Article

Scurvy, caused by vitamin C or ascorbic acid deficiency, historically has been associated primarily with developing nations and famine; however, specific populations in industrialized nations remain at an increased risk, particularly individuals with a history of smoking, alcohol use, restrictive diet, poor oral intake, psychiatric disorders, dementia, bone marrow transplantation, gastroesophageal reflux disease, end-stage renal disease, and hospitalization.¹ Micronutrient deficiency– associated dermatoses have been linked to poor clinical outcomes in hospitalized patients.² In this case series, we report 4 hospitalized patients with scurvy, each presenting with unique comorbidities and risk factors for vitamin C deficiency (eTable).

Case Reports

Patient 1—A 50-year-old man with a 6-month history of eczema and restrictive dietary intake was admitted to the hospital for septic shock attributed to a left foot infection of 5-days’ duration. The patient had experienced unintentional weight loss with severe protein-calorie malnutrition. His dietary history was notable for selective eating behaviors, intermittent meal skipping, and vegetarianism. Mucocutaneous examination by the dermatology consult team showed exfoliative dermatitis with angular cheilitis, corkscrew hairs on the legs (eFigure 1), and scattered purpura throughout the body. The differential diagnosis included eczema exacerbation, cutaneous T-cell lymphoma/Sézary syndrome, and malnutrition-related dermatosis. Punch biopsies of the left medial knee and right lateral arm revealed impetiginized, spongiotic, psoriasiform dermatitis with papillary dermal edema. The histologic changes were consistent with malnutrition-related dermatosis. Laboratory results included low vitamin C levels (0.1 mg/dL [reference range, 0.2-2.1 mg/dL]), undetectable zinc levels (<10 μg/dL [reference range ,60-130 μg/dL]), a low platelet count (21 kμ/L [reference range, 150-400 k/μL]),low albumin levels (0.9 mg/dL (13.0 g/dL [reference range, 14.0-17.4 g/dL]). The final diagnosis was exfoliative dermatitis due to eczema and multiple nutrient deficiencies (vitamin C and zinc). The patient was treated with vitamin C 500 mg/d and was started on mirtazapine to improve his appetite. Following a 3-month hospitalization, the patient was lost to follow-up after discharge.

Patient 2—A 55-year-old woman with a history of multiple psychiatric disorders presented to the dermatology consult service with an asymptomatic purpuric eruption on the right antecubital fossa of 2 days’ duration that spread to the proximal thighs. Five days prior to presentation, she had received an allogeneic bone marrow transplant complicated by mucositis. She also reported a 4-month history of decreased appetite. At the current presentation, numerous acral, follicular based, purpuric macules and papules without associated corkscrew hairs were observed (eFigure 2). The differential diagnosis included a purpuric drug reaction, viral exanthem, acute graft-vs-host disease, neutrophilic dermatoses, and vitamin C deficiency–related dermatosis. Laboratory results revealed undetectable vitamin C levels (<0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), a low platelet count (8 k/μL [reference range, 150-400 k/μL]), normal albumin levels (3.7 g/dL [reference range, 3.5-5.0 g/dL]), and low hemoglobin (7.8 g/dL [reference range, 14.0-17.4 g/dL]). Based on the histopathologic finding of subtle interface dermatitis with purpura from a punch biopsy of the right forearm, the eruption was attributed to scurvy. Although dermatology recommended supplementation with vitamin C 1000 mg/d, the decision was deferred by the primary team and the purpura improved without it—suggesting the purpura was only partly attributable to low vitamin C.

Patient 3—A 77-year-old woman with a history of low oral intake, a low body mass index (18.15 kg/m² [reference range, 18.5-24.9]), vegetarianism, multiple psychiatric disorders, dementia, recent Clostridioides difficile colitis treated with meropenem, and recurrent idiopathic pancytopenia presented to the hospital with recurrent oral erosions and purpura of the legs for an unknown period. Physical examination by the dermatology consult team revealed superficial lip desquamation; erosions of the buccal mucosa with no involvement of the inner lip or gingiva; mild gingival hyperplasia (eFigure 3); and scaly, purpuric, follicular macules and papules on the legs. The arms and legs were devoid of hair. Laboratory results were notable for low vitamin C levels (0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), a low platelet count (28 k/μL [reference range, 150-500 k/μL]), low albumin levels (2.9 g/dL [reference range, 3.5-5.0 g/dL]), and low hemoglobin (8.8 g/dL [reference range, 12.0-16.0 g/ dL]). A punch biopsy from the left thigh revealed pauci-inflammatory interface dermatitis with purpura. Based on the clinical and histologic findings, a final diagnosis of purpuric drug eruption (from the meropenem) and scurvy was made. Nutritional support included supplementation with vitamin C 1000 mg/d. The patient’s oral erosions and purpura gradually resolved with treatment throughout her 1.5-month hospitalization.

