. Another coauthor reported receiving grants from AbbVie, Bausch Health, Celgene, Lilly, Incyte, Janssen, LEO Pharma, L’Oréal, Novartis, Organon, Pfizer, Sandoz, Amgen, and Boehringer Ingelheim; receiving payment or honoraria for speaking from Sanofi China; participating on advisory boards for LEO Pharma, Novartis, Sanofi, and Union Therapeutics; and receiving equipment donation from L’Oréal. Dr. Adalja reported no relevant disclosures.

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

Potentially life-threatening cutaneous adverse drug reactions (cADRs) are associated with commonly prescribed oral antibiotics, according to a large, population-based, nested case-control study of older adults, spanning two decades.

The findings, published online in JAMA, “underscore the importance of judicious prescribing, with preferential use of antibiotics associated with a lower risk when clinically appropriate,” noted senior author David Juurlink, MD, PhD, professor of medicine; pediatrics; and health policy, management and evaluation at the University of Toronto, and head of the Clinical Pharmacology and Toxicology Division at Sunnybrook Health Sciences Centre, also in Toronto, Ontario, Canada, and coauthors.

“We hope our study raises awareness about the importance of drug allergy and gains support for future studies to improve drug allergy care,” lead author Erika Lee, MD, clinical immunology and allergy lecturer at the University of Toronto’s Drug Allergy Clinic, Sunnybrook Health Sciences Centre, said in an interview. “It is important to recognize symptoms and signs of a severe drug rash and promptly stop culprit drugs to prevent worsening reaction.”

Serious cADRs are “a group of rare but potentially life-threatening drug hypersensitivity reactions involving the skin and, frequently, internal organs,” the authors wrote. “Typically delayed in onset, these reactions include drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) — the most severe cADR, which has a reported mortality of 20%-40%,” they noted.

Speculation Without Data

Although it has been speculated that some oral antibiotics are more likely than others to be associated with serious cADRs, there have been no population-based studies examining this, they added.

The study included adults aged 66 years or older and used administrative health databases in Ontario, spanning from April 1, 2002, to March 31, 2022. Data on antibiotic use were taken from the Ontario Drug Benefit database. The Canadian Institute for Health Information (CIHI) National Ambulatory Care Reporting System was used to obtain data on emergency department (ED) visits for cADRs, while the CIHI Discharge Abstract Database was used to identify hospitalizations for cADRs. Finally, demographic information and outpatient healthcare utilization data were obtained from the Registered Persons Database and the Ontario Health Insurance Plan database, respectively.

A cohort of 21,758 older adults (median age, 75 years; 64.1% women) who had an ED visit or hospitalization for serious cADRs within 60 days of receiving antibiotic therapy was matched by age and sex with 87,025 antibiotic-treated controls who did not have a cutaneous reaction.

The median duration of antibiotic prescription was 7 days among cases and controls, and among the cases, the median latency period between antibiotic prescriptions and hospital visits for cADRs was 14 days. Most of the case patients went to the ED only (86.9%), and the rest were hospitalized.

The most commonly prescribed antibiotic class was penicillins (28.9%), followed by cephalosporins (18.2%), fluoroquinolones (16.5%), macrolides (14.8%), nitrofurantoin (8.6%), and sulfonamides (6.2%). Less commonly used antibiotics (“other” antibiotics) accounted for 6.9%.

Macrolide antibiotics were used as the reference because they are rarely associated with serious cADRs, noted the authors, and the multivariable analysis, adjusted for risk factors associated with serious cADRs, including malignancy, chronic liver disease, chronic kidney disease, and HIV.

After multivariable adjustment, relative to macrolides, sulfonamides were most strongly associated with serious cADRs (adjusted odds ratio [aOR], 2.9) but so were all other antibiotic classes, including cephalosporins (aOR, 2.6), “other” antibiotics (aOR, 2.3), nitrofurantoin (aOR, 2.2), penicillins (aOR, 1.4), and fluoroquinolones (aOR,1.3).

In the secondary analysis, the crude rate of ED visits or hospitalizations for cADRs was highest for cephalosporins (4.92 per 1000 prescriptions), followed by sulfonamides (3.22 per 1000 prescriptions). Among hospitalized patients, the median length of stay was 6 days, with 9.6% requiring transfer to a critical care unit and 5.3% dying in the hospital.
 

Hospitalizations, ED Visits Not Studied Previously

“Notably, the rate of antibiotic-associated serious cADRs leading to an ED visit or hospitalization has not been previously studied,” noted the authors. “We found that at least two hospital encounters for serious cADRs ensued for every 1000 antibiotic prescriptions. This rate is considerably higher than suggested by studies that examine only SJS/TEN and drug reaction with eosinophilia and systemic symptoms.”

Dr. Lee also emphasized the previously unreported findings about nitrofurantoin. “It is surprising to find that nitrofurantoin, a commonly prescribed antibiotic for urinary tract infection, is also associated with an increased risk of severe drug rash,” she said in an interview.

“This finding highlights a potential novel risk at a population-based level and should be further explored in other populations to verify this association,” the authors wrote.

Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security in Baltimore, Maryland, and a spokesperson for the Infectious Diseases Society of America, who was not involved in the study, agreed that the nitrofurantoin finding was surprising, but he was not surprised that sulfonamides were high on the list.

“The study reinforces that antibiotics are not benign medications to be dispensed injudiciously,” he said in an interview. “Antibiotics have risks, including serious skin reactions, as well as the fostering of antibiotic resistance. Clinicians should always first ask themselves if their patient actually merits an antibiotic and then assess what is the safest antibiotic for the purpose, bearing in mind that certain antibiotics are more likely to result in adverse reactions than others.”

The study was supported by the Canadian Institutes of Health Research. The study was conducted at ICES, which is funded in part by an annual grant from the Ontario Ministry of Health and Long-Term Care. One coauthor reported receiving compensation from the British Journal of Dermatology as reviewer and section editor, the American Academy of Dermatology as guidelines writer, Canadian Dermatology Today as manuscript writer, and the National Eczema Association and the Canadian Agency for Drugs and Technologies in Health as consultant; as well as receiving research grants to the coauthor’s institution from the National Eczema Association, Eczema Society of Canada, Canadian Dermatology Foundation, Canadian Institutes of Health Research, US National Institutes of Health, and PSI Foundation. Another coauthor reported receiving grants from AbbVie, Bausch Health, Celgene, Lilly, Incyte, Janssen, LEO Pharma, L’Oréal, Novartis, Organon, Pfizer, Sandoz, Amgen, and Boehringer Ingelheim; receiving payment or honoraria for speaking from Sanofi China; participating on advisory boards for LEO Pharma, Novartis, Sanofi, and Union Therapeutics; and receiving equipment donation from L’Oréal. Dr. Adalja reported no relevant disclosures.

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

Potentially life-threatening cutaneous adverse drug reactions (cADRs) are associated with commonly prescribed oral antibiotics, according to a large, population-based, nested case-control study of older adults, spanning two decades.

The findings, published online in JAMA, “underscore the importance of judicious prescribing, with preferential use of antibiotics associated with a lower risk when clinically appropriate,” noted senior author David Juurlink, MD, PhD, professor of medicine; pediatrics; and health policy, management and evaluation at the University of Toronto, and head of the Clinical Pharmacology and Toxicology Division at Sunnybrook Health Sciences Centre, also in Toronto, Ontario, Canada, and coauthors.

