Article

The Diagnosis: Flagellate Dermatitis

Upon further questioning by dermatology, the patient noted recent ingestion of shiitake mushrooms, which were not a part of his typical diet. Based on the appearance of the rash in the context of ingesting shiitake mushrooms, our patient was diagnosed with flagellate dermatitis. At 6-week followup, the patient’s rash had resolved spontaneously without further intervention.

Flagellate dermatitis usually appears on the torso as linear whiplike streaks.¹ The eruption often is pruritic and may be preceded by severe pruritus. Flagellate dermatitis also is a well-documented complication of bleomycin sulfate therapy with an incidence rate of 8% to 66%.²

Other chemotherapeutic causes include peplomycin, bendamustine, docetaxel, cisplatin, and trastuzumab.³ Flagellate dermatitis also is seen in some patients with dermatomyositis.⁴ A thorough patient history, including medications and dietary habits, is necessary to differentiate flagellate dermatitis from dermatomyositis.

Flagellate dermatitis, also known as shiitake dermatitis, is observed as erythematous flagellate eruptions involving the trunk or extremities that present within 2 hours to 5 days of handling or consuming undercooked or raw shiitake mushrooms (Lentinula edodes),^5,6 as was observed in our patient. Lentinan is the polysaccharide component of the shiitake species and is destabilized by heat.⁶ Ingestion of polysaccharide is associated with dermatitis, particularly in Japan, China, and Korea; however, the consumption of shiitake mushrooms has increased worldwide, and cases increasingly are reported outside of these typical regions. The rash typically resolves spontaneously; therefore, treatment is supportive. However, more severe symptomatic cases may require courses of topical corticosteroids and antihistamines.⁶

In our case, the differential diagnosis consisted of acute urticaria, cutaneous dermatomyositis, dermatographism, and maculopapular cutaneous mastocytosis. Acute urticaria displays well-circumscribed edematous papules or plaques, and individual lesions last less than 24 hours. Cutaneous dermatomyositis includes additional systemic manifestations such as fatigue, malaise, and myalgia, as well as involvement of the gastrointestinal, respiratory, or cardiac organs. Dermatographism is evoked by stroking or rubbing of the skin, which results in asymptomatic lesions that persist for 15 to 30 minutes. Cases of maculopapular cutaneous mastocytosis more often are seen in children, and the histamine release most often causes gastrointestinal tract symptoms such as nausea, vomiting, and diarrhea, as well as flushing, blushing, pruritus, respiratory difficulty, and malaise.

The Diagnosis: Flagellate Dermatitis

Upon further questioning by dermatology, the patient noted recent ingestion of shiitake mushrooms, which were not a part of his typical diet. Based on the appearance of the rash in the context of ingesting shiitake mushrooms, our patient was diagnosed with flagellate dermatitis. At 6-week followup, the patient’s rash had resolved spontaneously without further intervention.

Flagellate dermatitis usually appears on the torso as linear whiplike streaks.¹ The eruption often is pruritic and may be preceded by severe pruritus. Flagellate dermatitis also is a well-documented complication of bleomycin sulfate therapy with an incidence rate of 8% to 66%.²

Other chemotherapeutic causes include peplomycin, bendamustine, docetaxel, cisplatin, and trastuzumab.³ Flagellate dermatitis also is seen in some patients with dermatomyositis.⁴ A thorough patient history, including medications and dietary habits, is necessary to differentiate flagellate dermatitis from dermatomyositis.

Flagellate dermatitis, also known as shiitake dermatitis, is observed as erythematous flagellate eruptions involving the trunk or extremities that present within 2 hours to 5 days of handling or consuming undercooked or raw shiitake mushrooms (Lentinula edodes),^5,6 as was observed in our patient. Lentinan is the polysaccharide component of the shiitake species and is destabilized by heat.⁶ Ingestion of polysaccharide is associated with dermatitis, particularly in Japan, China, and Korea; however, the consumption of shiitake mushrooms has increased worldwide, and cases increasingly are reported outside of these typical regions. The rash typically resolves spontaneously; therefore, treatment is supportive. However, more severe symptomatic cases may require courses of topical corticosteroids and antihistamines.⁶

In our case, the differential diagnosis consisted of acute urticaria, cutaneous dermatomyositis, dermatographism, and maculopapular cutaneous mastocytosis. Acute urticaria displays well-circumscribed edematous papules or plaques, and individual lesions last less than 24 hours. Cutaneous dermatomyositis includes additional systemic manifestations such as fatigue, malaise, and myalgia, as well as involvement of the gastrointestinal, respiratory, or cardiac organs. Dermatographism is evoked by stroking or rubbing of the skin, which results in asymptomatic lesions that persist for 15 to 30 minutes. Cases of maculopapular cutaneous mastocytosis more often are seen in children, and the histamine release most often causes gastrointestinal tract symptoms such as nausea, vomiting, and diarrhea, as well as flushing, blushing, pruritus, respiratory difficulty, and malaise.

The Diagnosis: Flagellate Dermatitis

Upon further questioning by dermatology, the patient noted recent ingestion of shiitake mushrooms, which were not a part of his typical diet. Based on the appearance of the rash in the context of ingesting shiitake mushrooms, our patient was diagnosed with flagellate dermatitis. At 6-week followup, the patient’s rash had resolved spontaneously without further intervention.

Flagellate dermatitis usually appears on the torso as linear whiplike streaks.¹ The eruption often is pruritic and may be preceded by severe pruritus. Flagellate dermatitis also is a well-documented complication of bleomycin sulfate therapy with an incidence rate of 8% to 66%.²

Other chemotherapeutic causes include peplomycin, bendamustine, docetaxel, cisplatin, and trastuzumab.³ Flagellate dermatitis also is seen in some patients with dermatomyositis.⁴ A thorough patient history, including medications and dietary habits, is necessary to differentiate flagellate dermatitis from dermatomyositis.

Flagellate dermatitis, also known as shiitake dermatitis, is observed as erythematous flagellate eruptions involving the trunk or extremities that present within 2 hours to 5 days of handling or consuming undercooked or raw shiitake mushrooms (Lentinula edodes),^5,6 as was observed in our patient. Lentinan is the polysaccharide component of the shiitake species and is destabilized by heat.⁶ Ingestion of polysaccharide is associated with dermatitis, particularly in Japan, China, and Korea; however, the consumption of shiitake mushrooms has increased worldwide, and cases increasingly are reported outside of these typical regions. The rash typically resolves spontaneously; therefore, treatment is supportive. However, more severe symptomatic cases may require courses of topical corticosteroids and antihistamines.⁶

In our case, the differential diagnosis consisted of acute urticaria, cutaneous dermatomyositis, dermatographism, and maculopapular cutaneous mastocytosis. Acute urticaria displays well-circumscribed edematous papules or plaques, and individual lesions last less than 24 hours. Cutaneous dermatomyositis includes additional systemic manifestations such as fatigue, malaise, and myalgia, as well as involvement of the gastrointestinal, respiratory, or cardiac organs. Dermatographism is evoked by stroking or rubbing of the skin, which results in asymptomatic lesions that persist for 15 to 30 minutes. Cases of maculopapular cutaneous mastocytosis more often are seen in children, and the histamine release most often causes gastrointestinal tract symptoms such as nausea, vomiting, and diarrhea, as well as flushing, blushing, pruritus, respiratory difficulty, and malaise.

The patient was having a flare of pemphigus vulgaris (PV), a rare and sometimes life-threatening acquired autoimmune blistering disease that affects the skin and/or mucosa. Ashkenazi Jewish patients and patients from Mediterranean and Middle Eastern countries are more likely to be affected.

In PV, acquired autoantibodies target the desmosomes that connect epithelial cells together, weakening the intercellular adhesion. It can affect skin, mucosa, or both. Patients present with fragile bullae or ulcers. The connections between the cells are often so damaged that rubbing on the skin creates a new blister called “Nikolsky sign.” In the mouth, bullae erode rapidly. Look for disease affecting the ocular conjunctiva or sclera, as well. PV can also occasionally affect the nasopharynx and esophagus, usually manifesting as hemoptysis, dysphagia, and nosebleeds with ulcer seen on endoscopy or otolaryngoscopy.

Although PV is often severe (and can warrant hospitalization when significant body surface area is involved), some patients may have few active lesions and can be managed safely as outpatients.

The diagnosis requires 2 biopsies and serum for indirect immunofluorescence. One biopsy (either by punch or shave to the upper dermis) is taken from the edge of a bulla or ulcer. Another biopsy (by punch or shave) is taken from nearby normal-looking skin or mucosa for testing the direct immunofluorescence pattern. In the mucosa, a punch biopsy may be left open or closed with absorbable sutures. A serum sample is taken for indirect immunofluorescence to differentiate pemphigus vulgaris from other forms of pemphigus.¹

PV is treated by suppressing the immune system. Focal disease may be treated with super-potent topical steroids, including clobetasol 0.05% ointment. Even in the mouth, topical clobetasol 0.05% may be used off-label twice daily until control is achieved. When topical treatment is used in the mouth, advise patients to apply the clobetasol ointment to a piece of gauze and place the gauze (ointment side down) over affected areas for 20 to 30 minutes twice daily.

Patients with widespread or severe disease should be hospitalized. In severe cases, supportive wound care is provided, and treatment is aimed at immunosuppression. Systemic options include high-dose prednisone 0.5 to 1 mg/kg daily until clear, a steroid-sparing immunosuppressant such as mycophenolate mofetil up to 1000 mg bid, or rituximab in 1 of several regimens.

Three years prior to this patient’s visit, she had been successfully treated for PV with a course of rituximab. To treat the current flare, she was started on prednisone 60 mg/d. In addition, the plan was for her to complete 2 infusions of 1000 mg rituximab 2 weeks apart.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, Maine.

The patient was having a flare of pemphigus vulgaris (PV), a rare and sometimes life-threatening acquired autoimmune blistering disease that affects the skin and/or mucosa. Ashkenazi Jewish patients and patients from Mediterranean and Middle Eastern countries are more likely to be affected.

In PV, acquired autoantibodies target the desmosomes that connect epithelial cells together, weakening the intercellular adhesion. It can affect skin, mucosa, or both. Patients present with fragile bullae or ulcers. The connections between the cells are often so damaged that rubbing on the skin creates a new blister called “Nikolsky sign.” In the mouth, bullae erode rapidly. Look for disease affecting the ocular conjunctiva or sclera, as well. PV can also occasionally affect the nasopharynx and esophagus, usually manifesting as hemoptysis, dysphagia, and nosebleeds with ulcer seen on endoscopy or otolaryngoscopy.

Although PV is often severe (and can warrant hospitalization when significant body surface area is involved), some patients may have few active lesions and can be managed safely as outpatients.

The diagnosis requires 2 biopsies and serum for indirect immunofluorescence. One biopsy (either by punch or shave to the upper dermis) is taken from the edge of a bulla or ulcer. Another biopsy (by punch or shave) is taken from nearby normal-looking skin or mucosa for testing the direct immunofluorescence pattern. In the mucosa, a punch biopsy may be left open or closed with absorbable sutures. A serum sample is taken for indirect immunofluorescence to differentiate pemphigus vulgaris from other forms of pemphigus.¹

PV is treated by suppressing the immune system. Focal disease may be treated with super-potent topical steroids, including clobetasol 0.05% ointment. Even in the mouth, topical clobetasol 0.05% may be used off-label twice daily until control is achieved. When topical treatment is used in the mouth, advise patients to apply the clobetasol ointment to a piece of gauze and place the gauze (ointment side down) over affected areas for 20 to 30 minutes twice daily.

Patients with widespread or severe disease should be hospitalized. In severe cases, supportive wound care is provided, and treatment is aimed at immunosuppression. Systemic options include high-dose prednisone 0.5 to 1 mg/kg daily until clear, a steroid-sparing immunosuppressant such as mycophenolate mofetil up to 1000 mg bid, or rituximab in 1 of several regimens.