Patient 4—A 67-year-old woman with a history of extensive cardiovascular disease, gastroesophageal reflux disease without esophagitis, end-stage renal disease not requiring hemodialysis, and loss of appetite presented with a painful pruritic eruption on the legs with groin involvement of 2 months’ duration. The patient was admitted to the hospital for worsening mental status and weakness accompanied by dark stools, hematuria, and a productive cough with red-tinged sputum. Physical examination by the dermatology consult team showed a scaly, follicular, purpuric eruption affecting the acral and intertriginous sites (eFigure 4). The patient had sparse leg hair, making it difficult to assess for hair tortuosity. A punch biopsy of the left posterior knee revealed purpuric psoriasiform dermatitis, which was consistent with nutritional deficiency– associated dermatosis. Laboratory results included low vitamin C (<0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), zinc, (58 μg/dL [reference range, 60-130 μg/dL]), and albumin levels (3.3 g/dL [reference range, 3.5-5.0 g/dL]) and a low platelet count (67 k/μL [reference range, 150- 500 k/μL]). The patient was started on supplementation with vitamin C 1000 mg/d with improvement of the purpura.

Comment

Micronutrient deficiencies may be common in hospitalized patients due to an increased prevalence of predisposing risk factors including infection, malnutrition, malabsorptive conditions, psychiatric diseases, and chronic illnesses.³ Acute-phase response in hospitalized patients also has been strongly associated with decreased plasma vitamin C levels.⁴ This phenomenon is postulated to be due to the increase in ascorbic acid uptake by circulating granulocytes in acute disease⁵; however because low vitamin C levels during the acute-phase response may not always accurately reflect total body stores, other clinical features should be assessed. Previously reported social history risk factors include smoking, alcohol consumption, marijuana use, restrictive diets, vegetarianism, and living alone.^6,7

The unifying clinical clues for scurvy in our 4 patients were a history of poor oral intake and purpura. While purpura is nonspecific and can appear after traumatic injury to the skin in elderly patients with photodamage and coagulation disorders, it also is associated with vitamin C deficiency, even with a normal platelet count, circulating von Willebrand factor levels, and prothrombin time/partial thromboplastin time.⁸ This is because vitamin C is vital in forming the collagen and extracellular matrix. Specifically, it is a cofactor for lysine and proline hydroxylase enzymes needed for the á-helix crosslinks in collagen, which are essential for its structural integrity.⁹ Collagen is a structural protein that maintains the blood vessel walls, skin, and the basement membrane. A deficiency in vitamin C leads to impairment in collagen synthesis, and insufficient collagen results in compromised connective tissue, blood vessels, and hair strength, which may lead to purpura. All of our patients had thrombocytopenia, and similarly, consideration for scurvy in hospitalized patients with risk factors for micronutrient deficiency is a must. Additional findings such as a follicular-based pattern of the purpura, hair tortuosity, restrictive dietary history, histopathology reports consistent with nutritional dermatoses, serum vitamin C levels, and improvement with vitamin C supplementation are more specific for scurvy. All of these factors can assist the clinician in detecting and confirming these micronutrient deficiencies.

Although there are no established therapeutic guidelines for scurvy, the mainstay of treatment is vitamin C repletion, either orally or parenterally. In hospitalized patients, one suggested regimen is 1000 mg of intravenous ascorbic acid daily for 3 days, followed by further supplementation with a dose of 250 to 500 mg twice daily for 1 month as needed after discharge.¹⁰ Symptom improvement occurs about 72 hours after vitamin replacement.⁸ We recommended 500 to 1000 mg of daily vitamin C supplementation for our patients.

Final Thoughts

This case series highlights the importance of maintaining a high index of suspicion for scurvy in hospitalized patients presenting with purpura, especially in a follicular-based pattern, who have multiple medical comorbidities and risk factors for vitamin C deficiency. The manifestations of scurvy are heterogeneous, necessitating a comprehensive mucocutaneous examination. The diagnosis of scurvy requires correlation of the findings from the patient history, clinical examination, laboratory results, and histopathology.

Scurvy, caused by vitamin C or ascorbic acid deficiency, historically has been associated primarily with developing nations and famine; however, specific populations in industrialized nations remain at an increased risk, particularly individuals with a history of smoking, alcohol use, restrictive diet, poor oral intake, psychiatric disorders, dementia, bone marrow transplantation, gastroesophageal reflux disease, end-stage renal disease, and hospitalization.¹ Micronutrient deficiency– associated dermatoses have been linked to poor clinical outcomes in hospitalized patients.² In this case series, we report 4 hospitalized patients with scurvy, each presenting with unique comorbidities and risk factors for vitamin C deficiency (eTable).