“We hope our study raises awareness about the importance of drug allergy and gains support for future studies to improve drug allergy care,” lead author Erika Lee, MD, clinical immunology and allergy lecturer at the University of Toronto’s Drug Allergy Clinic, Sunnybrook Health Sciences Centre, said in an interview. “It is important to recognize symptoms and signs of a severe drug rash and promptly stop culprit drugs to prevent worsening reaction.”

Serious cADRs are “a group of rare but potentially life-threatening drug hypersensitivity reactions involving the skin and, frequently, internal organs,” the authors wrote. “Typically delayed in onset, these reactions include drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) — the most severe cADR, which has a reported mortality of 20%-40%,” they noted.

Speculation Without Data

Although it has been speculated that some oral antibiotics are more likely than others to be associated with serious cADRs, there have been no population-based studies examining this, they added.

The study included adults aged 66 years or older and used administrative health databases in Ontario, spanning from April 1, 2002, to March 31, 2022. Data on antibiotic use were taken from the Ontario Drug Benefit database. The Canadian Institute for Health Information (CIHI) National Ambulatory Care Reporting System was used to obtain data on emergency department (ED) visits for cADRs, while the CIHI Discharge Abstract Database was used to identify hospitalizations for cADRs. Finally, demographic information and outpatient healthcare utilization data were obtained from the Registered Persons Database and the Ontario Health Insurance Plan database, respectively.

A cohort of 21,758 older adults (median age, 75 years; 64.1% women) who had an ED visit or hospitalization for serious cADRs within 60 days of receiving antibiotic therapy was matched by age and sex with 87,025 antibiotic-treated controls who did not have a cutaneous reaction.

The median duration of antibiotic prescription was 7 days among cases and controls, and among the cases, the median latency period between antibiotic prescriptions and hospital visits for cADRs was 14 days. Most of the case patients went to the ED only (86.9%), and the rest were hospitalized.

The most commonly prescribed antibiotic class was penicillins (28.9%), followed by cephalosporins (18.2%), fluoroquinolones (16.5%), macrolides (14.8%), nitrofurantoin (8.6%), and sulfonamides (6.2%). Less commonly used antibiotics (“other” antibiotics) accounted for 6.9%.

Macrolide antibiotics were used as the reference because they are rarely associated with serious cADRs, noted the authors, and the multivariable analysis, adjusted for risk factors associated with serious cADRs, including malignancy, chronic liver disease, chronic kidney disease, and HIV.

After multivariable adjustment, relative to macrolides, sulfonamides were most strongly associated with serious cADRs (adjusted odds ratio [aOR], 2.9) but so were all other antibiotic classes, including cephalosporins (aOR, 2.6), “other” antibiotics (aOR, 2.3), nitrofurantoin (aOR, 2.2), penicillins (aOR, 1.4), and fluoroquinolones (aOR,1.3).

In the secondary analysis, the crude rate of ED visits or hospitalizations for cADRs was highest for cephalosporins (4.92 per 1000 prescriptions), followed by sulfonamides (3.22 per 1000 prescriptions). Among hospitalized patients, the median length of stay was 6 days, with 9.6% requiring transfer to a critical care unit and 5.3% dying in the hospital.
 

Hospitalizations, ED Visits Not Studied Previously

“Notably, the rate of antibiotic-associated serious cADRs leading to an ED visit or hospitalization has not been previously studied,” noted the authors. “We found that at least two hospital encounters for serious cADRs ensued for every 1000 antibiotic prescriptions. This rate is considerably higher than suggested by studies that examine only SJS/TEN and drug reaction with eosinophilia and systemic symptoms.”

Dr. Lee also emphasized the previously unreported findings about nitrofurantoin. “It is surprising to find that nitrofurantoin, a commonly prescribed antibiotic for urinary tract infection, is also associated with an increased risk of severe drug rash,” she said in an interview.

“This finding highlights a potential novel risk at a population-based level and should be further explored in other populations to verify this association,” the authors wrote.

Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security in Baltimore, Maryland, and a spokesperson for the Infectious Diseases Society of America, who was not involved in the study, agreed that the nitrofurantoin finding was surprising, but he was not surprised that sulfonamides were high on the list.

“The study reinforces that antibiotics are not benign medications to be dispensed injudiciously,” he said in an interview. “Antibiotics have risks, including serious skin reactions, as well as the fostering of antibiotic resistance. Clinicians should always first ask themselves if their patient actually merits an antibiotic and then assess what is the safest antibiotic for the purpose, bearing in mind that certain antibiotics are more likely to result in adverse reactions than others.”

The study was supported by the Canadian Institutes of Health Research. The study was conducted at ICES, which is funded in part by an annual grant from the Ontario Ministry of Health and Long-Term Care. One coauthor reported receiving compensation from the British Journal of Dermatology as reviewer and section editor, the American Academy of Dermatology as guidelines writer, Canadian Dermatology Today as manuscript writer, and the National Eczema Association and the Canadian Agency for Drugs and Technologies in Health as consultant; as well as receiving research grants to the coauthor’s institution from the National Eczema Association, Eczema Society of Canada, Canadian Dermatology Foundation, Canadian Institutes of Health Research, US National Institutes of Health, and PSI Foundation. Another coauthor reported receiving grants from AbbVie, Bausch Health, Celgene, Lilly, Incyte, Janssen, LEO Pharma, L’Oréal, Novartis, Organon, Pfizer, Sandoz, Amgen, and Boehringer Ingelheim; receiving payment or honoraria for speaking from Sanofi China; participating on advisory boards for LEO Pharma, Novartis, Sanofi, and Union Therapeutics; and receiving equipment donation from L’Oréal. Dr. Adalja reported no relevant disclosures.

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

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

To the Editor:

Generalized bullous fixed drug eruption (GBFDE) is a rare subtype of fixed drug eruption (FDE) that manifests as widespread blisters and erosions following exposure to a causative drug.¹ Diagnostic criteria include involvement of at least 3 to 6 anatomic sites—head and neck, anterior trunk, posterior trunk, upper extremities, lower extremities, or genitalia—and more than 10% of the body surface area. It can be challenging to differentiate GBFDE from severe drug rashes such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) due to extensive body surface area involvement of blisters and erosions. Specific features distinguishing GBFDE from SJS/TEN include primary lesions consisting of larger erythematous to dusky, circular plaques that progress to bullae and coalesce into widespread erosions; history of FDE; lack of severe mucosal involvement; and better overall prognosis.² Treatment typically involves discontinuation of the culprit medication and supportive care; evidence for systemic therapies is not well established.

Our study aimed to characterize the clinical and demographic features of GBFDE in our institution to highlight potential key differences between this diagnosis and SJS/TEN. An electronic medical record search was performed to identify patients who were clinically diagnosed with GBFDE at New York-Presbyterian/Weill Cornell Medical Center (New York, New York) in both outpatient and inpatient settings from January 2015 to December 2022. This retrospective study was approved by the Weill Cornell Medicine institutional review board (#22-05024777).