Three years prior to this patient’s visit, she had been successfully treated for PV with a course of rituximab. To treat the current flare, she was started on prednisone 60 mg/d. In addition, the plan was for her to complete 2 infusions of 1000 mg rituximab 2 weeks apart.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, Maine.

The patient was having a flare of pemphigus vulgaris (PV), a rare and sometimes life-threatening acquired autoimmune blistering disease that affects the skin and/or mucosa. Ashkenazi Jewish patients and patients from Mediterranean and Middle Eastern countries are more likely to be affected.

In PV, acquired autoantibodies target the desmosomes that connect epithelial cells together, weakening the intercellular adhesion. It can affect skin, mucosa, or both. Patients present with fragile bullae or ulcers. The connections between the cells are often so damaged that rubbing on the skin creates a new blister called “Nikolsky sign.” In the mouth, bullae erode rapidly. Look for disease affecting the ocular conjunctiva or sclera, as well. PV can also occasionally affect the nasopharynx and esophagus, usually manifesting as hemoptysis, dysphagia, and nosebleeds with ulcer seen on endoscopy or otolaryngoscopy.

Although PV is often severe (and can warrant hospitalization when significant body surface area is involved), some patients may have few active lesions and can be managed safely as outpatients.

The diagnosis requires 2 biopsies and serum for indirect immunofluorescence. One biopsy (either by punch or shave to the upper dermis) is taken from the edge of a bulla or ulcer. Another biopsy (by punch or shave) is taken from nearby normal-looking skin or mucosa for testing the direct immunofluorescence pattern. In the mucosa, a punch biopsy may be left open or closed with absorbable sutures. A serum sample is taken for indirect immunofluorescence to differentiate pemphigus vulgaris from other forms of pemphigus.¹

PV is treated by suppressing the immune system. Focal disease may be treated with super-potent topical steroids, including clobetasol 0.05% ointment. Even in the mouth, topical clobetasol 0.05% may be used off-label twice daily until control is achieved. When topical treatment is used in the mouth, advise patients to apply the clobetasol ointment to a piece of gauze and place the gauze (ointment side down) over affected areas for 20 to 30 minutes twice daily.

Patients with widespread or severe disease should be hospitalized. In severe cases, supportive wound care is provided, and treatment is aimed at immunosuppression. Systemic options include high-dose prednisone 0.5 to 1 mg/kg daily until clear, a steroid-sparing immunosuppressant such as mycophenolate mofetil up to 1000 mg bid, or rituximab in 1 of several regimens.

Three years prior to this patient’s visit, she had been successfully treated for PV with a course of rituximab. To treat the current flare, she was started on prednisone 60 mg/d. In addition, the plan was for her to complete 2 infusions of 1000 mg rituximab 2 weeks apart.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, Maine.

Although the usual age at onset of PsA is in the fourth or fifth decade of life, children may develop juvenile-onset PsA (JPsA). Less attention has been paid to this form of juvenile idiopathic arthritis (JIA), and the impact of JPsA vis-à-vis other forms of JIA is not well known. In addition, only about half of the patients with JPsA have cutaneous psoriasis. The impact of psoriasis on children with JPsA is not known. In order to evaluate differences in disease outcomes in patients with JPsA, Low and colleagues evaluated 1653 children and young people with JIA who were recruited to the Childhood Arthritis Prospective Study, of whom 111 had JPsA at diagnosis. They demonstrated that there were no significant differences in patient-reported outcomes between children with JPsA and other JIA categories. However, children with JPsA and psoriasis at JPsA diagnosis had more depressive symptoms compared with those without psoriasis. Moreover, children with JPsA vs other JIA categories had 2.35 times higher odds of having persistently poor well-being scores despite improvements in joint counts and physician global scores. Thus, children with JPsA have poorer well-being scores and a higher prevalence of depression, which requires multidisciplinary care.

Apart from immunomodulatory therapies, weight loss leads to improvement in disease activity in patients with obesity and PsA. However, the mechanisms by which weight loss improves PsA is currently not known, but is likely to be due to changes in adipokines and inflammation-related cytokines. In a recent study¹that included patients with PsA and obesity, it was demonstrated that weight loss through a Very Low Energy Diet (VLED) resulted in significant improvements in PsA disease activity. Landgren and colleagues now aimed to determine the effects of VLED on cytokines and adipokines. They obtained blood samples from patients with PsA and obesity (n = 41) and matched control individuals without rheumatic disease or psoriasis (n = 39) who were on VLED. At month 6, along with significant weight loss, serum levels of interleukin-23 and leptin decreased significantly, while those of total adiponectin and high-molecular-weight adiponectin increased significantly in patients with PsA and control individuals. The change in body mass index correlated positively with a reduction in serum interleukin-23 (r_S = 0.671, P < .001) and improvement in PsA disease activity (P = .003). This study highlights the anti-inflammatory effect of weight loss in patients with PsA. Weight loss can complement immunomodulatory therapy in PsA patients with obesity.

Additional Reference

1. Klingberg E, Bilberg A, Björkman S, et al. Weight loss improves disease activity in patients with psoriatic arthritis and obesity: an interventional study. Arthritis Res Ther. 2019;21:17. doi: 10.1186/s13075-019-1810-5

Although the usual age at onset of PsA is in the fourth or fifth decade of life, children may develop juvenile-onset PsA (JPsA). Less attention has been paid to this form of juvenile idiopathic arthritis (JIA), and the impact of JPsA vis-à-vis other forms of JIA is not well known. In addition, only about half of the patients with JPsA have cutaneous psoriasis. The impact of psoriasis on children with JPsA is not known. In order to evaluate differences in disease outcomes in patients with JPsA, Low and colleagues evaluated 1653 children and young people with JIA who were recruited to the Childhood Arthritis Prospective Study, of whom 111 had JPsA at diagnosis. They demonstrated that there were no significant differences in patient-reported outcomes between children with JPsA and other JIA categories. However, children with JPsA and psoriasis at JPsA diagnosis had more depressive symptoms compared with those without psoriasis. Moreover, children with JPsA vs other JIA categories had 2.35 times higher odds of having persistently poor well-being scores despite improvements in joint counts and physician global scores. Thus, children with JPsA have poorer well-being scores and a higher prevalence of depression, which requires multidisciplinary care.

Apart from immunomodulatory therapies, weight loss leads to improvement in disease activity in patients with obesity and PsA. However, the mechanisms by which weight loss improves PsA is currently not known, but is likely to be due to changes in adipokines and inflammation-related cytokines. In a recent study¹that included patients with PsA and obesity, it was demonstrated that weight loss through a Very Low Energy Diet (VLED) resulted in significant improvements in PsA disease activity. Landgren and colleagues now aimed to determine the effects of VLED on cytokines and adipokines. They obtained blood samples from patients with PsA and obesity (n = 41) and matched control individuals without rheumatic disease or psoriasis (n = 39) who were on VLED. At month 6, along with significant weight loss, serum levels of interleukin-23 and leptin decreased significantly, while those of total adiponectin and high-molecular-weight adiponectin increased significantly in patients with PsA and control individuals. The change in body mass index correlated positively with a reduction in serum interleukin-23 (r_S = 0.671, P < .001) and improvement in PsA disease activity (P = .003). This study highlights the anti-inflammatory effect of weight loss in patients with PsA. Weight loss can complement immunomodulatory therapy in PsA patients with obesity.

Additional Reference

1. Klingberg E, Bilberg A, Björkman S, et al. Weight loss improves disease activity in patients with psoriatic arthritis and obesity: an interventional study. Arthritis Res Ther. 2019;21:17. doi: 10.1186/s13075-019-1810-5

Although the usual age at onset of PsA is in the fourth or fifth decade of life, children may develop juvenile-onset PsA (JPsA). Less attention has been paid to this form of juvenile idiopathic arthritis (JIA), and the impact of JPsA vis-à-vis other forms of JIA is not well known. In addition, only about half of the patients with JPsA have cutaneous psoriasis. The impact of psoriasis on children with JPsA is not known. In order to evaluate differences in disease outcomes in patients with JPsA, Low and colleagues evaluated 1653 children and young people with JIA who were recruited to the Childhood Arthritis Prospective Study, of whom 111 had JPsA at diagnosis. They demonstrated that there were no significant differences in patient-reported outcomes between children with JPsA and other JIA categories. However, children with JPsA and psoriasis at JPsA diagnosis had more depressive symptoms compared with those without psoriasis. Moreover, children with JPsA vs other JIA categories had 2.35 times higher odds of having persistently poor well-being scores despite improvements in joint counts and physician global scores. Thus, children with JPsA have poorer well-being scores and a higher prevalence of depression, which requires multidisciplinary care.

Apart from immunomodulatory therapies, weight loss leads to improvement in disease activity in patients with obesity and PsA. However, the mechanisms by which weight loss improves PsA is currently not known, but is likely to be due to changes in adipokines and inflammation-related cytokines. In a recent study¹that included patients with PsA and obesity, it was demonstrated that weight loss through a Very Low Energy Diet (VLED) resulted in significant improvements in PsA disease activity. Landgren and colleagues now aimed to determine the effects of VLED on cytokines and adipokines. They obtained blood samples from patients with PsA and obesity (n = 41) and matched control individuals without rheumatic disease or psoriasis (n = 39) who were on VLED. At month 6, along with significant weight loss, serum levels of interleukin-23 and leptin decreased significantly, while those of total adiponectin and high-molecular-weight adiponectin increased significantly in patients with PsA and control individuals. The change in body mass index correlated positively with a reduction in serum interleukin-23 (r_S = 0.671, P < .001) and improvement in PsA disease activity (P = .003). This study highlights the anti-inflammatory effect of weight loss in patients with PsA. Weight loss can complement immunomodulatory therapy in PsA patients with obesity.

Additional Reference

1. Klingberg E, Bilberg A, Björkman S, et al. Weight loss improves disease activity in patients with psoriatic arthritis and obesity: an interventional study. Arthritis Res Ther. 2019;21:17. doi: 10.1186/s13075-019-1810-5

Diffuse large B-cell lymphoma (DLBCL) is the most diagnosed non-Hodgkin lymphoma (NHL), accounting for up to one-third of cases. For many decades, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment approach for eligible patients in the first-line setting, resulting in long-term remissions in about two-thirds of patients. However, as our understanding of the biologic heterogeneity of this disease has advanced with the ability to perform more sophisticated molecular testing at diagnosis, researchers have been able to identify high-risk patient subtypes with suboptimal outcomes. While survival outcomes among low-risk patient subgroups are favorable with first-line immunochemotherapy, the majority of high-risk patients will experience relapse and often succumb to their disease. 

Given the poor outcomes among patients with relapsed or refractory (R/R) DLBCL, there has been a massive research effort over the last decade to improve survival in this setting. Many experts agree that the approval of chimeric antigen receptor (CAR) T-cell therapy was the first major victory in this uphill battle. First approved in October of 2017, axicabtagene ciloleucel was the first of the 3 currently available commercial CAR T-cell therapy constructs to be approved in the third-line setting for DLBCL. Compared to historical controls, CAR T-cell therapy is associated with significant improvement in patient survival with complete response (CR) rates of 40%-50% compared to <20% with standard salvage immunochemotherapy. 

Following approval in the third-line setting, these agents were quickly expedited to second-line therapy with pivotal trials demonstrating superiority with CAR T-cell therapy in the second line compared to salvage immunochemotherapy followed by autologous stem cell transplant. In 2022 the ZUMA-7 study reported a 24-month event-free survival (EFS) of 41% with axicabtagene ciloleucel compared to 16% with standard of care, and the TRANSFORM study documented a median EFS not yet reached with lisocabtagene ciloleucel compared to 2.3 months with standard of care. Despite these drastic improvements in patient outcomes, more than half of patients will still fail CAR T-cell therapy and require further systemic therapy. 

Thankfully, this year has seen even more advancement in the treatment landscape of R/R DLBCL with two new commercially approved agents in yet another novel therapeutic category: bispecific antibodies. The following is a description of the newest data leading to the latest approvals by the US Food and Drug Administration.