Case Reports

Patient 1—A 50-year-old man with a 6-month history of eczema and restrictive dietary intake was admitted to the hospital for septic shock attributed to a left foot infection of 5-days’ duration. The patient had experienced unintentional weight loss with severe protein-calorie malnutrition. His dietary history was notable for selective eating behaviors, intermittent meal skipping, and vegetarianism. Mucocutaneous examination by the dermatology consult team showed exfoliative dermatitis with angular cheilitis, corkscrew hairs on the legs (eFigure 1), and scattered purpura throughout the body. The differential diagnosis included eczema exacerbation, cutaneous T-cell lymphoma/Sézary syndrome, and malnutrition-related dermatosis. Punch biopsies of the left medial knee and right lateral arm revealed impetiginized, spongiotic, psoriasiform dermatitis with papillary dermal edema. The histologic changes were consistent with malnutrition-related dermatosis. Laboratory results included low vitamin C levels (0.1 mg/dL [reference range, 0.2-2.1 mg/dL]), undetectable zinc levels (<10 μg/dL [reference range ,60-130 μg/dL]), a low platelet count (21 kμ/L [reference range, 150-400 k/μL]),low albumin levels (0.9 mg/dL (13.0 g/dL [reference range, 14.0-17.4 g/dL]). The final diagnosis was exfoliative dermatitis due to eczema and multiple nutrient deficiencies (vitamin C and zinc). The patient was treated with vitamin C 500 mg/d and was started on mirtazapine to improve his appetite. Following a 3-month hospitalization, the patient was lost to follow-up after discharge.

Patient 2—A 55-year-old woman with a history of multiple psychiatric disorders presented to the dermatology consult service with an asymptomatic purpuric eruption on the right antecubital fossa of 2 days’ duration that spread to the proximal thighs. Five days prior to presentation, she had received an allogeneic bone marrow transplant complicated by mucositis. She also reported a 4-month history of decreased appetite. At the current presentation, numerous acral, follicular based, purpuric macules and papules without associated corkscrew hairs were observed (eFigure 2). The differential diagnosis included a purpuric drug reaction, viral exanthem, acute graft-vs-host disease, neutrophilic dermatoses, and vitamin C deficiency–related dermatosis. Laboratory results revealed undetectable vitamin C levels (<0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), a low platelet count (8 k/μL [reference range, 150-400 k/μL]), normal albumin levels (3.7 g/dL [reference range, 3.5-5.0 g/dL]), and low hemoglobin (7.8 g/dL [reference range, 14.0-17.4 g/dL]). Based on the histopathologic finding of subtle interface dermatitis with purpura from a punch biopsy of the right forearm, the eruption was attributed to scurvy. Although dermatology recommended supplementation with vitamin C 1000 mg/d, the decision was deferred by the primary team and the purpura improved without it—suggesting the purpura was only partly attributable to low vitamin C.

Patient 3—A 77-year-old woman with a history of low oral intake, a low body mass index (18.15 kg/m² [reference range, 18.5-24.9]), vegetarianism, multiple psychiatric disorders, dementia, recent Clostridioides difficile colitis treated with meropenem, and recurrent idiopathic pancytopenia presented to the hospital with recurrent oral erosions and purpura of the legs for an unknown period. Physical examination by the dermatology consult team revealed superficial lip desquamation; erosions of the buccal mucosa with no involvement of the inner lip or gingiva; mild gingival hyperplasia (eFigure 3); and scaly, purpuric, follicular macules and papules on the legs. The arms and legs were devoid of hair. Laboratory results were notable for low vitamin C levels (0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), a low platelet count (28 k/μL [reference range, 150-500 k/μL]), low albumin levels (2.9 g/dL [reference range, 3.5-5.0 g/dL]), and low hemoglobin (8.8 g/dL [reference range, 12.0-16.0 g/ dL]). A punch biopsy from the left thigh revealed pauci-inflammatory interface dermatitis with purpura. Based on the clinical and histologic findings, a final diagnosis of purpuric drug eruption (from the meropenem) and scurvy was made. Nutritional support included supplementation with vitamin C 1000 mg/d. The patient’s oral erosions and purpura gradually resolved with treatment throughout her 1.5-month hospitalization.