Ten patients were identified and included in the analysis (eTable). The mean age of the patients was 56 years (range, 39–76 years). Seven (70%) patients had skin of color (non-White) and 6 (60%) were female. The mean body mass index was 35 (range, 20–57), and 7 (70%) patients were clinically obese (body mass index >30). Only 2 (20%) patients had a history of a documented drug eruption (hives and erythema multiforme), and no patients had a history of FDE. Erythematous dusky patches followed by rapid development of blisters were noted within 3 days of drug initiation in 40% (4/10) and within 5 days in 80% (8/10) of patients. Antibiotics were identified as likely inciting agents in 8 (80%) patients. Biopsies were obtained in 3 (30%) patients and all 3 demonstrated cytotoxic CD8⁺ interface dermatitis with marked epithelial necrosis, neutrophilia, eosinophilia, and melanophage accumulation. Fever was present at initial presentation in only 4 (40%) patients, and only 1 (10%) patient had oral mucosal involvement. All 10 patients had intertriginous involvement (axillae, 90% [9/10]; gluteal cleft, 80% [8/10]; groin, 80% [8/10]; inframammary folds, 20% [2/10]), and there was considerable flank involvement in 9 (90%) patients. All 10 patients had initial erythematous to dusky, circular patches on the trunk and proximal extremities that then denuded most dramatically in the intertriginous areas (Figure). Six (60%) patients received systemic therapy, including 5 patients treated with a single dose of etanercept 50 mg. In patients with continued progression, 1 or 2 additional doses of etanercept 50 mg were administered at 48- to 72-hour intervals until blistering halted. Treatment with etanercept resulted in clinical improvement in all 5 patients, and there were no identifiable adverse events. The mean hospital stay was 19.7 days (range, 1–63 days).

This study highlights notable demographic and clinical features of GBFDE that have not been widely described in the literature. Large erythematous and dusky patches with broad zones of blistering with particular localization to the neck, intertriginous areas, and flanks typically are not described in SJS/TEN and may be helpful in distinguishing these conditions from GBFDE. Mild or complete lack of mucosal and facial involvement as well as more rapid time from drug initiation to rash (as rapid as 1 day) were key factors that aided in distinguishing GBFDE from SJS/TEN in our patients. Although a history of FDE is considered a key characteristic in the diagnosis of GBFDE, none of our patients had a known history of FDE, suggesting GBFDE may be the initial manifestation of FDE in some patients. Histopathology showed similar findings consistent with FDE in the 3 patients in whom a biopsy was performed. The remaining patients were diagnosed clinically based on the presence of distinctive, perfectly circular, dusky plaques present at the periphery of larger denuded areas, which are characteristic of GBFDE. Lower levels of serum granulysin³ have been shown to help distinguish GBFDE from SJS/TEN, but this test is not readily available with time-sensitive results at most institutions, and exact diagnostic ranges for GBFDE vs SJS/TEN are not yet known.

Our study was limited by a small number of patients at a single institution. Another limitation was the retrospective design.

Interestingly, a high proportion of our patients were non-White and clinically obese, which are factors that should be considered for future research. Sixty percent (6/10) of the patients in our study were Black, which is a notable difference from our hospital’s general admission demographics with Black individuals constituting 12% of patients.⁴ Our study also highlighted the utility of etanercept, which has reported mortality benefits and decreased time to re-epithelialization in other severe blistering cutaneous drug reactions including SJS/TEN,⁵ as a potential therapeutic option in GBFDE.

It is imperative that clinicians recognize the differences between GBFDE and SJS/TEN, as correct diagnosis is crucial for identifying the most likely causative drug as well as providing accurate prognostic information and may have future therapeutic implications as we further understand the immunologic profiles of these severe blistering drug reactions.

To the Editor:

Generalized bullous fixed drug eruption (GBFDE) is a rare subtype of fixed drug eruption (FDE) that manifests as widespread blisters and erosions following exposure to a causative drug.¹ Diagnostic criteria include involvement of at least 3 to 6 anatomic sites—head and neck, anterior trunk, posterior trunk, upper extremities, lower extremities, or genitalia—and more than 10% of the body surface area. It can be challenging to differentiate GBFDE from severe drug rashes such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) due to extensive body surface area involvement of blisters and erosions. Specific features distinguishing GBFDE from SJS/TEN include primary lesions consisting of larger erythematous to dusky, circular plaques that progress to bullae and coalesce into widespread erosions; history of FDE; lack of severe mucosal involvement; and better overall prognosis.² Treatment typically involves discontinuation of the culprit medication and supportive care; evidence for systemic therapies is not well established.

Our study aimed to characterize the clinical and demographic features of GBFDE in our institution to highlight potential key differences between this diagnosis and SJS/TEN. An electronic medical record search was performed to identify patients who were clinically diagnosed with GBFDE at New York-Presbyterian/Weill Cornell Medical Center (New York, New York) in both outpatient and inpatient settings from January 2015 to December 2022. This retrospective study was approved by the Weill Cornell Medicine institutional review board (#22-05024777).

Ten patients were identified and included in the analysis (eTable). The mean age of the patients was 56 years (range, 39–76 years). Seven (70%) patients had skin of color (non-White) and 6 (60%) were female. The mean body mass index was 35 (range, 20–57), and 7 (70%) patients were clinically obese (body mass index >30). Only 2 (20%) patients had a history of a documented drug eruption (hives and erythema multiforme), and no patients had a history of FDE. Erythematous dusky patches followed by rapid development of blisters were noted within 3 days of drug initiation in 40% (4/10) and within 5 days in 80% (8/10) of patients. Antibiotics were identified as likely inciting agents in 8 (80%) patients. Biopsies were obtained in 3 (30%) patients and all 3 demonstrated cytotoxic CD8⁺ interface dermatitis with marked epithelial necrosis, neutrophilia, eosinophilia, and melanophage accumulation. Fever was present at initial presentation in only 4 (40%) patients, and only 1 (10%) patient had oral mucosal involvement. All 10 patients had intertriginous involvement (axillae, 90% [9/10]; gluteal cleft, 80% [8/10]; groin, 80% [8/10]; inframammary folds, 20% [2/10]), and there was considerable flank involvement in 9 (90%) patients. All 10 patients had initial erythematous to dusky, circular patches on the trunk and proximal extremities that then denuded most dramatically in the intertriginous areas (Figure). Six (60%) patients received systemic therapy, including 5 patients treated with a single dose of etanercept 50 mg. In patients with continued progression, 1 or 2 additional doses of etanercept 50 mg were administered at 48- to 72-hour intervals until blistering halted. Treatment with etanercept resulted in clinical improvement in all 5 patients, and there were no identifiable adverse events. The mean hospital stay was 19.7 days (range, 1–63 days).

This study highlights notable demographic and clinical features of GBFDE that have not been widely described in the literature. Large erythematous and dusky patches with broad zones of blistering with particular localization to the neck, intertriginous areas, and flanks typically are not described in SJS/TEN and may be helpful in distinguishing these conditions from GBFDE. Mild or complete lack of mucosal and facial involvement as well as more rapid time from drug initiation to rash (as rapid as 1 day) were key factors that aided in distinguishing GBFDE from SJS/TEN in our patients. Although a history of FDE is considered a key characteristic in the diagnosis of GBFDE, none of our patients had a known history of FDE, suggesting GBFDE may be the initial manifestation of FDE in some patients. Histopathology showed similar findings consistent with FDE in the 3 patients in whom a biopsy was performed. The remaining patients were diagnosed clinically based on the presence of distinctive, perfectly circular, dusky plaques present at the periphery of larger denuded areas, which are characteristic of GBFDE. Lower levels of serum granulysin³ have been shown to help distinguish GBFDE from SJS/TEN, but this test is not readily available with time-sensitive results at most institutions, and exact diagnostic ranges for GBFDE vs SJS/TEN are not yet known.

Our study was limited by a small number of patients at a single institution. Another limitation was the retrospective design.