Bispecific antibodies (BsAbs) are an off-the-shelf product that activate endogenous immune cells by cotargeting both tumor antigens as well as host T cells or natural killer cells. Several different experimental agents with varying constructs are under active observation in a wide variety of both hematologic and solid malignancies. Specifically within the realm of B-cell NHL, however, this class of agents is extremely promising and possibly represents the next significant milestone in the treatment of lymphoma. 

The toxicity profile of these agents has been reliably predictable in most early phase clinical studies and is related predominantly to T-cell overactivation. The most commonly reported adverse events consist of cytokine release syndrome (CRS) as well as neutropenia, anemia, and hypophosphatemia. While neurologic toxicity has been reported, the incidence is low, and the mechanism is thought to be different than that reported with CAR T-cell therapy given that BsAbs are not likely to cross the blood–brain barrier. 

Epcoritamab is a subcutaneously administered bispecific antibody that targets CD3 and CD20 in a 1:1 ratio and activates T cells to destroy CD20-expressing malignant cells. The recent EPCORE NHL-1 clinical trial investigated epcoritamab monotherapy in R/R mature B-cell lymphomas. This agent is administered with a step-up dosing strategy seen consistently across the BsAb drug class. Patients receive a first priming dose of 0.16 mg on cycle 1 day 1, followed by an intermediate dose of 0.8 mg on cycle 1 day 8, followed by the first full dose of 48 mg on cycle 1 day 15. Subsequent doses are administered once weekly for cycles 1-3 followed by every 2 weeks for cycles 4-9, and every 4 weeks starting with cycle 10.

The study enrolled 157 patients globally with median age of 64 and 3 median prior lines of antilymphoma therapy. Nearly 40% of patients had received at least 4 prior lines of therapy, and 83% of patients were refractory to last systemic therapy. Thirty-nine percent of patients had received prior CAR T-cell therapy; 75% of these patients developed progressive disease within 6 months of CAR T-cell therapy.

Among patients treated in the study, the results were as follows:

• CR rate 39% with an overall response rate (ORR) of 63%

• Duration of response 12 months; duration of objective response not reached in patients with CR

• Duration of CR 12 months

• Median PFS 4.4 months; median OS not reached

• Time to CR of 2.7 months

Toxicity profile was notable for the following:

• Any grade CRS in 50%, grade ≥3 in 2.5%

  • Most CRS occurs with first full dose on cycle 1 day 15 with median time to onset of 20 hours and median time to resolution of 48 hours

• Any grade neutropenia in 22%, grade ≥3 in 15%, febrile neutropenia in 2.5%

• Any grade anemia in 18%, grade ≥3 in 10%

• Injection site reaction, any grade, in 20%

• Any grade neurotoxicity in 6%, grade ≥3 in 1 patient (0.6%)

Epcoritamab was granted accelerated approval on May 19, 2023, for use in patients with R/R DLBCL who have received at least 2 prior lines of systemic therapy.

Glofitamab is the more recently approved BsAb for DLBCL. This agent is distinguished by its 2:1 binding configuration that confers bivalency for the CD20 binding site. Glofitamab is delivered intravenously and requires pretreatment with obinutuzumab 1000 mg 7 days before the first dose. With a similar step-up dosing strategy, patients receive a priming dose of 2.5mg on cycle 1 day 8, an intermediate dose of 10mg on cycle 1 day 15, and a first full dose of 30mg on cycle 2 day 1. Subsequent treatments are administered every 21 days for up to 12 cycles. 

The open-label phase 1-2 clinical trial of glofitamab monotherapy enrolled 155 patients with a median age of 66 and 3 median prior lines of therapy. Thirty-three percent of patients had received prior CAR T-cell therapy, and 86% were refractory to last line of therapy with 30% refractory to CAR T-cell therapy. 

Results were as follows:

• CR rate of 39%, ORR 52%

• Median duration of CR not reached, median duration of objective response 18.4 months

• Median PFS 4.9 months, median OS not reached

Toxicity profile demonstrated the following:

• Any grade CRS 66%, grade ≥ 2 in 18%

  • Median time to onset 13.5 hours from cycle 1 day 8, median duration 30.5 hours

• Any grade neutropenia in 38%, grade ≥ 3 in 27%

• Grade ≥ 2 neurologic event in 15%

Glofitamab received accelerated approval from the FDA on June 15, 2023, with an identical indication to epcoritamab. 

The introduction of BsAbs in DLBCL has highlighted some important issues. Will BsAbs supplant CAR T-cell therapy in DLBCL? Experts can be found on both sides of this debate. BsAbs circumvent the logistics surrounding the production of CAR T-cell therapy products and can, for the large part, be administered in the outpatient setting. However, CAR T-cell therapy has significantly longer follow-up times, which speaks to the curative potential of these agents even in the third-line setting. BsAbs, some may argue, seem to carry a more favorable toxicity profile with the CRS mitigation strategies. However, we still have much to learn about the downstream side effects with prolonged T-cell activation and the potential for T-cell exhaustion.

Finally, with the continued development of new agents in this arena, the art of sequencing therapies will become ever more important. What is the efficacy of CAR T-cell therapy after BsAb exposure? Can BsAbs be used as bridging therapy to a curative option with CAR T-cell therapy? With longer-term follow-up in several years, will we see late relapses after CR with BsAbs? Ongoing clinical trials investigating combination strategies and CAR T-cell therapy consolidation with BsAbs will hopefully eventually clarify some of these questions.

Diffuse large B-cell lymphoma (DLBCL) is the most diagnosed non-Hodgkin lymphoma (NHL), accounting for up to one-third of cases. For many decades, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment approach for eligible patients in the first-line setting, resulting in long-term remissions in about two-thirds of patients. However, as our understanding of the biologic heterogeneity of this disease has advanced with the ability to perform more sophisticated molecular testing at diagnosis, researchers have been able to identify high-risk patient subtypes with suboptimal outcomes. While survival outcomes among low-risk patient subgroups are favorable with first-line immunochemotherapy, the majority of high-risk patients will experience relapse and often succumb to their disease. 

Given the poor outcomes among patients with relapsed or refractory (R/R) DLBCL, there has been a massive research effort over the last decade to improve survival in this setting. Many experts agree that the approval of chimeric antigen receptor (CAR) T-cell therapy was the first major victory in this uphill battle. First approved in October of 2017, axicabtagene ciloleucel was the first of the 3 currently available commercial CAR T-cell therapy constructs to be approved in the third-line setting for DLBCL. Compared to historical controls, CAR T-cell therapy is associated with significant improvement in patient survival with complete response (CR) rates of 40%-50% compared to <20% with standard salvage immunochemotherapy. 

Following approval in the third-line setting, these agents were quickly expedited to second-line therapy with pivotal trials demonstrating superiority with CAR T-cell therapy in the second line compared to salvage immunochemotherapy followed by autologous stem cell transplant. In 2022 the ZUMA-7 study reported a 24-month event-free survival (EFS) of 41% with axicabtagene ciloleucel compared to 16% with standard of care, and the TRANSFORM study documented a median EFS not yet reached with lisocabtagene ciloleucel compared to 2.3 months with standard of care. Despite these drastic improvements in patient outcomes, more than half of patients will still fail CAR T-cell therapy and require further systemic therapy. 

Thankfully, this year has seen even more advancement in the treatment landscape of R/R DLBCL with two new commercially approved agents in yet another novel therapeutic category: bispecific antibodies. The following is a description of the newest data leading to the latest approvals by the US Food and Drug Administration.

Bispecific antibodies (BsAbs) are an off-the-shelf product that activate endogenous immune cells by cotargeting both tumor antigens as well as host T cells or natural killer cells. Several different experimental agents with varying constructs are under active observation in a wide variety of both hematologic and solid malignancies. Specifically within the realm of B-cell NHL, however, this class of agents is extremely promising and possibly represents the next significant milestone in the treatment of lymphoma. 

The toxicity profile of these agents has been reliably predictable in most early phase clinical studies and is related predominantly to T-cell overactivation. The most commonly reported adverse events consist of cytokine release syndrome (CRS) as well as neutropenia, anemia, and hypophosphatemia. While neurologic toxicity has been reported, the incidence is low, and the mechanism is thought to be different than that reported with CAR T-cell therapy given that BsAbs are not likely to cross the blood–brain barrier. 

Epcoritamab is a subcutaneously administered bispecific antibody that targets CD3 and CD20 in a 1:1 ratio and activates T cells to destroy CD20-expressing malignant cells. The recent EPCORE NHL-1 clinical trial investigated epcoritamab monotherapy in R/R mature B-cell lymphomas. This agent is administered with a step-up dosing strategy seen consistently across the BsAb drug class. Patients receive a first priming dose of 0.16 mg on cycle 1 day 1, followed by an intermediate dose of 0.8 mg on cycle 1 day 8, followed by the first full dose of 48 mg on cycle 1 day 15. Subsequent doses are administered once weekly for cycles 1-3 followed by every 2 weeks for cycles 4-9, and every 4 weeks starting with cycle 10.

The study enrolled 157 patients globally with median age of 64 and 3 median prior lines of antilymphoma therapy. Nearly 40% of patients had received at least 4 prior lines of therapy, and 83% of patients were refractory to last systemic therapy. Thirty-nine percent of patients had received prior CAR T-cell therapy; 75% of these patients developed progressive disease within 6 months of CAR T-cell therapy.

Among patients treated in the study, the results were as follows:

• CR rate 39% with an overall response rate (ORR) of 63%

• Duration of response 12 months; duration of objective response not reached in patients with CR

• Duration of CR 12 months

• Median PFS 4.4 months; median OS not reached

• Time to CR of 2.7 months

Toxicity profile was notable for the following:

• Any grade CRS in 50%, grade ≥3 in 2.5%

  • Most CRS occurs with first full dose on cycle 1 day 15 with median time to onset of 20 hours and median time to resolution of 48 hours

• Any grade neutropenia in 22%, grade ≥3 in 15%, febrile neutropenia in 2.5%

• Any grade anemia in 18%, grade ≥3 in 10%

• Injection site reaction, any grade, in 20%

• Any grade neurotoxicity in 6%, grade ≥3 in 1 patient (0.6%)

Epcoritamab was granted accelerated approval on May 19, 2023, for use in patients with R/R DLBCL who have received at least 2 prior lines of systemic therapy.

Glofitamab is the more recently approved BsAb for DLBCL. This agent is distinguished by its 2:1 binding configuration that confers bivalency for the CD20 binding site. Glofitamab is delivered intravenously and requires pretreatment with obinutuzumab 1000 mg 7 days before the first dose. With a similar step-up dosing strategy, patients receive a priming dose of 2.5mg on cycle 1 day 8, an intermediate dose of 10mg on cycle 1 day 15, and a first full dose of 30mg on cycle 2 day 1. Subsequent treatments are administered every 21 days for up to 12 cycles. 

The open-label phase 1-2 clinical trial of glofitamab monotherapy enrolled 155 patients with a median age of 66 and 3 median prior lines of therapy. Thirty-three percent of patients had received prior CAR T-cell therapy, and 86% were refractory to last line of therapy with 30% refractory to CAR T-cell therapy. 

Results were as follows:

• CR rate of 39%, ORR 52%

• Median duration of CR not reached, median duration of objective response 18.4 months

• Median PFS 4.9 months, median OS not reached

Toxicity profile demonstrated the following:

• Any grade CRS 66%, grade ≥ 2 in 18%

  • Median time to onset 13.5 hours from cycle 1 day 8, median duration 30.5 hours

• Any grade neutropenia in 38%, grade ≥ 3 in 27%

• Grade ≥ 2 neurologic event in 15%

Glofitamab received accelerated approval from the FDA on June 15, 2023, with an identical indication to epcoritamab. 