Patient 4—A 67-year-old woman with a history of extensive cardiovascular disease, gastroesophageal reflux disease without esophagitis, end-stage renal disease not requiring hemodialysis, and loss of appetite presented with a painful pruritic eruption on the legs with groin involvement of 2 months’ duration. The patient was admitted to the hospital for worsening mental status and weakness accompanied by dark stools, hematuria, and a productive cough with red-tinged sputum. Physical examination by the dermatology consult team showed a scaly, follicular, purpuric eruption affecting the acral and intertriginous sites (eFigure 4). The patient had sparse leg hair, making it difficult to assess for hair tortuosity. A punch biopsy of the left posterior knee revealed purpuric psoriasiform dermatitis, which was consistent with nutritional deficiency– associated dermatosis. Laboratory results included low vitamin C (<0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), zinc, (58 μg/dL [reference range, 60-130 μg/dL]), and albumin levels (3.3 g/dL [reference range, 3.5-5.0 g/dL]) and a low platelet count (67 k/μL [reference range, 150- 500 k/μL]). The patient was started on supplementation with vitamin C 1000 mg/d with improvement of the purpura.

Comment

Micronutrient deficiencies may be common in hospitalized patients due to an increased prevalence of predisposing risk factors including infection, malnutrition, malabsorptive conditions, psychiatric diseases, and chronic illnesses.³ Acute-phase response in hospitalized patients also has been strongly associated with decreased plasma vitamin C levels.⁴ This phenomenon is postulated to be due to the increase in ascorbic acid uptake by circulating granulocytes in acute disease⁵; however because low vitamin C levels during the acute-phase response may not always accurately reflect total body stores, other clinical features should be assessed. Previously reported social history risk factors include smoking, alcohol consumption, marijuana use, restrictive diets, vegetarianism, and living alone.^6,7

The unifying clinical clues for scurvy in our 4 patients were a history of poor oral intake and purpura. While purpura is nonspecific and can appear after traumatic injury to the skin in elderly patients with photodamage and coagulation disorders, it also is associated with vitamin C deficiency, even with a normal platelet count, circulating von Willebrand factor levels, and prothrombin time/partial thromboplastin time.⁸ This is because vitamin C is vital in forming the collagen and extracellular matrix. Specifically, it is a cofactor for lysine and proline hydroxylase enzymes needed for the á-helix crosslinks in collagen, which are essential for its structural integrity.⁹ Collagen is a structural protein that maintains the blood vessel walls, skin, and the basement membrane. A deficiency in vitamin C leads to impairment in collagen synthesis, and insufficient collagen results in compromised connective tissue, blood vessels, and hair strength, which may lead to purpura. All of our patients had thrombocytopenia, and similarly, consideration for scurvy in hospitalized patients with risk factors for micronutrient deficiency is a must. Additional findings such as a follicular-based pattern of the purpura, hair tortuosity, restrictive dietary history, histopathology reports consistent with nutritional dermatoses, serum vitamin C levels, and improvement with vitamin C supplementation are more specific for scurvy. All of these factors can assist the clinician in detecting and confirming these micronutrient deficiencies.

Although there are no established therapeutic guidelines for scurvy, the mainstay of treatment is vitamin C repletion, either orally or parenterally. In hospitalized patients, one suggested regimen is 1000 mg of intravenous ascorbic acid daily for 3 days, followed by further supplementation with a dose of 250 to 500 mg twice daily for 1 month as needed after discharge.¹⁰ Symptom improvement occurs about 72 hours after vitamin replacement.⁸ We recommended 500 to 1000 mg of daily vitamin C supplementation for our patients.

Final Thoughts

This case series highlights the importance of maintaining a high index of suspicion for scurvy in hospitalized patients presenting with purpura, especially in a follicular-based pattern, who have multiple medical comorbidities and risk factors for vitamin C deficiency. The manifestations of scurvy are heterogeneous, necessitating a comprehensive mucocutaneous examination. The diagnosis of scurvy requires correlation of the findings from the patient history, clinical examination, laboratory results, and histopathology.

Scurvy, caused by vitamin C or ascorbic acid deficiency, historically has been associated primarily with developing nations and famine; however, specific populations in industrialized nations remain at an increased risk, particularly individuals with a history of smoking, alcohol use, restrictive diet, poor oral intake, psychiatric disorders, dementia, bone marrow transplantation, gastroesophageal reflux disease, end-stage renal disease, and hospitalization.¹ Micronutrient deficiency– associated dermatoses have been linked to poor clinical outcomes in hospitalized patients.² In this case series, we report 4 hospitalized patients with scurvy, each presenting with unique comorbidities and risk factors for vitamin C deficiency (eTable).