Interestingly, a high proportion of our patients were non-White and clinically obese, which are factors that should be considered for future research. Sixty percent (6/10) of the patients in our study were Black, which is a notable difference from our hospital’s general admission demographics with Black individuals constituting 12% of patients.⁴ Our study also highlighted the utility of etanercept, which has reported mortality benefits and decreased time to re-epithelialization in other severe blistering cutaneous drug reactions including SJS/TEN,⁵ as a potential therapeutic option in GBFDE.

It is imperative that clinicians recognize the differences between GBFDE and SJS/TEN, as correct diagnosis is crucial for identifying the most likely causative drug as well as providing accurate prognostic information and may have future therapeutic implications as we further understand the immunologic profiles of these severe blistering drug reactions.

To the Editor:

Generalized bullous fixed drug eruption (GBFDE) is a rare subtype of fixed drug eruption (FDE) that manifests as widespread blisters and erosions following exposure to a causative drug.¹ Diagnostic criteria include involvement of at least 3 to 6 anatomic sites—head and neck, anterior trunk, posterior trunk, upper extremities, lower extremities, or genitalia—and more than 10% of the body surface area. It can be challenging to differentiate GBFDE from severe drug rashes such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) due to extensive body surface area involvement of blisters and erosions. Specific features distinguishing GBFDE from SJS/TEN include primary lesions consisting of larger erythematous to dusky, circular plaques that progress to bullae and coalesce into widespread erosions; history of FDE; lack of severe mucosal involvement; and better overall prognosis.² Treatment typically involves discontinuation of the culprit medication and supportive care; evidence for systemic therapies is not well established.

Our study aimed to characterize the clinical and demographic features of GBFDE in our institution to highlight potential key differences between this diagnosis and SJS/TEN. An electronic medical record search was performed to identify patients who were clinically diagnosed with GBFDE at New York-Presbyterian/Weill Cornell Medical Center (New York, New York) in both outpatient and inpatient settings from January 2015 to December 2022. This retrospective study was approved by the Weill Cornell Medicine institutional review board (#22-05024777).

Ten patients were identified and included in the analysis (eTable). The mean age of the patients was 56 years (range, 39–76 years). Seven (70%) patients had skin of color (non-White) and 6 (60%) were female. The mean body mass index was 35 (range, 20–57), and 7 (70%) patients were clinically obese (body mass index >30). Only 2 (20%) patients had a history of a documented drug eruption (hives and erythema multiforme), and no patients had a history of FDE. Erythematous dusky patches followed by rapid development of blisters were noted within 3 days of drug initiation in 40% (4/10) and within 5 days in 80% (8/10) of patients. Antibiotics were identified as likely inciting agents in 8 (80%) patients. Biopsies were obtained in 3 (30%) patients and all 3 demonstrated cytotoxic CD8⁺ interface dermatitis with marked epithelial necrosis, neutrophilia, eosinophilia, and melanophage accumulation. Fever was present at initial presentation in only 4 (40%) patients, and only 1 (10%) patient had oral mucosal involvement. All 10 patients had intertriginous involvement (axillae, 90% [9/10]; gluteal cleft, 80% [8/10]; groin, 80% [8/10]; inframammary folds, 20% [2/10]), and there was considerable flank involvement in 9 (90%) patients. All 10 patients had initial erythematous to dusky, circular patches on the trunk and proximal extremities that then denuded most dramatically in the intertriginous areas (Figure). Six (60%) patients received systemic therapy, including 5 patients treated with a single dose of etanercept 50 mg. In patients with continued progression, 1 or 2 additional doses of etanercept 50 mg were administered at 48- to 72-hour intervals until blistering halted. Treatment with etanercept resulted in clinical improvement in all 5 patients, and there were no identifiable adverse events. The mean hospital stay was 19.7 days (range, 1–63 days).

This study highlights notable demographic and clinical features of GBFDE that have not been widely described in the literature. Large erythematous and dusky patches with broad zones of blistering with particular localization to the neck, intertriginous areas, and flanks typically are not described in SJS/TEN and may be helpful in distinguishing these conditions from GBFDE. Mild or complete lack of mucosal and facial involvement as well as more rapid time from drug initiation to rash (as rapid as 1 day) were key factors that aided in distinguishing GBFDE from SJS/TEN in our patients. Although a history of FDE is considered a key characteristic in the diagnosis of GBFDE, none of our patients had a known history of FDE, suggesting GBFDE may be the initial manifestation of FDE in some patients. Histopathology showed similar findings consistent with FDE in the 3 patients in whom a biopsy was performed. The remaining patients were diagnosed clinically based on the presence of distinctive, perfectly circular, dusky plaques present at the periphery of larger denuded areas, which are characteristic of GBFDE. Lower levels of serum granulysin³ have been shown to help distinguish GBFDE from SJS/TEN, but this test is not readily available with time-sensitive results at most institutions, and exact diagnostic ranges for GBFDE vs SJS/TEN are not yet known.

Our study was limited by a small number of patients at a single institution. Another limitation was the retrospective design.

Interestingly, a high proportion of our patients were non-White and clinically obese, which are factors that should be considered for future research. Sixty percent (6/10) of the patients in our study were Black, which is a notable difference from our hospital’s general admission demographics with Black individuals constituting 12% of patients.⁴ Our study also highlighted the utility of etanercept, which has reported mortality benefits and decreased time to re-epithelialization in other severe blistering cutaneous drug reactions including SJS/TEN,⁵ as a potential therapeutic option in GBFDE.

It is imperative that clinicians recognize the differences between GBFDE and SJS/TEN, as correct diagnosis is crucial for identifying the most likely causative drug as well as providing accurate prognostic information and may have future therapeutic implications as we further understand the immunologic profiles of these severe blistering drug reactions.

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

The field of GI is rapidly evolving, fueled by new scientific discoveries leading to improved understanding of disease mechanisms and more effective treatment approaches for patients with digestive and liver diseases. But there are many challenges confronting the pipeline of early-career investigators essential to future discovery, most notably a constrained funding environment leading to decreased protected time for research during these critical early years.

Foundation awards, such as those funded by the AGA Research Foundation, play a pivotal role in supporting the career development of promising young investigators in basic, translational, clinical, and health services research and ensure that we have a strong pipeline of independent investigators to stimulate ongoing discovery and innovation in our field. This year, the AGA Research Foundation distributed $2.6 million in funding to 76 investigators, including six coveted Research Scholar Awards awarded to early-career investigators. These promising young researchers represent the best and the brightest in our field — I hope you enjoy learning more about them in the pages of this issue and will join me in continuing to support the Foundation and its work under the leadership of Dr. Michael Camilleri.

University of Michigan

Also in our August issue, we bring you continued coverage from DDW and June’s EASL Congress, and report on innovative science published in AGA’s flagship journals, including a study investigating the impact of H pylori eradication on esophageal cancer risk. We also highlight several important studies relating to eosinophilic esophagitis, including a recent RCT published in The New England Journal of Medicine demonstrating the effectiveness of dupilumab in treatment of PPI-refractory pediatric EoE. Our August Member Spotlight features Dr. Neelendu Dey of Fred Hutchinson Cancer Center, who shares his perspectives on pursuing a career as a physician-scientist and chronicles his research focused on harnessing the microbiome for cancer prevention.

Finally, our quarterly In Focus column from The New Gastroenterologist provides practical advice regarding how best to evaluate patients with chronic bloating symptoms, a frequent presentation in our GI clinics. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.
 

Megan A. Adams, MD, JD, MSc

Editor in Chief

The field of GI is rapidly evolving, fueled by new scientific discoveries leading to improved understanding of disease mechanisms and more effective treatment approaches for patients with digestive and liver diseases. But there are many challenges confronting the pipeline of early-career investigators essential to future discovery, most notably a constrained funding environment leading to decreased protected time for research during these critical early years.