The introduction of BsAbs in DLBCL has highlighted some important issues. Will BsAbs supplant CAR T-cell therapy in DLBCL? Experts can be found on both sides of this debate. BsAbs circumvent the logistics surrounding the production of CAR T-cell therapy products and can, for the large part, be administered in the outpatient setting. However, CAR T-cell therapy has significantly longer follow-up times, which speaks to the curative potential of these agents even in the third-line setting. BsAbs, some may argue, seem to carry a more favorable toxicity profile with the CRS mitigation strategies. However, we still have much to learn about the downstream side effects with prolonged T-cell activation and the potential for T-cell exhaustion.

Finally, with the continued development of new agents in this arena, the art of sequencing therapies will become ever more important. What is the efficacy of CAR T-cell therapy after BsAb exposure? Can BsAbs be used as bridging therapy to a curative option with CAR T-cell therapy? With longer-term follow-up in several years, will we see late relapses after CR with BsAbs? Ongoing clinical trials investigating combination strategies and CAR T-cell therapy consolidation with BsAbs will hopefully eventually clarify some of these questions.

Diffuse large B-cell lymphoma (DLBCL) is the most diagnosed non-Hodgkin lymphoma (NHL), accounting for up to one-third of cases. For many decades, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment approach for eligible patients in the first-line setting, resulting in long-term remissions in about two-thirds of patients. However, as our understanding of the biologic heterogeneity of this disease has advanced with the ability to perform more sophisticated molecular testing at diagnosis, researchers have been able to identify high-risk patient subtypes with suboptimal outcomes. While survival outcomes among low-risk patient subgroups are favorable with first-line immunochemotherapy, the majority of high-risk patients will experience relapse and often succumb to their disease. 

Given the poor outcomes among patients with relapsed or refractory (R/R) DLBCL, there has been a massive research effort over the last decade to improve survival in this setting. Many experts agree that the approval of chimeric antigen receptor (CAR) T-cell therapy was the first major victory in this uphill battle. First approved in October of 2017, axicabtagene ciloleucel was the first of the 3 currently available commercial CAR T-cell therapy constructs to be approved in the third-line setting for DLBCL. Compared to historical controls, CAR T-cell therapy is associated with significant improvement in patient survival with complete response (CR) rates of 40%-50% compared to <20% with standard salvage immunochemotherapy. 

Following approval in the third-line setting, these agents were quickly expedited to second-line therapy with pivotal trials demonstrating superiority with CAR T-cell therapy in the second line compared to salvage immunochemotherapy followed by autologous stem cell transplant. In 2022 the ZUMA-7 study reported a 24-month event-free survival (EFS) of 41% with axicabtagene ciloleucel compared to 16% with standard of care, and the TRANSFORM study documented a median EFS not yet reached with lisocabtagene ciloleucel compared to 2.3 months with standard of care. Despite these drastic improvements in patient outcomes, more than half of patients will still fail CAR T-cell therapy and require further systemic therapy. 

Thankfully, this year has seen even more advancement in the treatment landscape of R/R DLBCL with two new commercially approved agents in yet another novel therapeutic category: bispecific antibodies. The following is a description of the newest data leading to the latest approvals by the US Food and Drug Administration.

Bispecific antibodies (BsAbs) are an off-the-shelf product that activate endogenous immune cells by cotargeting both tumor antigens as well as host T cells or natural killer cells. Several different experimental agents with varying constructs are under active observation in a wide variety of both hematologic and solid malignancies. Specifically within the realm of B-cell NHL, however, this class of agents is extremely promising and possibly represents the next significant milestone in the treatment of lymphoma. 

The toxicity profile of these agents has been reliably predictable in most early phase clinical studies and is related predominantly to T-cell overactivation. The most commonly reported adverse events consist of cytokine release syndrome (CRS) as well as neutropenia, anemia, and hypophosphatemia. While neurologic toxicity has been reported, the incidence is low, and the mechanism is thought to be different than that reported with CAR T-cell therapy given that BsAbs are not likely to cross the blood–brain barrier. 

Epcoritamab is a subcutaneously administered bispecific antibody that targets CD3 and CD20 in a 1:1 ratio and activates T cells to destroy CD20-expressing malignant cells. The recent EPCORE NHL-1 clinical trial investigated epcoritamab monotherapy in R/R mature B-cell lymphomas. This agent is administered with a step-up dosing strategy seen consistently across the BsAb drug class. Patients receive a first priming dose of 0.16 mg on cycle 1 day 1, followed by an intermediate dose of 0.8 mg on cycle 1 day 8, followed by the first full dose of 48 mg on cycle 1 day 15. Subsequent doses are administered once weekly for cycles 1-3 followed by every 2 weeks for cycles 4-9, and every 4 weeks starting with cycle 10.

The study enrolled 157 patients globally with median age of 64 and 3 median prior lines of antilymphoma therapy. Nearly 40% of patients had received at least 4 prior lines of therapy, and 83% of patients were refractory to last systemic therapy. Thirty-nine percent of patients had received prior CAR T-cell therapy; 75% of these patients developed progressive disease within 6 months of CAR T-cell therapy.

Among patients treated in the study, the results were as follows:

• CR rate 39% with an overall response rate (ORR) of 63%

• Duration of response 12 months; duration of objective response not reached in patients with CR

• Duration of CR 12 months

• Median PFS 4.4 months; median OS not reached

• Time to CR of 2.7 months

Toxicity profile was notable for the following:

• Any grade CRS in 50%, grade ≥3 in 2.5%

  • Most CRS occurs with first full dose on cycle 1 day 15 with median time to onset of 20 hours and median time to resolution of 48 hours

• Any grade neutropenia in 22%, grade ≥3 in 15%, febrile neutropenia in 2.5%

• Any grade anemia in 18%, grade ≥3 in 10%

• Injection site reaction, any grade, in 20%

• Any grade neurotoxicity in 6%, grade ≥3 in 1 patient (0.6%)

Epcoritamab was granted accelerated approval on May 19, 2023, for use in patients with R/R DLBCL who have received at least 2 prior lines of systemic therapy.

Glofitamab is the more recently approved BsAb for DLBCL. This agent is distinguished by its 2:1 binding configuration that confers bivalency for the CD20 binding site. Glofitamab is delivered intravenously and requires pretreatment with obinutuzumab 1000 mg 7 days before the first dose. With a similar step-up dosing strategy, patients receive a priming dose of 2.5mg on cycle 1 day 8, an intermediate dose of 10mg on cycle 1 day 15, and a first full dose of 30mg on cycle 2 day 1. Subsequent treatments are administered every 21 days for up to 12 cycles. 

The open-label phase 1-2 clinical trial of glofitamab monotherapy enrolled 155 patients with a median age of 66 and 3 median prior lines of therapy. Thirty-three percent of patients had received prior CAR T-cell therapy, and 86% were refractory to last line of therapy with 30% refractory to CAR T-cell therapy. 

Results were as follows:

• CR rate of 39%, ORR 52%

• Median duration of CR not reached, median duration of objective response 18.4 months

• Median PFS 4.9 months, median OS not reached

Toxicity profile demonstrated the following:

• Any grade CRS 66%, grade ≥ 2 in 18%

  • Median time to onset 13.5 hours from cycle 1 day 8, median duration 30.5 hours

• Any grade neutropenia in 38%, grade ≥ 3 in 27%

• Grade ≥ 2 neurologic event in 15%

Glofitamab received accelerated approval from the FDA on June 15, 2023, with an identical indication to epcoritamab. 

The introduction of BsAbs in DLBCL has highlighted some important issues. Will BsAbs supplant CAR T-cell therapy in DLBCL? Experts can be found on both sides of this debate. BsAbs circumvent the logistics surrounding the production of CAR T-cell therapy products and can, for the large part, be administered in the outpatient setting. However, CAR T-cell therapy has significantly longer follow-up times, which speaks to the curative potential of these agents even in the third-line setting. BsAbs, some may argue, seem to carry a more favorable toxicity profile with the CRS mitigation strategies. However, we still have much to learn about the downstream side effects with prolonged T-cell activation and the potential for T-cell exhaustion.

Finally, with the continued development of new agents in this arena, the art of sequencing therapies will become ever more important. What is the efficacy of CAR T-cell therapy after BsAb exposure? Can BsAbs be used as bridging therapy to a curative option with CAR T-cell therapy? With longer-term follow-up in several years, will we see late relapses after CR with BsAbs? Ongoing clinical trials investigating combination strategies and CAR T-cell therapy consolidation with BsAbs will hopefully eventually clarify some of these questions.

Amlitelimab is a monoclonal antibody that targets the OX40 ligand (Weidinger et al). It is predicted to have broad potential therapeutic application for multiple immune diseases, including atopic dermatitis. I'm not looking for that. I've been spoiled by drugs that have narrow therapeutic application (like IL-23 blockade and IL-4/IL-13 blockade) that target a specific disease very effectively with very little in the way of side effects.

The OX40 ligand/receptor interaction may be too important. When I Google "OX40 deficiency," the first thing that pops up is a combined T- and B-cell immunodeficiency associated with possible aggressive, childhood-onset, disseminated, cutaneous, and systemic Kaposi sarcoma. That doesn't mean that such a horrible outcome will come with the level of pharmacologic OX40 blockade that we would try to achieve in our patients. Clinical trials don't show horrible adverse events — so far. I'm in no hurry to find out in my patients whether real-life efficacy in large numbers of people treated for long periods of time matches up with the short-term safety profiles seen in relatively small clinical trial populations.

It might be nice to give patients upadacitinib only as needed, for example for a flare of their atopic dermatitis, then cut down the dose or stop altogether until the next flare. The study by Guttman-Yassky and colleagues found that atopic dermatitis came back quickly when upadacitinib was stopped. However, their study looked at patients with chronically bad atopic dermatitis. If we have a patient who tends to flare only intermittently, it may be that we could use upadacitinib or other systemic treatments on an intermittent basis. I know when it came to my son's mild atopic dermatitis, intermittent use of a little triamcinolone ointment was all that was needed. Yes, I know that's a "reactive," roller-coaster approach. Yes, I know that a "proactive" keep-the-disease-away approach sounds better. But I'm realistic when it comes to patients' adherence behaviors. I think there's a lot to be said for minimizing drug exposure and just using treatments as needed. Guttman-Yassky's work makes me believe that a lot of patients will need continuous treatment to keep their severe disease under control. I'm not convinced that everyone will need continuous treatment to be happy with their treatment.

O'Connor and colleagues found that emollient bathing is associated with later development of atopic dermatitis. They defined emollient bathing as baths with oil or emulsifier-based additives. This study illustrates the importance of randomization in a controlled trial. Because their study was not randomized, we don't know whether the emollient bathing caused atopic dermatitis or whether families that had more dry skin or more family history of atopic dermatitis were more likely to use emollient bathing.

When dupilumab was first approved, I prescribed it to my patients to take every 2 weeks as recommended on the label. I'm not so sure how many patients actually used it that way. I suspect that a lot of them took the medicine less often than recommended, especially when they were doing well. This report by Sánchez-García and colleagues suggests that patients who are doing very well on dupilumab may be able to take the drug less often. That's probably not news to my patients who are already taking the drug less often than I told them to.

I think less frequent dosing may become even more common over time, particularly for drugs that may have more safety risks than dupilumab. Many patients with atopic dermatitis probably don't need to be taking drugs all the time. Patients who tend to have flare-ups but who do very well for a long period of time between flares may only need drugs intermittently. It will be interesting to see if our patients can use oral treatments for atopic dermatitis that way.

Siegfried and colleagues assessed how well dupilumab worked in children with atopic dermatitis in different areas of the body: head and neck, trunk, upper extremities, lower extremities. Dupilumab worked well in all these areas, as expected.

Xu and colleagues did a meta-analysis of studies of dupilumab for atopic dermatitis and concluded, not shockingly, that dupilumab is safe and effective for atopic dermatitis. Okay, I believe that. They further concluded: "More long-term, high-quality, controlled studies in different regions are needed for further verification." I don't think so. I think the evidence is clear already.

Studies that measure the levels of things are generally not particularly helpful. The study by García-Reyes and colleagues studied the levels of serum thymic stromal lymphopoietin (TSLP) in patients with atopic dermatitis. TSLP levels were higher in patients with atopic dermatitis compared with patients without atopic dermatitis. This basically tells us nothing about the role of TSLP in atopic dermatitis. The elevated levels could be causing atopic dermatitis or they could be the body's response to having atopic dermatitis.