Case Reports

Patient 1—A 50-year-old man with a 6-month history of eczema and restrictive dietary intake was admitted to the hospital for septic shock attributed to a left foot infection of 5-days’ duration. The patient had experienced unintentional weight loss with severe protein-calorie malnutrition. His dietary history was notable for selective eating behaviors, intermittent meal skipping, and vegetarianism. Mucocutaneous examination by the dermatology consult team showed exfoliative dermatitis with angular cheilitis, corkscrew hairs on the legs (eFigure 1), and scattered purpura throughout the body. The differential diagnosis included eczema exacerbation, cutaneous T-cell lymphoma/Sézary syndrome, and malnutrition-related dermatosis. Punch biopsies of the left medial knee and right lateral arm revealed impetiginized, spongiotic, psoriasiform dermatitis with papillary dermal edema. The histologic changes were consistent with malnutrition-related dermatosis. Laboratory results included low vitamin C levels (0.1 mg/dL [reference range, 0.2-2.1 mg/dL]), undetectable zinc levels (<10 μg/dL [reference range ,60-130 μg/dL]), a low platelet count (21 kμ/L [reference range, 150-400 k/μL]),low albumin levels (0.9 mg/dL (13.0 g/dL [reference range, 14.0-17.4 g/dL]). The final diagnosis was exfoliative dermatitis due to eczema and multiple nutrient deficiencies (vitamin C and zinc). The patient was treated with vitamin C 500 mg/d and was started on mirtazapine to improve his appetite. Following a 3-month hospitalization, the patient was lost to follow-up after discharge.

Patient 2—A 55-year-old woman with a history of multiple psychiatric disorders presented to the dermatology consult service with an asymptomatic purpuric eruption on the right antecubital fossa of 2 days’ duration that spread to the proximal thighs. Five days prior to presentation, she had received an allogeneic bone marrow transplant complicated by mucositis. She also reported a 4-month history of decreased appetite. At the current presentation, numerous acral, follicular based, purpuric macules and papules without associated corkscrew hairs were observed (eFigure 2). The differential diagnosis included a purpuric drug reaction, viral exanthem, acute graft-vs-host disease, neutrophilic dermatoses, and vitamin C deficiency–related dermatosis. Laboratory results revealed undetectable vitamin C levels (<0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), a low platelet count (8 k/μL [reference range, 150-400 k/μL]), normal albumin levels (3.7 g/dL [reference range, 3.5-5.0 g/dL]), and low hemoglobin (7.8 g/dL [reference range, 14.0-17.4 g/dL]). Based on the histopathologic finding of subtle interface dermatitis with purpura from a punch biopsy of the right forearm, the eruption was attributed to scurvy. Although dermatology recommended supplementation with vitamin C 1000 mg/d, the decision was deferred by the primary team and the purpura improved without it—suggesting the purpura was only partly attributable to low vitamin C.

Patient 3—A 77-year-old woman with a history of low oral intake, a low body mass index (18.15 kg/m² [reference range, 18.5-24.9]), vegetarianism, multiple psychiatric disorders, dementia, recent Clostridioides difficile colitis treated with meropenem, and recurrent idiopathic pancytopenia presented to the hospital with recurrent oral erosions and purpura of the legs for an unknown period. Physical examination by the dermatology consult team revealed superficial lip desquamation; erosions of the buccal mucosa with no involvement of the inner lip or gingiva; mild gingival hyperplasia (eFigure 3); and scaly, purpuric, follicular macules and papules on the legs. The arms and legs were devoid of hair. Laboratory results were notable for low vitamin C levels (0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), a low platelet count (28 k/μL [reference range, 150-500 k/μL]), low albumin levels (2.9 g/dL [reference range, 3.5-5.0 g/dL]), and low hemoglobin (8.8 g/dL [reference range, 12.0-16.0 g/ dL]). A punch biopsy from the left thigh revealed pauci-inflammatory interface dermatitis with purpura. Based on the clinical and histologic findings, a final diagnosis of purpuric drug eruption (from the meropenem) and scurvy was made. Nutritional support included supplementation with vitamin C 1000 mg/d. The patient’s oral erosions and purpura gradually resolved with treatment throughout her 1.5-month hospitalization.

Patient 4—A 67-year-old woman with a history of extensive cardiovascular disease, gastroesophageal reflux disease without esophagitis, end-stage renal disease not requiring hemodialysis, and loss of appetite presented with a painful pruritic eruption on the legs with groin involvement of 2 months’ duration. The patient was admitted to the hospital for worsening mental status and weakness accompanied by dark stools, hematuria, and a productive cough with red-tinged sputum. Physical examination by the dermatology consult team showed a scaly, follicular, purpuric eruption affecting the acral and intertriginous sites (eFigure 4). The patient had sparse leg hair, making it difficult to assess for hair tortuosity. A punch biopsy of the left posterior knee revealed purpuric psoriasiform dermatitis, which was consistent with nutritional deficiency– associated dermatosis. Laboratory results included low vitamin C (<0.1 mg/dL [reference range, 0.3-2.7 mg/dL]), zinc, (58 μg/dL [reference range, 60-130 μg/dL]), and albumin levels (3.3 g/dL [reference range, 3.5-5.0 g/dL]) and a low platelet count (67 k/μL [reference range, 150- 500 k/μL]). The patient was started on supplementation with vitamin C 1000 mg/d with improvement of the purpura.