Foundation awards, such as those funded by the AGA Research Foundation, play a pivotal role in supporting the career development of promising young investigators in basic, translational, clinical, and health services research and ensure that we have a strong pipeline of independent investigators to stimulate ongoing discovery and innovation in our field. This year, the AGA Research Foundation distributed $2.6 million in funding to 76 investigators, including six coveted Research Scholar Awards awarded to early-career investigators. These promising young researchers represent the best and the brightest in our field — I hope you enjoy learning more about them in the pages of this issue and will join me in continuing to support the Foundation and its work under the leadership of Dr. Michael Camilleri.

University of Michigan

Also in our August issue, we bring you continued coverage from DDW and June’s EASL Congress, and report on innovative science published in AGA’s flagship journals, including a study investigating the impact of H pylori eradication on esophageal cancer risk. We also highlight several important studies relating to eosinophilic esophagitis, including a recent RCT published in The New England Journal of Medicine demonstrating the effectiveness of dupilumab in treatment of PPI-refractory pediatric EoE. Our August Member Spotlight features Dr. Neelendu Dey of Fred Hutchinson Cancer Center, who shares his perspectives on pursuing a career as a physician-scientist and chronicles his research focused on harnessing the microbiome for cancer prevention.

Finally, our quarterly In Focus column from The New Gastroenterologist provides practical advice regarding how best to evaluate patients with chronic bloating symptoms, a frequent presentation in our GI clinics. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.
 

Megan A. Adams, MD, JD, MSc

Editor in Chief

The field of GI is rapidly evolving, fueled by new scientific discoveries leading to improved understanding of disease mechanisms and more effective treatment approaches for patients with digestive and liver diseases. But there are many challenges confronting the pipeline of early-career investigators essential to future discovery, most notably a constrained funding environment leading to decreased protected time for research during these critical early years.

Foundation awards, such as those funded by the AGA Research Foundation, play a pivotal role in supporting the career development of promising young investigators in basic, translational, clinical, and health services research and ensure that we have a strong pipeline of independent investigators to stimulate ongoing discovery and innovation in our field. This year, the AGA Research Foundation distributed $2.6 million in funding to 76 investigators, including six coveted Research Scholar Awards awarded to early-career investigators. These promising young researchers represent the best and the brightest in our field — I hope you enjoy learning more about them in the pages of this issue and will join me in continuing to support the Foundation and its work under the leadership of Dr. Michael Camilleri.

University of Michigan

Also in our August issue, we bring you continued coverage from DDW and June’s EASL Congress, and report on innovative science published in AGA’s flagship journals, including a study investigating the impact of H pylori eradication on esophageal cancer risk. We also highlight several important studies relating to eosinophilic esophagitis, including a recent RCT published in The New England Journal of Medicine demonstrating the effectiveness of dupilumab in treatment of PPI-refractory pediatric EoE. Our August Member Spotlight features Dr. Neelendu Dey of Fred Hutchinson Cancer Center, who shares his perspectives on pursuing a career as a physician-scientist and chronicles his research focused on harnessing the microbiome for cancer prevention.

Finally, our quarterly In Focus column from The New Gastroenterologist provides practical advice regarding how best to evaluate patients with chronic bloating symptoms, a frequent presentation in our GI clinics. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.
 

Megan A. Adams, MD, JD, MSc

Editor in Chief

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

Peter Grinspoon, MD, has some advice for clinicians when patients ask questions about microdosing of psychedelics: Keep the lines of communication open — and don’t be judgmental.

“If you’re dismissive or critical or sound like you’re judging them, then the patients just clam up,” said Dr. Grinspoon, a professor of medicine at Harvard Medical School and a primary care physician at Massachusetts General Hospital, both in Boston.

Psychedelic drugs are still illegal in the majority of states despite the growth of public interest in and use of these substances. That growth is evidenced by a flurry of workshops, reports, law enforcement seizures, and pressure by Congressional members for the Food and Drug Administration to approve new psychedelic drugs, just in the past year.

A recent study in JAMA Health Forum showed a nearly 14-fold increase in Google searches — from 7.9 to 105.6 per 10 million nationwide — for the term “microdosing” and related wording, between 2015 and 2023.

Two states — Oregon and Colorado — have decriminalized certain psychedelic drugs and are in various stages of establishing regulations and centers for prospective clients. Almost two dozen localities, like Ann Arbor, Michigan, have decriminalized psychedelic drugs. A handful of states have active legislation to decriminalize use, while others have bills that never made it out of committee.

But no definitive studies have reported that microdosing produces positive mental effects at a higher rate than placebo, according to Dr. Grinspoon. So responding to patient inquiries about microdosing can be complicated, and clinicians must provide counsel on issues of legality and therapeutic appropriateness.

“We’re in this renaissance where everybody is idealizing these medications, as opposed to 20 years ago when we were in the war on drugs and everybody was dismissing them,” Dr. Grinspoon said. “The truth is somewhere in between.”
 

The Science

Microdosing is defined as taking doses of 1/5 to 1/20 of the conventional recreational amount, which might include a dried psilocybin mushroom, lysergic acid diethylamide, or 3,4-methylenedioxymethamphetamine. But even that much may be neither effective nor safe.

Dr. Grinspoon said clinicians should tell patients that psychedelics may cause harm, although the drugs are relatively nontoxic and are not addictive. An illegally obtained psilocybin could cause negative reactions, especially if the drug has been adulterated with other substances and if the actual dose is higher than what was indicated by the seller.

He noted that people have different reactions to psychedelics, just as they have to prescription medications. He cited one example of a woman who microdosed and could not sleep for 2 weeks afterward. Only recently have randomized, double-blinded studies begun on benefits and harms.

Researchers have also begun investigating whether long-term microdosing of psilocybin could lead to valvular heart disease (VHD), said Kevin Yang, MD, a psychiatry resident at the University of California San Diego School of Medicine. A recent review of evidence concluded that microdosing various psychedelics over a period of months can lead to drug-induced VHD.

“It’s extremely important to emphasize with patients that not only do we not know if it works or not, we also don’t really know how safe it is,” Dr. Yang said.

Dr. Yang also said clinicians should consider referring patients to a mental health professional, and especially those that may have expertise in psychedelic therapies.

One of those experts is Rachel Yehuda, PhD, director of the Center for Psychedelic Psychotherapy and Trauma Research at Icahn School of Medicine at Mount Sinai in New York City. She said therapists should be able to assess the patient’s perceived need for microdosing and “invite reflections about why current approaches are falling short.”

“I would also not actively discourage it either but remain curious until both of you have a better understanding of the reasons for seeking this out and potential alternative strategies for obtaining more therapeutic benefits,” she said. “I think it is really important to study the effects of both micro- and macrodosing of psychedelics but not move in advance of the data.”
 

Navigating Legality

Recent ballot measures in Oregon and Colorado directed the states to develop regulated and licensed psilocybin-assisted therapy centers for legal “trips.” Oregon’s first center was opened in 2023, and Colorado is now developing its own licensing model.

According to the Oregon Health Authority, the centers are not medical facilities, and prescription or referral from a medical professional is not required.

The Oregon Academy of Family Physicians (OAFP) has yet to release guidance to clinicians on how to talk to their patients about these drugs or potential interest in visiting a licensed therapy center.