To tell whether something is causal we have to look at either genetic studies or studies with specific inhibitors. A specific inhibitor study was done by atopic dermatitis expert Eric Simpson and colleagues.1 This was a randomized, placebo-controlled study in which an anti-TSLP antibody was given to patients with atopic dermatitis. Both the anti-TSLP antibody and placebo groups were permitted to use topical steroids. While the anti-TSLP antibody–treated patients did better than placebo-treated patients, the difference did not achieve statistical significance, probably, I believe, because the placebo-treated patients used more topical steroids. When you want to assess whether a drug for atopic dermatitis is better than placebo, you must be careful about how much topical steroid you let patients in the study use!

Additional Reference

1. Simpson EL, Parnes JR, She D, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80(4):1013-1021. doi: 10.1016/j.jaad.2018.11.059

Amlitelimab is a monoclonal antibody that targets the OX40 ligand (Weidinger et al). It is predicted to have broad potential therapeutic application for multiple immune diseases, including atopic dermatitis. I'm not looking for that. I've been spoiled by drugs that have narrow therapeutic application (like IL-23 blockade and IL-4/IL-13 blockade) that target a specific disease very effectively with very little in the way of side effects.

The OX40 ligand/receptor interaction may be too important. When I Google "OX40 deficiency," the first thing that pops up is a combined T- and B-cell immunodeficiency associated with possible aggressive, childhood-onset, disseminated, cutaneous, and systemic Kaposi sarcoma. That doesn't mean that such a horrible outcome will come with the level of pharmacologic OX40 blockade that we would try to achieve in our patients. Clinical trials don't show horrible adverse events — so far. I'm in no hurry to find out in my patients whether real-life efficacy in large numbers of people treated for long periods of time matches up with the short-term safety profiles seen in relatively small clinical trial populations.

It might be nice to give patients upadacitinib only as needed, for example for a flare of their atopic dermatitis, then cut down the dose or stop altogether until the next flare. The study by Guttman-Yassky and colleagues found that atopic dermatitis came back quickly when upadacitinib was stopped. However, their study looked at patients with chronically bad atopic dermatitis. If we have a patient who tends to flare only intermittently, it may be that we could use upadacitinib or other systemic treatments on an intermittent basis. I know when it came to my son's mild atopic dermatitis, intermittent use of a little triamcinolone ointment was all that was needed. Yes, I know that's a "reactive," roller-coaster approach. Yes, I know that a "proactive" keep-the-disease-away approach sounds better. But I'm realistic when it comes to patients' adherence behaviors. I think there's a lot to be said for minimizing drug exposure and just using treatments as needed. Guttman-Yassky's work makes me believe that a lot of patients will need continuous treatment to keep their severe disease under control. I'm not convinced that everyone will need continuous treatment to be happy with their treatment.

O'Connor and colleagues found that emollient bathing is associated with later development of atopic dermatitis. They defined emollient bathing as baths with oil or emulsifier-based additives. This study illustrates the importance of randomization in a controlled trial. Because their study was not randomized, we don't know whether the emollient bathing caused atopic dermatitis or whether families that had more dry skin or more family history of atopic dermatitis were more likely to use emollient bathing.

When dupilumab was first approved, I prescribed it to my patients to take every 2 weeks as recommended on the label. I'm not so sure how many patients actually used it that way. I suspect that a lot of them took the medicine less often than recommended, especially when they were doing well. This report by Sánchez-García and colleagues suggests that patients who are doing very well on dupilumab may be able to take the drug less often. That's probably not news to my patients who are already taking the drug less often than I told them to.

I think less frequent dosing may become even more common over time, particularly for drugs that may have more safety risks than dupilumab. Many patients with atopic dermatitis probably don't need to be taking drugs all the time. Patients who tend to have flare-ups but who do very well for a long period of time between flares may only need drugs intermittently. It will be interesting to see if our patients can use oral treatments for atopic dermatitis that way.

Siegfried and colleagues assessed how well dupilumab worked in children with atopic dermatitis in different areas of the body: head and neck, trunk, upper extremities, lower extremities. Dupilumab worked well in all these areas, as expected.

Xu and colleagues did a meta-analysis of studies of dupilumab for atopic dermatitis and concluded, not shockingly, that dupilumab is safe and effective for atopic dermatitis. Okay, I believe that. They further concluded: "More long-term, high-quality, controlled studies in different regions are needed for further verification." I don't think so. I think the evidence is clear already.

Studies that measure the levels of things are generally not particularly helpful. The study by García-Reyes and colleagues studied the levels of serum thymic stromal lymphopoietin (TSLP) in patients with atopic dermatitis. TSLP levels were higher in patients with atopic dermatitis compared with patients without atopic dermatitis. This basically tells us nothing about the role of TSLP in atopic dermatitis. The elevated levels could be causing atopic dermatitis or they could be the body's response to having atopic dermatitis.

To tell whether something is causal we have to look at either genetic studies or studies with specific inhibitors. A specific inhibitor study was done by atopic dermatitis expert Eric Simpson and colleagues.1 This was a randomized, placebo-controlled study in which an anti-TSLP antibody was given to patients with atopic dermatitis. Both the anti-TSLP antibody and placebo groups were permitted to use topical steroids. While the anti-TSLP antibody–treated patients did better than placebo-treated patients, the difference did not achieve statistical significance, probably, I believe, because the placebo-treated patients used more topical steroids. When you want to assess whether a drug for atopic dermatitis is better than placebo, you must be careful about how much topical steroid you let patients in the study use!

Additional Reference

1. Simpson EL, Parnes JR, She D, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80(4):1013-1021. doi: 10.1016/j.jaad.2018.11.059

Amlitelimab is a monoclonal antibody that targets the OX40 ligand (Weidinger et al). It is predicted to have broad potential therapeutic application for multiple immune diseases, including atopic dermatitis. I'm not looking for that. I've been spoiled by drugs that have narrow therapeutic application (like IL-23 blockade and IL-4/IL-13 blockade) that target a specific disease very effectively with very little in the way of side effects.

The OX40 ligand/receptor interaction may be too important. When I Google "OX40 deficiency," the first thing that pops up is a combined T- and B-cell immunodeficiency associated with possible aggressive, childhood-onset, disseminated, cutaneous, and systemic Kaposi sarcoma. That doesn't mean that such a horrible outcome will come with the level of pharmacologic OX40 blockade that we would try to achieve in our patients. Clinical trials don't show horrible adverse events — so far. I'm in no hurry to find out in my patients whether real-life efficacy in large numbers of people treated for long periods of time matches up with the short-term safety profiles seen in relatively small clinical trial populations.

It might be nice to give patients upadacitinib only as needed, for example for a flare of their atopic dermatitis, then cut down the dose or stop altogether until the next flare. The study by Guttman-Yassky and colleagues found that atopic dermatitis came back quickly when upadacitinib was stopped. However, their study looked at patients with chronically bad atopic dermatitis. If we have a patient who tends to flare only intermittently, it may be that we could use upadacitinib or other systemic treatments on an intermittent basis. I know when it came to my son's mild atopic dermatitis, intermittent use of a little triamcinolone ointment was all that was needed. Yes, I know that's a "reactive," roller-coaster approach. Yes, I know that a "proactive" keep-the-disease-away approach sounds better. But I'm realistic when it comes to patients' adherence behaviors. I think there's a lot to be said for minimizing drug exposure and just using treatments as needed. Guttman-Yassky's work makes me believe that a lot of patients will need continuous treatment to keep their severe disease under control. I'm not convinced that everyone will need continuous treatment to be happy with their treatment.

O'Connor and colleagues found that emollient bathing is associated with later development of atopic dermatitis. They defined emollient bathing as baths with oil or emulsifier-based additives. This study illustrates the importance of randomization in a controlled trial. Because their study was not randomized, we don't know whether the emollient bathing caused atopic dermatitis or whether families that had more dry skin or more family history of atopic dermatitis were more likely to use emollient bathing.

When dupilumab was first approved, I prescribed it to my patients to take every 2 weeks as recommended on the label. I'm not so sure how many patients actually used it that way. I suspect that a lot of them took the medicine less often than recommended, especially when they were doing well. This report by Sánchez-García and colleagues suggests that patients who are doing very well on dupilumab may be able to take the drug less often. That's probably not news to my patients who are already taking the drug less often than I told them to.

I think less frequent dosing may become even more common over time, particularly for drugs that may have more safety risks than dupilumab. Many patients with atopic dermatitis probably don't need to be taking drugs all the time. Patients who tend to have flare-ups but who do very well for a long period of time between flares may only need drugs intermittently. It will be interesting to see if our patients can use oral treatments for atopic dermatitis that way.

Siegfried and colleagues assessed how well dupilumab worked in children with atopic dermatitis in different areas of the body: head and neck, trunk, upper extremities, lower extremities. Dupilumab worked well in all these areas, as expected.

Xu and colleagues did a meta-analysis of studies of dupilumab for atopic dermatitis and concluded, not shockingly, that dupilumab is safe and effective for atopic dermatitis. Okay, I believe that. They further concluded: "More long-term, high-quality, controlled studies in different regions are needed for further verification." I don't think so. I think the evidence is clear already.

Studies that measure the levels of things are generally not particularly helpful. The study by García-Reyes and colleagues studied the levels of serum thymic stromal lymphopoietin (TSLP) in patients with atopic dermatitis. TSLP levels were higher in patients with atopic dermatitis compared with patients without atopic dermatitis. This basically tells us nothing about the role of TSLP in atopic dermatitis. The elevated levels could be causing atopic dermatitis or they could be the body's response to having atopic dermatitis.

To tell whether something is causal we have to look at either genetic studies or studies with specific inhibitors. A specific inhibitor study was done by atopic dermatitis expert Eric Simpson and colleagues.1 This was a randomized, placebo-controlled study in which an anti-TSLP antibody was given to patients with atopic dermatitis. Both the anti-TSLP antibody and placebo groups were permitted to use topical steroids. While the anti-TSLP antibody–treated patients did better than placebo-treated patients, the difference did not achieve statistical significance, probably, I believe, because the placebo-treated patients used more topical steroids. When you want to assess whether a drug for atopic dermatitis is better than placebo, you must be careful about how much topical steroid you let patients in the study use!

Additional Reference

1. Simpson EL, Parnes JR, She D, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80(4):1013-1021. doi: 10.1016/j.jaad.2018.11.059

To the Editor:

Approximately 3% of the US population, or 6.9 million adults, is affected by psoriasis.¹ Psoriasis has a substantial impact on quality of life and is associated with increased health care expenses and medication costs. In 2013, it was reported that the estimated US annual cost—direct, indirect, intangible, and comorbidity costs—of psoriasis for adults was $112 billion.² We investigated the prevalence and sociodemographic characteristics of adult psoriasis patients (aged ≥20 years) with financial insecurity utilizing the 2009–2014 National Health and Nutrition Examination Survey (NHANES) data.³

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 2009-2014 NHANES database to evaluate financial insecurity. Financial insecurity was evaluated by 2 outcome variables. The primary outcome variable was assessed by the question “Are you covered by health insurance or some other kind of health care plan (including health insurance obtained through employment or purchased directly as well as government programs like Medicare and Medicaid that provide medical care or help pay medical bills)?”³ Our secondary outcome variable was evaluated by a reported annual household income of less than $20,000. P values in Table 1 were calculated using Pearson χ² tests. In Table 2, multivariate logistic regressions were performed using Stata/MP 17 (StataCorp LLC) to analyze associations between outcome variables and sociodemographic characteristics. Additionally, we controlled for age, race/ethnicity, sex, education, marital status, US citizenship status, and tobacco use. Subsequently, relationships with P<.05 were considered statistically significant.