Comment

Micronutrient deficiencies may be common in hospitalized patients due to an increased prevalence of predisposing risk factors including infection, malnutrition, malabsorptive conditions, psychiatric diseases, and chronic illnesses.³ Acute-phase response in hospitalized patients also has been strongly associated with decreased plasma vitamin C levels.⁴ This phenomenon is postulated to be due to the increase in ascorbic acid uptake by circulating granulocytes in acute disease⁵; however because low vitamin C levels during the acute-phase response may not always accurately reflect total body stores, other clinical features should be assessed. Previously reported social history risk factors include smoking, alcohol consumption, marijuana use, restrictive diets, vegetarianism, and living alone.^6,7

The unifying clinical clues for scurvy in our 4 patients were a history of poor oral intake and purpura. While purpura is nonspecific and can appear after traumatic injury to the skin in elderly patients with photodamage and coagulation disorders, it also is associated with vitamin C deficiency, even with a normal platelet count, circulating von Willebrand factor levels, and prothrombin time/partial thromboplastin time.⁸ This is because vitamin C is vital in forming the collagen and extracellular matrix. Specifically, it is a cofactor for lysine and proline hydroxylase enzymes needed for the á-helix crosslinks in collagen, which are essential for its structural integrity.⁹ Collagen is a structural protein that maintains the blood vessel walls, skin, and the basement membrane. A deficiency in vitamin C leads to impairment in collagen synthesis, and insufficient collagen results in compromised connective tissue, blood vessels, and hair strength, which may lead to purpura. All of our patients had thrombocytopenia, and similarly, consideration for scurvy in hospitalized patients with risk factors for micronutrient deficiency is a must. Additional findings such as a follicular-based pattern of the purpura, hair tortuosity, restrictive dietary history, histopathology reports consistent with nutritional dermatoses, serum vitamin C levels, and improvement with vitamin C supplementation are more specific for scurvy. All of these factors can assist the clinician in detecting and confirming these micronutrient deficiencies.

Although there are no established therapeutic guidelines for scurvy, the mainstay of treatment is vitamin C repletion, either orally or parenterally. In hospitalized patients, one suggested regimen is 1000 mg of intravenous ascorbic acid daily for 3 days, followed by further supplementation with a dose of 250 to 500 mg twice daily for 1 month as needed after discharge.¹⁰ Symptom improvement occurs about 72 hours after vitamin replacement.⁸ We recommended 500 to 1000 mg of daily vitamin C supplementation for our patients.

Final Thoughts

This case series highlights the importance of maintaining a high index of suspicion for scurvy in hospitalized patients presenting with purpura, especially in a follicular-based pattern, who have multiple medical comorbidities and risk factors for vitamin C deficiency. The manifestations of scurvy are heterogeneous, necessitating a comprehensive mucocutaneous examination. The diagnosis of scurvy requires correlation of the findings from the patient history, clinical examination, laboratory results, and histopathology.

To the Editor:

Online resources that are convenient and affordable play a crucial role in mitigating health inequality and improving patient access to health care information; however, the benefits are limited by the quality of information available, as medical misinformation can lead to patients engaging in harmful practices, making dangerous decisions, and even avoiding safe and effective treatments. In this study, we aimed to assess and compare the quality of patient guidance on dermatologic care generated by ChatGPT vs Reddit based on accuracy, appropriateness, and safety. It is essential to assess the quality and reliability of online health information to support patients in making informed decisions about their health.

The emergence and advancement of artificial intelligence and large language models such as ChatGPT present a new method for patients to access health care advice. ChatGPT can engage in conversation by accessing information from existing publicly available data on the internet, including books and websites, up to the year 2023 and providing humanlike responses with context.¹ ChatGPT’s access to a breadth of online evidence-based literature ensures the dissemination of quality information that is quick and without inherent bias, offering the potential to more closely align with health care professionals. ChatGPT’s use in dermatology by patients has shown efficacy, with a 98.87% approval rate by dermatologists scoring its ability to recommend appropriate medication for common dermatologic conditions.² However, ChatGPT has limitations when providing health care advice and has been observed to misunderstand health care standards, lack personalization, and offer incorrect references; currently, the latest publicly available version (ChatGPT 3.5) also is unable to analyze clinical images.^3,4

Reddit is an online social media forum that allows users to post questions and photographs to which anyone can reply and offer advice. Patients may find comfort in online communities where they can connect with others facing similar challenges related to their diagnosis. Within these communities, the responses often share users’ own lived experiences and offer support based on what has and has not worked for them. Prior research found that users intentionally seeking health information via Reddit are likely to implement the advice they receive even without verification of its credibility, suggesting a trust and receptibility to ideas offered on the platform.⁵ Furthermore, a study analyzing the dermatologic content of 17 dermatology related subreddits that had 1000 or more subscribers found that 70.6% of posts fell under the category of “seeking health/cosmetic advice.”⁶ Reddit users thus are vulnerable to receiving advice based on personal bias and exposing their health information to the public.