However, Betsy Boyd-Flynn, executive director of OAFP, said the organization is working on continuing medical education for what the average family physician needs to know if a patient asks about use.

“We suspect that many of our members have interest and want to learn more,” she said.

Dr. Grinspoon said clinicians should talk with patients about legality during these conversations.

“The big question I get is: ‘I really want to try microdosing, but how do I obtain the mushrooms?’ ” he said. “You can’t really as a physician tell them to do anything illegal. So you tell them to be safe, be careful, and to use their judgment.”

Patients who want to pursue microdosing who do not live in Oregon have two legal and safe options, Dr. Grinspoon said: Enroll in a clinical study or find a facility in a state or country — such as Oregon or Jamaica — that offers microdosing with psilocybin.

Clinicians also should warn their patients that the consequences of obtaining illicit psilocybin could exacerbate the mental health stresses they are seeking to alleviate.

“It’s going to get worse if they get tangled up with law enforcement or take something that’s contaminated and they get real sick,” he said.

Lisa Gillespie contributed reporting to this story. A version of this article appeared on Medscape.com.

Peter Grinspoon, MD, has some advice for clinicians when patients ask questions about microdosing of psychedelics: Keep the lines of communication open — and don’t be judgmental.

“If you’re dismissive or critical or sound like you’re judging them, then the patients just clam up,” said Dr. Grinspoon, a professor of medicine at Harvard Medical School and a primary care physician at Massachusetts General Hospital, both in Boston.

Psychedelic drugs are still illegal in the majority of states despite the growth of public interest in and use of these substances. That growth is evidenced by a flurry of workshops, reports, law enforcement seizures, and pressure by Congressional members for the Food and Drug Administration to approve new psychedelic drugs, just in the past year.

A recent study in JAMA Health Forum showed a nearly 14-fold increase in Google searches — from 7.9 to 105.6 per 10 million nationwide — for the term “microdosing” and related wording, between 2015 and 2023.

Two states — Oregon and Colorado — have decriminalized certain psychedelic drugs and are in various stages of establishing regulations and centers for prospective clients. Almost two dozen localities, like Ann Arbor, Michigan, have decriminalized psychedelic drugs. A handful of states have active legislation to decriminalize use, while others have bills that never made it out of committee.

But no definitive studies have reported that microdosing produces positive mental effects at a higher rate than placebo, according to Dr. Grinspoon. So responding to patient inquiries about microdosing can be complicated, and clinicians must provide counsel on issues of legality and therapeutic appropriateness.

“We’re in this renaissance where everybody is idealizing these medications, as opposed to 20 years ago when we were in the war on drugs and everybody was dismissing them,” Dr. Grinspoon said. “The truth is somewhere in between.”
 

The Science

Microdosing is defined as taking doses of 1/5 to 1/20 of the conventional recreational amount, which might include a dried psilocybin mushroom, lysergic acid diethylamide, or 3,4-methylenedioxymethamphetamine. But even that much may be neither effective nor safe.

Dr. Grinspoon said clinicians should tell patients that psychedelics may cause harm, although the drugs are relatively nontoxic and are not addictive. An illegally obtained psilocybin could cause negative reactions, especially if the drug has been adulterated with other substances and if the actual dose is higher than what was indicated by the seller.

He noted that people have different reactions to psychedelics, just as they have to prescription medications. He cited one example of a woman who microdosed and could not sleep for 2 weeks afterward. Only recently have randomized, double-blinded studies begun on benefits and harms.

Researchers have also begun investigating whether long-term microdosing of psilocybin could lead to valvular heart disease (VHD), said Kevin Yang, MD, a psychiatry resident at the University of California San Diego School of Medicine. A recent review of evidence concluded that microdosing various psychedelics over a period of months can lead to drug-induced VHD.

“It’s extremely important to emphasize with patients that not only do we not know if it works or not, we also don’t really know how safe it is,” Dr. Yang said.

Dr. Yang also said clinicians should consider referring patients to a mental health professional, and especially those that may have expertise in psychedelic therapies.

One of those experts is Rachel Yehuda, PhD, director of the Center for Psychedelic Psychotherapy and Trauma Research at Icahn School of Medicine at Mount Sinai in New York City. She said therapists should be able to assess the patient’s perceived need for microdosing and “invite reflections about why current approaches are falling short.”

“I would also not actively discourage it either but remain curious until both of you have a better understanding of the reasons for seeking this out and potential alternative strategies for obtaining more therapeutic benefits,” she said. “I think it is really important to study the effects of both micro- and macrodosing of psychedelics but not move in advance of the data.”
 

Navigating Legality

Recent ballot measures in Oregon and Colorado directed the states to develop regulated and licensed psilocybin-assisted therapy centers for legal “trips.” Oregon’s first center was opened in 2023, and Colorado is now developing its own licensing model.

According to the Oregon Health Authority, the centers are not medical facilities, and prescription or referral from a medical professional is not required.

The Oregon Academy of Family Physicians (OAFP) has yet to release guidance to clinicians on how to talk to their patients about these drugs or potential interest in visiting a licensed therapy center.

However, Betsy Boyd-Flynn, executive director of OAFP, said the organization is working on continuing medical education for what the average family physician needs to know if a patient asks about use.

“We suspect that many of our members have interest and want to learn more,” she said.

Dr. Grinspoon said clinicians should talk with patients about legality during these conversations.

“The big question I get is: ‘I really want to try microdosing, but how do I obtain the mushrooms?’ ” he said. “You can’t really as a physician tell them to do anything illegal. So you tell them to be safe, be careful, and to use their judgment.”

Patients who want to pursue microdosing who do not live in Oregon have two legal and safe options, Dr. Grinspoon said: Enroll in a clinical study or find a facility in a state or country — such as Oregon or Jamaica — that offers microdosing with psilocybin.

Clinicians also should warn their patients that the consequences of obtaining illicit psilocybin could exacerbate the mental health stresses they are seeking to alleviate.

“It’s going to get worse if they get tangled up with law enforcement or take something that’s contaminated and they get real sick,” he said.

Lisa Gillespie contributed reporting to this story. A version of this article appeared on Medscape.com.

Peter Grinspoon, MD, has some advice for clinicians when patients ask questions about microdosing of psychedelics: Keep the lines of communication open — and don’t be judgmental.

“If you’re dismissive or critical or sound like you’re judging them, then the patients just clam up,” said Dr. Grinspoon, a professor of medicine at Harvard Medical School and a primary care physician at Massachusetts General Hospital, both in Boston.

Psychedelic drugs are still illegal in the majority of states despite the growth of public interest in and use of these substances. That growth is evidenced by a flurry of workshops, reports, law enforcement seizures, and pressure by Congressional members for the Food and Drug Administration to approve new psychedelic drugs, just in the past year.

A recent study in JAMA Health Forum showed a nearly 14-fold increase in Google searches — from 7.9 to 105.6 per 10 million nationwide — for the term “microdosing” and related wording, between 2015 and 2023.

Two states — Oregon and Colorado — have decriminalized certain psychedelic drugs and are in various stages of establishing regulations and centers for prospective clients. Almost two dozen localities, like Ann Arbor, Michigan, have decriminalized psychedelic drugs. A handful of states have active legislation to decriminalize use, while others have bills that never made it out of committee.

But no definitive studies have reported that microdosing produces positive mental effects at a higher rate than placebo, according to Dr. Grinspoon. So responding to patient inquiries about microdosing can be complicated, and clinicians must provide counsel on issues of legality and therapeutic appropriateness.