Our analysis comprised 480 individuals with psoriasis; 40 individuals were excluded from our analysis because they did not report annual household income and health insurance status (Table 1). Among the 480 individuals with psoriasis, approximately 16% (weighted) reported a lack of health insurance, and approximately 17% (weighted) reported an annual household income of less than $20,000. Among those who reported an annual household income of less than $20,000, approximately 38% (weighted) of them reported that they did not have health insurance.

Multivariate logistic regression analyses revealed that elderly individuals (aged >60 years), college graduates, married individuals, and US citizens had decreased odds of lacking health insurance (Table 2). Additionally, those with a history of tobacco use (adjusted odds ratio [AOR] 2.02; 95% CI, 1.00-4.05) were associated with lacking health insurance. Non-Hispanic Black individuals (AOR 2.26; 95% CI, 1.09-4.71) and US citizens (AOR 5.01; 95% CI, 1.28-19.63) had a significant association with an annual household income of less than $20,000 (P<.05). Lastly, males, those with education beyond ninth grade, and married individuals had a significantly decreased odds of having an annual household income of less than $20,000 (P<.05)(Table 2).

Our findings indicate that certain sociodemographic groups of psoriasis patients have an increased risk for being financially insecure. It is important to evaluate the cost of treatment, number of necessary visits to the office, and cost of transportation, as these factors can serve as a major economic burden to patients being managed for psoriasis.⁴ Additionally, the cost of biologics has been increasing over time.⁵ Taking all of this into account when caring for psoriasis patients is crucial, as understanding the financial status of patients can assist with determining appropriate individualized treatment regimens.

To the Editor:

Approximately 3% of the US population, or 6.9 million adults, is affected by psoriasis.¹ Psoriasis has a substantial impact on quality of life and is associated with increased health care expenses and medication costs. In 2013, it was reported that the estimated US annual cost—direct, indirect, intangible, and comorbidity costs—of psoriasis for adults was $112 billion.² We investigated the prevalence and sociodemographic characteristics of adult psoriasis patients (aged ≥20 years) with financial insecurity utilizing the 2009–2014 National Health and Nutrition Examination Survey (NHANES) data.³

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 2009-2014 NHANES database to evaluate financial insecurity. Financial insecurity was evaluated by 2 outcome variables. The primary outcome variable was assessed by the question “Are you covered by health insurance or some other kind of health care plan (including health insurance obtained through employment or purchased directly as well as government programs like Medicare and Medicaid that provide medical care or help pay medical bills)?”³ Our secondary outcome variable was evaluated by a reported annual household income of less than $20,000. P values in Table 1 were calculated using Pearson χ² tests. In Table 2, multivariate logistic regressions were performed using Stata/MP 17 (StataCorp LLC) to analyze associations between outcome variables and sociodemographic characteristics. Additionally, we controlled for age, race/ethnicity, sex, education, marital status, US citizenship status, and tobacco use. Subsequently, relationships with P<.05 were considered statistically significant.

Our analysis comprised 480 individuals with psoriasis; 40 individuals were excluded from our analysis because they did not report annual household income and health insurance status (Table 1). Among the 480 individuals with psoriasis, approximately 16% (weighted) reported a lack of health insurance, and approximately 17% (weighted) reported an annual household income of less than $20,000. Among those who reported an annual household income of less than $20,000, approximately 38% (weighted) of them reported that they did not have health insurance.

Multivariate logistic regression analyses revealed that elderly individuals (aged >60 years), college graduates, married individuals, and US citizens had decreased odds of lacking health insurance (Table 2). Additionally, those with a history of tobacco use (adjusted odds ratio [AOR] 2.02; 95% CI, 1.00-4.05) were associated with lacking health insurance. Non-Hispanic Black individuals (AOR 2.26; 95% CI, 1.09-4.71) and US citizens (AOR 5.01; 95% CI, 1.28-19.63) had a significant association with an annual household income of less than $20,000 (P<.05). Lastly, males, those with education beyond ninth grade, and married individuals had a significantly decreased odds of having an annual household income of less than $20,000 (P<.05)(Table 2).

Our findings indicate that certain sociodemographic groups of psoriasis patients have an increased risk for being financially insecure. It is important to evaluate the cost of treatment, number of necessary visits to the office, and cost of transportation, as these factors can serve as a major economic burden to patients being managed for psoriasis.⁴ Additionally, the cost of biologics has been increasing over time.⁵ Taking all of this into account when caring for psoriasis patients is crucial, as understanding the financial status of patients can assist with determining appropriate individualized treatment regimens.

To the Editor:

Approximately 3% of the US population, or 6.9 million adults, is affected by psoriasis.¹ Psoriasis has a substantial impact on quality of life and is associated with increased health care expenses and medication costs. In 2013, it was reported that the estimated US annual cost—direct, indirect, intangible, and comorbidity costs—of psoriasis for adults was $112 billion.² We investigated the prevalence and sociodemographic characteristics of adult psoriasis patients (aged ≥20 years) with financial insecurity utilizing the 2009–2014 National Health and Nutrition Examination Survey (NHANES) data.³

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 2009-2014 NHANES database to evaluate financial insecurity. Financial insecurity was evaluated by 2 outcome variables. The primary outcome variable was assessed by the question “Are you covered by health insurance or some other kind of health care plan (including health insurance obtained through employment or purchased directly as well as government programs like Medicare and Medicaid that provide medical care or help pay medical bills)?”³ Our secondary outcome variable was evaluated by a reported annual household income of less than $20,000. P values in Table 1 were calculated using Pearson χ² tests. In Table 2, multivariate logistic regressions were performed using Stata/MP 17 (StataCorp LLC) to analyze associations between outcome variables and sociodemographic characteristics. Additionally, we controlled for age, race/ethnicity, sex, education, marital status, US citizenship status, and tobacco use. Subsequently, relationships with P<.05 were considered statistically significant.

Our analysis comprised 480 individuals with psoriasis; 40 individuals were excluded from our analysis because they did not report annual household income and health insurance status (Table 1). Among the 480 individuals with psoriasis, approximately 16% (weighted) reported a lack of health insurance, and approximately 17% (weighted) reported an annual household income of less than $20,000. Among those who reported an annual household income of less than $20,000, approximately 38% (weighted) of them reported that they did not have health insurance.

Multivariate logistic regression analyses revealed that elderly individuals (aged >60 years), college graduates, married individuals, and US citizens had decreased odds of lacking health insurance (Table 2). Additionally, those with a history of tobacco use (adjusted odds ratio [AOR] 2.02; 95% CI, 1.00-4.05) were associated with lacking health insurance. Non-Hispanic Black individuals (AOR 2.26; 95% CI, 1.09-4.71) and US citizens (AOR 5.01; 95% CI, 1.28-19.63) had a significant association with an annual household income of less than $20,000 (P<.05). Lastly, males, those with education beyond ninth grade, and married individuals had a significantly decreased odds of having an annual household income of less than $20,000 (P<.05)(Table 2).

Our findings indicate that certain sociodemographic groups of psoriasis patients have an increased risk for being financially insecure. It is important to evaluate the cost of treatment, number of necessary visits to the office, and cost of transportation, as these factors can serve as a major economic burden to patients being managed for psoriasis.⁴ Additionally, the cost of biologics has been increasing over time.⁵ Taking all of this into account when caring for psoriasis patients is crucial, as understanding the financial status of patients can assist with determining appropriate individualized treatment regimens.

Studies have shown that breast cancer survivors have increased rates of age-related conditions, including cardiovascular disease and osteoporosis among others, therefore postulating that the biological aging process may be accelerated in this population.² Among 417 women enrolled in the prospective Sister Study cohort, paired blood samples collected an average of 7.7 years apart compared three epigenetic metrics of biological aging (calculated on the basis of DNA methylation data) between women who were diagnosed and treated for breast cancer (n = 190) vs those who remained breast cancer–free (n = 227) (Kresovich et al). Women diagnosed and treated for breast cancer had higher biological aging metrics than women who were cancer-free at the time of follow-up: PhenoAgeAccel³ (standardized mean difference [β] = 0.13; P = .04), GrimAgeAccel⁴ (β = 0.14; P = .01), and DunedinPACE⁵ (β = 0.37; P < .001). Regarding breast cancer therapies received, the increases in biological aging were most striking for those women who underwent radiation. The effect of cancer treatments, specifically chemotherapy and radiation, on DNA methylation profiles and accelerating the aging process has been demonstrated in prior studies as well.⁶ Future research should strive to improve our understanding of the specific mechanisms underlying these age-related changes, identify ways to affect those which are modifiable, and positively influence long-term cognitive and functional consequences.

The association between cardiometabolic abnormalities, including obesity, hyperinsulinemia, diabetes, hypertension, and dyslipidemia, and an elevated breast cancer risk has been demonstrated in various studies.⁷ Furthermore, dysregulation of obesity-related proteins plays a role in breast cancer development and progression. A study by Xu and colleagues evaluated the temporal relationships and longitudinal associations of body mass index (BMI), cardiometabolic risk score (CRS), and obesity-related protein score (OPS) among 444 healthy women in a breast cancer screening cohort. After adjustment for demographics, lifestyle, and reproductive factors, a 1-kg/m² increase in BMI per year increased CRS in both premenopausal (0.057 unit; P = .025) and postmenopausal women (0.054 unit; P = .033) and increased OPS by 0.588 unit (P = .001) in postmenopausal women. A significant association was also observed between CRS and OPS in postmenopausal women (β = 0.281; P = .034). These results support the importance of weight management and its effect on cardiometabolic and obesity-related parameters in breast cancer prevention. Research focused on lifestyle interventions to modify risk factors and effective implementation of these techniques will contribute to further reducing breast cancer risk.

Additional References

1. García-Albéniz X, Hernán MA, Logan RW, et al. Continuation of annual screening mammography and breast cancer mortality in women older than 70 years. Ann Intern Med. 2020;172(6):381-389. doi: 10.7326/M18-1199
2. Greenlee H, Iribarren C, Rana JS, et al. Risk of cardiovascular disease in women with and without breast cancer: The Pathways Heart Study. J Clin Oncol. 2022;40(15):1647-1658. doi: 10.1200/JCO.21.01736
3. Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018;10(4):573-591. doi: 10.18632/aging.101414
4. Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303-327. doi: 10.18632/aging.101684
5. Belsky DW, Caspi A, Corcoran DL, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife. 2022:11:e73420. doi: 10.7554/eLife.73420
6. Sehl ME, Carroll JE, Horvath S, Bower JE. The acute effects of adjuvant radiation and chemotherapy on peripheral blood epigenetic age in early stage breast cancer patients. NPJ Breast Cancer. 2020;6:23. doi: 10.1038/s41523-020-0161-3
7. Nouri M, Mohsenpour MA, Katsiki N, et al. Effect of serum lipid profile on the risk of breast cancer: Systematic review and meta-analysis of 1,628,871 women. J Clin Med. 2022;11(15):4503. doi: 10.3390/jcm11154503

Studies have shown that breast cancer survivors have increased rates of age-related conditions, including cardiovascular disease and osteoporosis among others, therefore postulating that the biological aging process may be accelerated in this population.² Among 417 women enrolled in the prospective Sister Study cohort, paired blood samples collected an average of 7.7 years apart compared three epigenetic metrics of biological aging (calculated on the basis of DNA methylation data) between women who were diagnosed and treated for breast cancer (n = 190) vs those who remained breast cancer–free (n = 227) (Kresovich et al). Women diagnosed and treated for breast cancer had higher biological aging metrics than women who were cancer-free at the time of follow-up: PhenoAgeAccel³ (standardized mean difference [β] = 0.13; P = .04), GrimAgeAccel⁴ (β = 0.14; P = .01), and DunedinPACE⁵ (β = 0.37; P < .001). Regarding breast cancer therapies received, the increases in biological aging were most striking for those women who underwent radiation. The effect of cancer treatments, specifically chemotherapy and radiation, on DNA methylation profiles and accelerating the aging process has been demonstrated in prior studies as well.⁶ Future research should strive to improve our understanding of the specific mechanisms underlying these age-related changes, identify ways to affect those which are modifiable, and positively influence long-term cognitive and functional consequences.