We hypothesized that ChatGPT would provide users with guidance that was more closely aligned with typical dermatologists’ advice due to its thorough analysis and compilation of diverse sources and recommendations available on the internet. We expected Reddit to yield recommendations of lesser quality and a diminished safety score, primarily due to the absence of credibility-vetting mechanisms and the influence of personal biases within the advice shared.

User-submitted posts to large dermatologic community Reddit forums representing a few of the most common skin conditions (r/eczema, r/acne, r/Folliculitis, r/SebDerm, r/Hidradenitis, r/keratosis, and r/Psoriasis) were retrospectively reviewed from January 2024 to March 2024. The most popular posts that did not include photographs were included in our study. Posts with photographs were excluded, as clinical images were not able to be uploaded to the publicly available ChatGPT 3.5. We collected real user questions about common skin conditions from Reddit forums and then asked ChatGPT to answer those same questions. We compared ChatGPT’s responses to the most upvoted Reddit comments to see how they matched up (eTable).

Each ChatGPT response and the top-rated Reddit comment were independently evaluated by a board certified dermatologist (S.A.) and a dermatology resident (A.H.K.). The quality of the ChatGPT and Reddit responses were determined by scoring the accuracy, appropriateness, safety consideration, and specificity on a 5-point Likert scale (1=low, 5=high). The 2 evaluators’ mean scores for each of the 4 categories were calculated based on adequate interrater reliability, which was tested using Cohen’s κ coefficient. Related-samples sign tests were used to compare ChatGPT and Reddit responses for each of the 4 categories. Analysis was completed using SPSS statistics software version 29.0 (IBM). The evaluators also were asked to provide qualitative feedback on the strengths and weaknesses of each response.

Our retrospective review yielded 20 total questions: 5 (25%) on atopic dermatitis, 4 (20%) on acne, 4 (20%) on hidradenitis suppurativa, 4 (20%) on psoriasis, 1 (5%) on folliculitis, 1 (5%) on keratosis pilaris, and 1 (5%) on seborrheic dermatitis. The number of posts was limited to 20 due to the extensive time required for grading each response. These 20 questions were selected from a larger pool of eligible posts based on factors such as clarity and relevance to common skin conditions. With regard to the types of questions that were asked, 6 (30%) were related to general management of a diagnosis, 5 (25%) were on treatment recommendations for symptom relief, 3 (15%) were on optimal utilization of current treatment regimens, 2 (10%) were on prescription side effects, 2 (10%) were on diagnosis presentation, 1 (5%) was on potential triggers of the diagnosis, and 1 (5%) was on natural treatment recommendations.

Mean (SD) evaluator scores for accuracy were significantly higher among ChatGPT responses compared with Reddit (4.63 [0.60] vs 2.60 [0.98])(P<.001). ChatGPT responses also were significantly higher for appropriateness compared with Reddit (4.55 [0.71] vs 2.58 [1.02])(P<.001) and safety consideration (4.88 [0.56] vs 2.80[0.97])(P <.001). There was no significant difference in mean specificity scores between ChatGPT and Reddit (4.25[1.02] vs 3.80 [0.70])(P=.096)(Figure).

For the Reddit responses, the weighted Cohen’s κ coefficient between the 2 evaluators was 0.200 (95% CI, –.089 to .489) for accuracy, 0.255 (95% CI, .014-.497) for appropriateness, 0.385 (95% CI, .176-.594) for safety consideration, and –0.024 (95% CI, –.177 to .129) for specificity. For the ChatGPT responses, the weighted Cohen’s κ coefficient between the 2 evaluators was 0.426 (95% CI, .122-.730) for accuracy, 0.571 (95% CI, .294-.849) for appropriateness, 0.655 (95% CI, .632-.678) for safety consideration, and 0.313 (95% CI, .043-.584) for specificity.