“We’re in this renaissance where everybody is idealizing these medications, as opposed to 20 years ago when we were in the war on drugs and everybody was dismissing them,” Dr. Grinspoon said. “The truth is somewhere in between.”
 

The Science

Microdosing is defined as taking doses of 1/5 to 1/20 of the conventional recreational amount, which might include a dried psilocybin mushroom, lysergic acid diethylamide, or 3,4-methylenedioxymethamphetamine. But even that much may be neither effective nor safe.

Dr. Grinspoon said clinicians should tell patients that psychedelics may cause harm, although the drugs are relatively nontoxic and are not addictive. An illegally obtained psilocybin could cause negative reactions, especially if the drug has been adulterated with other substances and if the actual dose is higher than what was indicated by the seller.

He noted that people have different reactions to psychedelics, just as they have to prescription medications. He cited one example of a woman who microdosed and could not sleep for 2 weeks afterward. Only recently have randomized, double-blinded studies begun on benefits and harms.

Researchers have also begun investigating whether long-term microdosing of psilocybin could lead to valvular heart disease (VHD), said Kevin Yang, MD, a psychiatry resident at the University of California San Diego School of Medicine. A recent review of evidence concluded that microdosing various psychedelics over a period of months can lead to drug-induced VHD.

“It’s extremely important to emphasize with patients that not only do we not know if it works or not, we also don’t really know how safe it is,” Dr. Yang said.

Dr. Yang also said clinicians should consider referring patients to a mental health professional, and especially those that may have expertise in psychedelic therapies.

One of those experts is Rachel Yehuda, PhD, director of the Center for Psychedelic Psychotherapy and Trauma Research at Icahn School of Medicine at Mount Sinai in New York City. She said therapists should be able to assess the patient’s perceived need for microdosing and “invite reflections about why current approaches are falling short.”

“I would also not actively discourage it either but remain curious until both of you have a better understanding of the reasons for seeking this out and potential alternative strategies for obtaining more therapeutic benefits,” she said. “I think it is really important to study the effects of both micro- and macrodosing of psychedelics but not move in advance of the data.”
 

Navigating Legality

Recent ballot measures in Oregon and Colorado directed the states to develop regulated and licensed psilocybin-assisted therapy centers for legal “trips.” Oregon’s first center was opened in 2023, and Colorado is now developing its own licensing model.

According to the Oregon Health Authority, the centers are not medical facilities, and prescription or referral from a medical professional is not required.

The Oregon Academy of Family Physicians (OAFP) has yet to release guidance to clinicians on how to talk to their patients about these drugs or potential interest in visiting a licensed therapy center.

However, Betsy Boyd-Flynn, executive director of OAFP, said the organization is working on continuing medical education for what the average family physician needs to know if a patient asks about use.

“We suspect that many of our members have interest and want to learn more,” she said.

Dr. Grinspoon said clinicians should talk with patients about legality during these conversations.

“The big question I get is: ‘I really want to try microdosing, but how do I obtain the mushrooms?’ ” he said. “You can’t really as a physician tell them to do anything illegal. So you tell them to be safe, be careful, and to use their judgment.”

Patients who want to pursue microdosing who do not live in Oregon have two legal and safe options, Dr. Grinspoon said: Enroll in a clinical study or find a facility in a state or country — such as Oregon or Jamaica — that offers microdosing with psilocybin.

Clinicians also should warn their patients that the consequences of obtaining illicit psilocybin could exacerbate the mental health stresses they are seeking to alleviate.

“It’s going to get worse if they get tangled up with law enforcement or take something that’s contaminated and they get real sick,” he said.

Lisa Gillespie contributed reporting to this story. A version of this article appeared on Medscape.com.

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

An easy-to-use web-based prognostic tool, MetroPancreas, may help predict the likelihood of futile pancreatectomy in patients with resectable pancreatic ductal adenocarcinoma and improve patient selection for upfront surgery.

METHODOLOGY:

• Immediate resection is associated with a high incidence of postoperative complications and disease recurrence within a year of surgery in patients with pancreatic ductal adenocarcinoma. Predicting which patients likely won’t benefit from upfront pancreatectomy is important.
• To identify preoperative risk factors for futile pancreatectomy, researchers evaluated 1426 patients (median age, 69 years; 53.2% men) with anatomically resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection between January 2010 and December 2021.
• The patients were divided into derivation (n = 885) and validation (n = 541) cohorts.
• The primary outcome was the rate of futile upfront pancreatectomy, defined as death or disease recurrence within 6 months of surgery. Patients were divided into three risk categories — low, intermediate, and high risk — each with escalating likelihoods of futile resection, worse pathological features, and worse outcomes.
• The secondary endpoint was to develop criteria for surgical candidacy, setting a futility likelihood threshold of < 20%. This threshold corresponds to the lower bound of the 95% confidence interval (CI) for postneoadjuvant resection rates (resection rate, 0.90; 95% CI, 0.80-1.01) from recent meta-analyses.

TAKEAWAY:

• The futility rate for pancreatectomy was 18.9% — 19.2% in the development cohort and 18.6% in the validation cohort. Three independent risk factors for futile resection included American Society of Anesthesiologists (ASA) class (95% CI for coefficients, 0.68-0.87), preoperative cancer antigen 19.9 serum levels (95% CI for coefficients, 0.05-0.75), and radiologic tumor size (95% CI for coefficients, 0.28-0.46).
• Using these independent risk factors, the predictive model demonstrated adequate calibration and discrimination in both the derivation and validation cohorts.
• The researchers then identified three risk groups. In the derivation cohort, the rate of futile pancreatectomy was 9.2% in the low-risk group, 18.0% in the intermediate-risk group, and 28.7% in the high-risk group (P < .001 for trend). In the validation cohort, the futility rate was 10.9% in the low-risk group, 20.2% in the intermediate-risk group, and 29.2% in the high-risk group (P < .001 for trend).
• Researchers identified four conditions associated with a futility likelihood below 20%, where larger tumor size is paired with lower cancer antigen 19.9 levels (defined as cancer antigen 19.9–adjusted-to-size). Patients who met these criteria experienced significantly longer disease-free survival (median 18.4 months vs 11.2 months) and overall survival (38.5 months vs 22.1 months).

IN PRACTICE:

“Although the study provides an easy-to-use calculator for clinical decision-making, there are some methodological limitations,” according to the authors of accompanying commentary. These limitations include failing to accurately describe how ASA class, cancer antigen 19.9 level, and tumor size were chosen for the model. “While we do not think the model is yet ready for standard clinical use, it may prove to be a viable tool if tested in future randomized trials comparing the neoadjuvant approach to upfront surgery in resectable pancreatic cancer,” the editorialists added.

SOURCE:

This study, led by Stefano Crippa, MD, PhD, Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and the accompanying commentary were published online in JAMA Surgery.

LIMITATIONS:

In addition to the limitations noted by the editorialists, others include the study’s retrospective design, which could introduce bias. Because preoperative imaging was not revised, the assigned resectability classes could show variability. Institutional differences existed in the selection process for upfront pancreatectomy. The model cannot be applied to cancer antigen 19.9 nonsecretors and was not externally validated.

DISCLOSURES:

The Italian Association for Cancer Research Special Program in Metastatic Disease and Italian Ministry of Health/Italian Foundation for the Research of Pancreatic Diseases supported the study in the form of a grant. Two authors reported receiving personal fees outside the submitted work. No other disclosures were reported.