The association between cardiometabolic abnormalities, including obesity, hyperinsulinemia, diabetes, hypertension, and dyslipidemia, and an elevated breast cancer risk has been demonstrated in various studies.⁷ Furthermore, dysregulation of obesity-related proteins plays a role in breast cancer development and progression. A study by Xu and colleagues evaluated the temporal relationships and longitudinal associations of body mass index (BMI), cardiometabolic risk score (CRS), and obesity-related protein score (OPS) among 444 healthy women in a breast cancer screening cohort. After adjustment for demographics, lifestyle, and reproductive factors, a 1-kg/m² increase in BMI per year increased CRS in both premenopausal (0.057 unit; P = .025) and postmenopausal women (0.054 unit; P = .033) and increased OPS by 0.588 unit (P = .001) in postmenopausal women. A significant association was also observed between CRS and OPS in postmenopausal women (β = 0.281; P = .034). These results support the importance of weight management and its effect on cardiometabolic and obesity-related parameters in breast cancer prevention. Research focused on lifestyle interventions to modify risk factors and effective implementation of these techniques will contribute to further reducing breast cancer risk.

Additional References

1. García-Albéniz X, Hernán MA, Logan RW, et al. Continuation of annual screening mammography and breast cancer mortality in women older than 70 years. Ann Intern Med. 2020;172(6):381-389. doi: 10.7326/M18-1199
2. Greenlee H, Iribarren C, Rana JS, et al. Risk of cardiovascular disease in women with and without breast cancer: The Pathways Heart Study. J Clin Oncol. 2022;40(15):1647-1658. doi: 10.1200/JCO.21.01736
3. Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018;10(4):573-591. doi: 10.18632/aging.101414
4. Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303-327. doi: 10.18632/aging.101684
5. Belsky DW, Caspi A, Corcoran DL, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife. 2022:11:e73420. doi: 10.7554/eLife.73420
6. Sehl ME, Carroll JE, Horvath S, Bower JE. The acute effects of adjuvant radiation and chemotherapy on peripheral blood epigenetic age in early stage breast cancer patients. NPJ Breast Cancer. 2020;6:23. doi: 10.1038/s41523-020-0161-3
7. Nouri M, Mohsenpour MA, Katsiki N, et al. Effect of serum lipid profile on the risk of breast cancer: Systematic review and meta-analysis of 1,628,871 women. J Clin Med. 2022;11(15):4503. doi: 10.3390/jcm11154503

Studies have shown that breast cancer survivors have increased rates of age-related conditions, including cardiovascular disease and osteoporosis among others, therefore postulating that the biological aging process may be accelerated in this population.² Among 417 women enrolled in the prospective Sister Study cohort, paired blood samples collected an average of 7.7 years apart compared three epigenetic metrics of biological aging (calculated on the basis of DNA methylation data) between women who were diagnosed and treated for breast cancer (n = 190) vs those who remained breast cancer–free (n = 227) (Kresovich et al). Women diagnosed and treated for breast cancer had higher biological aging metrics than women who were cancer-free at the time of follow-up: PhenoAgeAccel³ (standardized mean difference [β] = 0.13; P = .04), GrimAgeAccel⁴ (β = 0.14; P = .01), and DunedinPACE⁵ (β = 0.37; P < .001). Regarding breast cancer therapies received, the increases in biological aging were most striking for those women who underwent radiation. The effect of cancer treatments, specifically chemotherapy and radiation, on DNA methylation profiles and accelerating the aging process has been demonstrated in prior studies as well.⁶ Future research should strive to improve our understanding of the specific mechanisms underlying these age-related changes, identify ways to affect those which are modifiable, and positively influence long-term cognitive and functional consequences.

The association between cardiometabolic abnormalities, including obesity, hyperinsulinemia, diabetes, hypertension, and dyslipidemia, and an elevated breast cancer risk has been demonstrated in various studies.⁷ Furthermore, dysregulation of obesity-related proteins plays a role in breast cancer development and progression. A study by Xu and colleagues evaluated the temporal relationships and longitudinal associations of body mass index (BMI), cardiometabolic risk score (CRS), and obesity-related protein score (OPS) among 444 healthy women in a breast cancer screening cohort. After adjustment for demographics, lifestyle, and reproductive factors, a 1-kg/m² increase in BMI per year increased CRS in both premenopausal (0.057 unit; P = .025) and postmenopausal women (0.054 unit; P = .033) and increased OPS by 0.588 unit (P = .001) in postmenopausal women. A significant association was also observed between CRS and OPS in postmenopausal women (β = 0.281; P = .034). These results support the importance of weight management and its effect on cardiometabolic and obesity-related parameters in breast cancer prevention. Research focused on lifestyle interventions to modify risk factors and effective implementation of these techniques will contribute to further reducing breast cancer risk.

Additional References

1. García-Albéniz X, Hernán MA, Logan RW, et al. Continuation of annual screening mammography and breast cancer mortality in women older than 70 years. Ann Intern Med. 2020;172(6):381-389. doi: 10.7326/M18-1199
2. Greenlee H, Iribarren C, Rana JS, et al. Risk of cardiovascular disease in women with and without breast cancer: The Pathways Heart Study. J Clin Oncol. 2022;40(15):1647-1658. doi: 10.1200/JCO.21.01736
3. Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018;10(4):573-591. doi: 10.18632/aging.101414
4. Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303-327. doi: 10.18632/aging.101684
5. Belsky DW, Caspi A, Corcoran DL, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife. 2022:11:e73420. doi: 10.7554/eLife.73420
6. Sehl ME, Carroll JE, Horvath S, Bower JE. The acute effects of adjuvant radiation and chemotherapy on peripheral blood epigenetic age in early stage breast cancer patients. NPJ Breast Cancer. 2020;6:23. doi: 10.1038/s41523-020-0161-3
7. Nouri M, Mohsenpour MA, Katsiki N, et al. Effect of serum lipid profile on the risk of breast cancer: Systematic review and meta-analysis of 1,628,871 women. J Clin Med. 2022;11(15):4503. doi: 10.3390/jcm11154503

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

Artificial intelligence (AI) technology has increasingly been incorporated in medicine. In dermatology, AI has been used to detect and diagnose skin lesions, including skin cancer.¹ ChatGPT (OpenAI) is a novel, highly popular development in generative AI technology. A large language model released in 2022, ChatGPT is a chatbot designed to mimic human conversation and generate specific detailed information when prompted. Free and publicly available, it has been used by millions of people. ChatGPT’s application in the medical field currently is being evaluated across several specialties, including plastic surgery, radiology, and urology.^2-4 ChatGPT has the potential to assist health care professionals, including dermatologists, though its use raises important ethical considerations. Herein, we focus on the potential benefits as well as the pitfalls of using ChatGPT in dermatology clinical practice.

Potential Uses of ChatGPT in Practice

A major benefit of ChatGPT is its ability to improve clinical efficiency. First, ChatGPT can provide quick access to general medical information, similar to a search engine but with more natural language processing and contextual understanding to synthesize information.⁵ This function is useful for rapid concise answers to specific and directed questions. ChatGPT also can interact with its user by asking follow-up questions to produce more precise and relevant responses; this feature may help dermatologists form more accurate differential diagnoses. Additionally, ChatGPT can increase efficiency in clinical practice by drafting generic medical documents,² including templates for after-visit summaries, postprocedure instructions, referrals, prior authorization appeal letters, and educational handouts. Importantly, increased efficiency can reduce provider burnout and lead to improved patient care. Another useful feature of ChatGPT is its ability to output information modeling human conversation. Because of this feature, ChatGPT also could be employed in clinical practice to serve as an interpreter for patients during clinic visits. Currently, the use of virtual translators can be cumbersome and subject to technical constraints. ChatGPT can provide accurate and conversational translations for patients and dermatologists, improving the patient-provider relationship.

ChatGPT also can contribute to major advancements in the field of dermatology beyond the clinical setting. Because of its ability to draw from extensive data that have already been uploaded, there are some uses of ChatGPT in a research context: to assist in finding resources for research and reviews, formulating hypotheses, drafting study protocols, and collecting large amounts of data within seconds.⁶

ChatGPT also has potential in advancing medical education. It could be used by medical schools to model interactive patient encounters to help students practice taking a patient’s history and creating differential diagnoses.⁶ This application of ChatGPT may help medical students hone their clinical skills in a low-stress environment without the restrictions that can come with hiring and training standardized patients, especially when mimicking dermatologic clinical encounters.

Other possibilities for ChatGPT in dermatologic practice include survey administration, clinical trial recruitment, and even automatic high-risk medication monitoring. Despite the many potential applications of ChatGPT in clinical practice, the question raised in each scenario is the quality, accuracy, and safety of what it produces.

Potential Pitfalls of ChatGPT in Practice and Possible Mitigation Strategies

A main concern in using ChatGPT in clinical practice is its potential to produce inaccurate or biased information. When prompted to create a research abstract based on previously published research, ChatGPT drafted abstracts that were clear and digestible but supplemented with incorrect data.⁷ A group of medical researchers who reviewed these ChatGPT-generated abstracts mistook 32% of the abstracts as having been written by human researchers. The implications of this finding are worrisome. If inaccurate or false information is used by ChatGPT in documents sent to insurance companies or patients, the patient’s safety as well as the dermatologist’s license and credibility are at stake. Thus, dermatologists looking to use ChatGPT to draft generic medical documents should actively review the output to ensure that the information is accurate. Importantly, ChatGPT also is only currently programmed with information up to 2021, limiting its access to recently published research articles and updated International Classification of Diseases, Tenth Revision codes.⁵ The continued development of ChatGPT will lead to regular updates by OpenAI that resolve this shortcoming in the future. Further, AI models may encode and perpetuate harmful stereotypes and social biases that are present in training data.⁸

When considering its potential in clinical practice, ChatGPT itself states that it can aid in clinical decision-making by processing patient information, including history, current symptoms, and biopsy and test results. This is uncharted territory, and providers who use ChatGPT at this stage to aid in decision-making should regard it similarly to information retrieved from a search engine. The information produced by ChatGPT should be used to substantiate but not definitively confirm a diagnosis or dictate management. Clinical suspicion by the dermatologist should always trump ChatGPT output. If physicians recommend ChatGPT output over their own advice, it can become a liability, as the technology is not regulated to any degree. Patients also should be cautious when seeking and following medical advice from ChatGPT, as it could be misleading or incorrect and could undermine the patient-physician relationship.⁶

Additionally, the specific use of ChatGPT to evaluate patient health records raises concerns related to patient privacy and confidentiality. Providers should never enter patient information protected by the Health Insurance Portability and Accountability Act into ChatGPT or anywhere else on the internet. Mitigation of this risk is not currently possible; ChatGPT requires more development and further understanding to even consider its integration into current electronic health records without compromising patient confidentiality.

The Bottom Line

Overall, ChatGPT has the potential to improve efficiency in clinical practice by assisting with informational searches and document drafting. Importantly, increased efficiency can reduce provider burnout and lead to improved patient care. However, dermatologists should carefully weigh the ethical issues of nonmaleficence and justice in evaluating ChatGPT for accuracy, biases, and the protection of patient confidentiality.

Finally, we asked ChatGPT on February 28, 2023, what it thinks:

User: Should dermatologists use ChatGPT in clinical practice?

ChatGPT: As an AI language model, ChatGPT can be a useful tool in dermatology clinical practice, but it should be used with caution in conjunction with other sources of information and clinical judgement.

Dermatologists should be aware of the potential benefits and risks of using ChatGPT and make informed decisions about how to integrate it into their clinical practice. It’s important to remember that ChatGPT is not a substitute for clinical expertise or human interaction with patients, and it should only be used as a supplement to enhance the quality of patient care.

Dermatologists who choose to use ChatGPT should also be aware of its limitations and potential risks, such as limited accuracy, lack of context, and liability issues if it provides incorrect information or recommendations that lead to patient harm. Dermatologists should use their professional judgement and consult with other health care professionals when making important decisions regarding patient care.