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

TOPLINE:

An easy-to-use web-based prognostic tool, MetroPancreas, may help predict the likelihood of futile pancreatectomy in patients with resectable pancreatic ductal adenocarcinoma and improve patient selection for upfront surgery.

METHODOLOGY:

• Immediate resection is associated with a high incidence of postoperative complications and disease recurrence within a year of surgery in patients with pancreatic ductal adenocarcinoma. Predicting which patients likely won’t benefit from upfront pancreatectomy is important.
• To identify preoperative risk factors for futile pancreatectomy, researchers evaluated 1426 patients (median age, 69 years; 53.2% men) with anatomically resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection between January 2010 and December 2021.
• The patients were divided into derivation (n = 885) and validation (n = 541) cohorts.
• The primary outcome was the rate of futile upfront pancreatectomy, defined as death or disease recurrence within 6 months of surgery. Patients were divided into three risk categories — low, intermediate, and high risk — each with escalating likelihoods of futile resection, worse pathological features, and worse outcomes.
• The secondary endpoint was to develop criteria for surgical candidacy, setting a futility likelihood threshold of < 20%. This threshold corresponds to the lower bound of the 95% confidence interval (CI) for postneoadjuvant resection rates (resection rate, 0.90; 95% CI, 0.80-1.01) from recent meta-analyses.

TAKEAWAY:

• The futility rate for pancreatectomy was 18.9% — 19.2% in the development cohort and 18.6% in the validation cohort. Three independent risk factors for futile resection included American Society of Anesthesiologists (ASA) class (95% CI for coefficients, 0.68-0.87), preoperative cancer antigen 19.9 serum levels (95% CI for coefficients, 0.05-0.75), and radiologic tumor size (95% CI for coefficients, 0.28-0.46).
• Using these independent risk factors, the predictive model demonstrated adequate calibration and discrimination in both the derivation and validation cohorts.
• The researchers then identified three risk groups. In the derivation cohort, the rate of futile pancreatectomy was 9.2% in the low-risk group, 18.0% in the intermediate-risk group, and 28.7% in the high-risk group (P < .001 for trend). In the validation cohort, the futility rate was 10.9% in the low-risk group, 20.2% in the intermediate-risk group, and 29.2% in the high-risk group (P < .001 for trend).
• Researchers identified four conditions associated with a futility likelihood below 20%, where larger tumor size is paired with lower cancer antigen 19.9 levels (defined as cancer antigen 19.9–adjusted-to-size). Patients who met these criteria experienced significantly longer disease-free survival (median 18.4 months vs 11.2 months) and overall survival (38.5 months vs 22.1 months).

IN PRACTICE:

“Although the study provides an easy-to-use calculator for clinical decision-making, there are some methodological limitations,” according to the authors of accompanying commentary. These limitations include failing to accurately describe how ASA class, cancer antigen 19.9 level, and tumor size were chosen for the model. “While we do not think the model is yet ready for standard clinical use, it may prove to be a viable tool if tested in future randomized trials comparing the neoadjuvant approach to upfront surgery in resectable pancreatic cancer,” the editorialists added.

SOURCE:

This study, led by Stefano Crippa, MD, PhD, Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and the accompanying commentary were published online in JAMA Surgery.

LIMITATIONS:

In addition to the limitations noted by the editorialists, others include the study’s retrospective design, which could introduce bias. Because preoperative imaging was not revised, the assigned resectability classes could show variability. Institutional differences existed in the selection process for upfront pancreatectomy. The model cannot be applied to cancer antigen 19.9 nonsecretors and was not externally validated.

DISCLOSURES:

The Italian Association for Cancer Research Special Program in Metastatic Disease and Italian Ministry of Health/Italian Foundation for the Research of Pancreatic Diseases supported the study in the form of a grant. Two authors reported receiving personal fees outside the submitted work. No other disclosures were reported.

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

TOPLINE:

An easy-to-use web-based prognostic tool, MetroPancreas, may help predict the likelihood of futile pancreatectomy in patients with resectable pancreatic ductal adenocarcinoma and improve patient selection for upfront surgery.

METHODOLOGY:

• Immediate resection is associated with a high incidence of postoperative complications and disease recurrence within a year of surgery in patients with pancreatic ductal adenocarcinoma. Predicting which patients likely won’t benefit from upfront pancreatectomy is important.
• To identify preoperative risk factors for futile pancreatectomy, researchers evaluated 1426 patients (median age, 69 years; 53.2% men) with anatomically resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection between January 2010 and December 2021.
• The patients were divided into derivation (n = 885) and validation (n = 541) cohorts.
• The primary outcome was the rate of futile upfront pancreatectomy, defined as death or disease recurrence within 6 months of surgery. Patients were divided into three risk categories — low, intermediate, and high risk — each with escalating likelihoods of futile resection, worse pathological features, and worse outcomes.
• The secondary endpoint was to develop criteria for surgical candidacy, setting a futility likelihood threshold of < 20%. This threshold corresponds to the lower bound of the 95% confidence interval (CI) for postneoadjuvant resection rates (resection rate, 0.90; 95% CI, 0.80-1.01) from recent meta-analyses.

TAKEAWAY:

• The futility rate for pancreatectomy was 18.9% — 19.2% in the development cohort and 18.6% in the validation cohort. Three independent risk factors for futile resection included American Society of Anesthesiologists (ASA) class (95% CI for coefficients, 0.68-0.87), preoperative cancer antigen 19.9 serum levels (95% CI for coefficients, 0.05-0.75), and radiologic tumor size (95% CI for coefficients, 0.28-0.46).
• Using these independent risk factors, the predictive model demonstrated adequate calibration and discrimination in both the derivation and validation cohorts.
• The researchers then identified three risk groups. In the derivation cohort, the rate of futile pancreatectomy was 9.2% in the low-risk group, 18.0% in the intermediate-risk group, and 28.7% in the high-risk group (P < .001 for trend). In the validation cohort, the futility rate was 10.9% in the low-risk group, 20.2% in the intermediate-risk group, and 29.2% in the high-risk group (P < .001 for trend).
• Researchers identified four conditions associated with a futility likelihood below 20%, where larger tumor size is paired with lower cancer antigen 19.9 levels (defined as cancer antigen 19.9–adjusted-to-size). Patients who met these criteria experienced significantly longer disease-free survival (median 18.4 months vs 11.2 months) and overall survival (38.5 months vs 22.1 months).

IN PRACTICE:

“Although the study provides an easy-to-use calculator for clinical decision-making, there are some methodological limitations,” according to the authors of accompanying commentary. These limitations include failing to accurately describe how ASA class, cancer antigen 19.9 level, and tumor size were chosen for the model. “While we do not think the model is yet ready for standard clinical use, it may prove to be a viable tool if tested in future randomized trials comparing the neoadjuvant approach to upfront surgery in resectable pancreatic cancer,” the editorialists added.

SOURCE:

This study, led by Stefano Crippa, MD, PhD, Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and the accompanying commentary were published online in JAMA Surgery.

LIMITATIONS:

In addition to the limitations noted by the editorialists, others include the study’s retrospective design, which could introduce bias. Because preoperative imaging was not revised, the assigned resectability classes could show variability. Institutional differences existed in the selection process for upfront pancreatectomy. The model cannot be applied to cancer antigen 19.9 nonsecretors and was not externally validated.

DISCLOSURES:

The Italian Association for Cancer Research Special Program in Metastatic Disease and Italian Ministry of Health/Italian Foundation for the Research of Pancreatic Diseases supported the study in the form of a grant. Two authors reported receiving personal fees outside the submitted work. No other disclosures were reported.

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