Artificial intelligence (AI) technology has increasingly been incorporated in medicine. In dermatology, AI has been used to detect and diagnose skin lesions, including skin cancer.¹ ChatGPT (OpenAI) is a novel, highly popular development in generative AI technology. A large language model released in 2022, ChatGPT is a chatbot designed to mimic human conversation and generate specific detailed information when prompted. Free and publicly available, it has been used by millions of people. ChatGPT’s application in the medical field currently is being evaluated across several specialties, including plastic surgery, radiology, and urology.^2-4 ChatGPT has the potential to assist health care professionals, including dermatologists, though its use raises important ethical considerations. Herein, we focus on the potential benefits as well as the pitfalls of using ChatGPT in dermatology clinical practice.

Potential Uses of ChatGPT in Practice

A major benefit of ChatGPT is its ability to improve clinical efficiency. First, ChatGPT can provide quick access to general medical information, similar to a search engine but with more natural language processing and contextual understanding to synthesize information.⁵ This function is useful for rapid concise answers to specific and directed questions. ChatGPT also can interact with its user by asking follow-up questions to produce more precise and relevant responses; this feature may help dermatologists form more accurate differential diagnoses. Additionally, ChatGPT can increase efficiency in clinical practice by drafting generic medical documents,² including templates for after-visit summaries, postprocedure instructions, referrals, prior authorization appeal letters, and educational handouts. Importantly, increased efficiency can reduce provider burnout and lead to improved patient care. Another useful feature of ChatGPT is its ability to output information modeling human conversation. Because of this feature, ChatGPT also could be employed in clinical practice to serve as an interpreter for patients during clinic visits. Currently, the use of virtual translators can be cumbersome and subject to technical constraints. ChatGPT can provide accurate and conversational translations for patients and dermatologists, improving the patient-provider relationship.

ChatGPT also can contribute to major advancements in the field of dermatology beyond the clinical setting. Because of its ability to draw from extensive data that have already been uploaded, there are some uses of ChatGPT in a research context: to assist in finding resources for research and reviews, formulating hypotheses, drafting study protocols, and collecting large amounts of data within seconds.⁶

ChatGPT also has potential in advancing medical education. It could be used by medical schools to model interactive patient encounters to help students practice taking a patient’s history and creating differential diagnoses.⁶ This application of ChatGPT may help medical students hone their clinical skills in a low-stress environment without the restrictions that can come with hiring and training standardized patients, especially when mimicking dermatologic clinical encounters.

Other possibilities for ChatGPT in dermatologic practice include survey administration, clinical trial recruitment, and even automatic high-risk medication monitoring. Despite the many potential applications of ChatGPT in clinical practice, the question raised in each scenario is the quality, accuracy, and safety of what it produces.

Potential Pitfalls of ChatGPT in Practice and Possible Mitigation Strategies

A main concern in using ChatGPT in clinical practice is its potential to produce inaccurate or biased information. When prompted to create a research abstract based on previously published research, ChatGPT drafted abstracts that were clear and digestible but supplemented with incorrect data.⁷ A group of medical researchers who reviewed these ChatGPT-generated abstracts mistook 32% of the abstracts as having been written by human researchers. The implications of this finding are worrisome. If inaccurate or false information is used by ChatGPT in documents sent to insurance companies or patients, the patient’s safety as well as the dermatologist’s license and credibility are at stake. Thus, dermatologists looking to use ChatGPT to draft generic medical documents should actively review the output to ensure that the information is accurate. Importantly, ChatGPT also is only currently programmed with information up to 2021, limiting its access to recently published research articles and updated International Classification of Diseases, Tenth Revision codes.⁵ The continued development of ChatGPT will lead to regular updates by OpenAI that resolve this shortcoming in the future. Further, AI models may encode and perpetuate harmful stereotypes and social biases that are present in training data.⁸

When considering its potential in clinical practice, ChatGPT itself states that it can aid in clinical decision-making by processing patient information, including history, current symptoms, and biopsy and test results. This is uncharted territory, and providers who use ChatGPT at this stage to aid in decision-making should regard it similarly to information retrieved from a search engine. The information produced by ChatGPT should be used to substantiate but not definitively confirm a diagnosis or dictate management. Clinical suspicion by the dermatologist should always trump ChatGPT output. If physicians recommend ChatGPT output over their own advice, it can become a liability, as the technology is not regulated to any degree. Patients also should be cautious when seeking and following medical advice from ChatGPT, as it could be misleading or incorrect and could undermine the patient-physician relationship.⁶

Additionally, the specific use of ChatGPT to evaluate patient health records raises concerns related to patient privacy and confidentiality. Providers should never enter patient information protected by the Health Insurance Portability and Accountability Act into ChatGPT or anywhere else on the internet. Mitigation of this risk is not currently possible; ChatGPT requires more development and further understanding to even consider its integration into current electronic health records without compromising patient confidentiality.

The Bottom Line

Overall, ChatGPT has the potential to improve efficiency in clinical practice by assisting with informational searches and document drafting. Importantly, increased efficiency can reduce provider burnout and lead to improved patient care. However, dermatologists should carefully weigh the ethical issues of nonmaleficence and justice in evaluating ChatGPT for accuracy, biases, and the protection of patient confidentiality.

Finally, we asked ChatGPT on February 28, 2023, what it thinks:

User: Should dermatologists use ChatGPT in clinical practice?

ChatGPT: As an AI language model, ChatGPT can be a useful tool in dermatology clinical practice, but it should be used with caution in conjunction with other sources of information and clinical judgement.

Dermatologists should be aware of the potential benefits and risks of using ChatGPT and make informed decisions about how to integrate it into their clinical practice. It’s important to remember that ChatGPT is not a substitute for clinical expertise or human interaction with patients, and it should only be used as a supplement to enhance the quality of patient care.

Dermatologists who choose to use ChatGPT should also be aware of its limitations and potential risks, such as limited accuracy, lack of context, and liability issues if it provides incorrect information or recommendations that lead to patient harm. Dermatologists should use their professional judgement and consult with other health care professionals when making important decisions regarding patient care.

Artificial intelligence (AI) technology has increasingly been incorporated in medicine. In dermatology, AI has been used to detect and diagnose skin lesions, including skin cancer.¹ ChatGPT (OpenAI) is a novel, highly popular development in generative AI technology. A large language model released in 2022, ChatGPT is a chatbot designed to mimic human conversation and generate specific detailed information when prompted. Free and publicly available, it has been used by millions of people. ChatGPT’s application in the medical field currently is being evaluated across several specialties, including plastic surgery, radiology, and urology.^2-4 ChatGPT has the potential to assist health care professionals, including dermatologists, though its use raises important ethical considerations. Herein, we focus on the potential benefits as well as the pitfalls of using ChatGPT in dermatology clinical practice.

Potential Uses of ChatGPT in Practice

A major benefit of ChatGPT is its ability to improve clinical efficiency. First, ChatGPT can provide quick access to general medical information, similar to a search engine but with more natural language processing and contextual understanding to synthesize information.⁵ This function is useful for rapid concise answers to specific and directed questions. ChatGPT also can interact with its user by asking follow-up questions to produce more precise and relevant responses; this feature may help dermatologists form more accurate differential diagnoses. Additionally, ChatGPT can increase efficiency in clinical practice by drafting generic medical documents,² including templates for after-visit summaries, postprocedure instructions, referrals, prior authorization appeal letters, and educational handouts. Importantly, increased efficiency can reduce provider burnout and lead to improved patient care. Another useful feature of ChatGPT is its ability to output information modeling human conversation. Because of this feature, ChatGPT also could be employed in clinical practice to serve as an interpreter for patients during clinic visits. Currently, the use of virtual translators can be cumbersome and subject to technical constraints. ChatGPT can provide accurate and conversational translations for patients and dermatologists, improving the patient-provider relationship.

ChatGPT also can contribute to major advancements in the field of dermatology beyond the clinical setting. Because of its ability to draw from extensive data that have already been uploaded, there are some uses of ChatGPT in a research context: to assist in finding resources for research and reviews, formulating hypotheses, drafting study protocols, and collecting large amounts of data within seconds.⁶

ChatGPT also has potential in advancing medical education. It could be used by medical schools to model interactive patient encounters to help students practice taking a patient’s history and creating differential diagnoses.⁶ This application of ChatGPT may help medical students hone their clinical skills in a low-stress environment without the restrictions that can come with hiring and training standardized patients, especially when mimicking dermatologic clinical encounters.

Other possibilities for ChatGPT in dermatologic practice include survey administration, clinical trial recruitment, and even automatic high-risk medication monitoring. Despite the many potential applications of ChatGPT in clinical practice, the question raised in each scenario is the quality, accuracy, and safety of what it produces.

Potential Pitfalls of ChatGPT in Practice and Possible Mitigation Strategies

A main concern in using ChatGPT in clinical practice is its potential to produce inaccurate or biased information. When prompted to create a research abstract based on previously published research, ChatGPT drafted abstracts that were clear and digestible but supplemented with incorrect data.⁷ A group of medical researchers who reviewed these ChatGPT-generated abstracts mistook 32% of the abstracts as having been written by human researchers. The implications of this finding are worrisome. If inaccurate or false information is used by ChatGPT in documents sent to insurance companies or patients, the patient’s safety as well as the dermatologist’s license and credibility are at stake. Thus, dermatologists looking to use ChatGPT to draft generic medical documents should actively review the output to ensure that the information is accurate. Importantly, ChatGPT also is only currently programmed with information up to 2021, limiting its access to recently published research articles and updated International Classification of Diseases, Tenth Revision codes.⁵ The continued development of ChatGPT will lead to regular updates by OpenAI that resolve this shortcoming in the future. Further, AI models may encode and perpetuate harmful stereotypes and social biases that are present in training data.⁸

When considering its potential in clinical practice, ChatGPT itself states that it can aid in clinical decision-making by processing patient information, including history, current symptoms, and biopsy and test results. This is uncharted territory, and providers who use ChatGPT at this stage to aid in decision-making should regard it similarly to information retrieved from a search engine. The information produced by ChatGPT should be used to substantiate but not definitively confirm a diagnosis or dictate management. Clinical suspicion by the dermatologist should always trump ChatGPT output. If physicians recommend ChatGPT output over their own advice, it can become a liability, as the technology is not regulated to any degree. Patients also should be cautious when seeking and following medical advice from ChatGPT, as it could be misleading or incorrect and could undermine the patient-physician relationship.⁶

Additionally, the specific use of ChatGPT to evaluate patient health records raises concerns related to patient privacy and confidentiality. Providers should never enter patient information protected by the Health Insurance Portability and Accountability Act into ChatGPT or anywhere else on the internet. Mitigation of this risk is not currently possible; ChatGPT requires more development and further understanding to even consider its integration into current electronic health records without compromising patient confidentiality.

The Bottom Line

Overall, ChatGPT has the potential to improve efficiency in clinical practice by assisting with informational searches and document drafting. Importantly, increased efficiency can reduce provider burnout and lead to improved patient care. However, dermatologists should carefully weigh the ethical issues of nonmaleficence and justice in evaluating ChatGPT for accuracy, biases, and the protection of patient confidentiality.

Finally, we asked ChatGPT on February 28, 2023, what it thinks:

User: Should dermatologists use ChatGPT in clinical practice?

ChatGPT: As an AI language model, ChatGPT can be a useful tool in dermatology clinical practice, but it should be used with caution in conjunction with other sources of information and clinical judgement.

Dermatologists should be aware of the potential benefits and risks of using ChatGPT and make informed decisions about how to integrate it into their clinical practice. It’s important to remember that ChatGPT is not a substitute for clinical expertise or human interaction with patients, and it should only be used as a supplement to enhance the quality of patient care.

Dermatologists who choose to use ChatGPT should also be aware of its limitations and potential risks, such as limited accuracy, lack of context, and liability issues if it provides incorrect information or recommendations that lead to patient harm. Dermatologists should use their professional judgement and consult with other health care professionals when making important decisions regarding patient care.