The strengths and weaknesses of the responses also were qualitatively analyzed. One commonly observed strength was ChatGPT’s frequent and appropriate recommendation for users to consult a dermatologist. In the case of atopic dermatitis—one of the more frequently asked about conditions—ChatGPT consistently emphasized evidence-based strategies such as gentle skin care and moisturization, reflecting alignment with clinical guidelines. Additionally, a common weakness of both ChatGPT and Reddit responses generally was the lack of personalized guidance and comprehensive discussion of the risks and benefits of specific treatments. It also was noted that neither platform consistently explored differential diagnoses—for example, distinguishing atopic dermatitis from conditions such as allergic contact dermatitis—limiting the diagnostic depth of the responses.

ChatGPT and Reddit can provide patients with quick and accessible health information for various dermatologic concerns. The results of our study demonstrated a significantly higher level of accuracy, appropriateness, and safety of responses generated by ChatGPT compared with human-generated responses on Reddit (P<.001). Both platforms offered similarly specific responses to user inquiries, demonstrating ChatGPT’s ability to comprehend user questions and draw from publicly available texts and Reddit users’ contributing insights based on their own first-hand experiences.

Reddit’s dermatologic forums often feature personal anecdotes and unique treatments described by individual users. Although specific to particular dermatologic concerns, such advice lacks an evidence-based standard of care. With the noted inherent trust of patients seeking guidance within Reddit communities, patients may follow unhelpful or potentially dangerous medical advice.⁵ A study examining 300 user-submitted posts on popular Reddit dermatology forums during the COVID-19 pandemic found that the mean scores for top-rated comments’ potential to be misleading or dangerous was 2.33 out of 5 on a Likert scale (95% CI, 2.18- 2.48).⁷ Dermatologists should be aware of the potential risks associated with dermatologic advice offered on Reddit and should caution patients against relying solely on this information without consulting a qualified dermatologist first.

Reddit’s open-forum design provides licensed dermatologists with the opportunity to disseminate evidence based information regarding dermatologic conditions. Currently, there is a subreddit (r/AskDocs) that allows users to post medical questions that can be answered by moderator-verified physicians. Participation from dermatologists in online communities such as this can improve the quality of dermatologic information shared online, combat misinformation, and promote safe skin care practices.

ChatGPT offers more accurate, appropriate, and safe information compared to Reddit responses, but its answers lack personalization. In a clinical setting, a personalized treatment plan from a physician can be tailored with a comprehensive discussion of the risks and benefits. Further, clinical settings allow for diagnosis and confirmation via biopsy and meticulous history taking to ensure that the diagnosis and treatment plan are accurate. While ChatGPT may be an option for seeking basic advice on dermatologic conditions, a licensed dermatologist should always be consulted for proper medical advice. Services such as telehealth may be another option to for patients with limited access to care.

Since ChatGPT 3.5 does not support the ability to upload images, our study acknowledges a limitation regarding the inclusion of Reddit posts containing photographs. Images can improve the response quality from both Reddit users and ChatGPT. While the updated ChatGPT 4o is capable of processing images, it requires a monthly subscription fee. The free version was chosen for use in this study, as this may reflect the most likely version that patients of low socioeconomic status would utilize to access dermatologic care; however, there is potential for growth and improvement of ChatGPT’s capability in providing medical advice.

This study compared the strengths and limitations of ChatGPT’s and Reddit’s responses to common dermatologic inquiries. ChatGPT and Reddit both show potential to be helpful sources of dermatologic health information; however, their current versions have many limitations and require caution and careful examination by patients of the guidance provided. Clinicians should be aware of these limitations when advising patients and emphasize the importance of consulting a licensed dermatologist for personalized, evidence-based care. For the best medical advice, it is always advisable to consult with a licensed dermatologist.

To the Editor:

Online resources that are convenient and affordable play a crucial role in mitigating health inequality and improving patient access to health care information; however, the benefits are limited by the quality of information available, as medical misinformation can lead to patients engaging in harmful practices, making dangerous decisions, and even avoiding safe and effective treatments. In this study, we aimed to assess and compare the quality of patient guidance on dermatologic care generated by ChatGPT vs Reddit based on accuracy, appropriateness, and safety. It is essential to assess the quality and reliability of online health information to support patients in making informed decisions about their health.

The emergence and advancement of artificial intelligence and large language models such as ChatGPT present a new method for patients to access health care advice. ChatGPT can engage in conversation by accessing information from existing publicly available data on the internet, including books and websites, up to the year 2023 and providing humanlike responses with context.¹ ChatGPT’s access to a breadth of online evidence-based literature ensures the dissemination of quality information that is quick and without inherent bias, offering the potential to more closely align with health care professionals. ChatGPT’s use in dermatology by patients has shown efficacy, with a 98.87% approval rate by dermatologists scoring its ability to recommend appropriate medication for common dermatologic conditions.² However, ChatGPT has limitations when providing health care advice and has been observed to misunderstand health care standards, lack personalization, and offer incorrect references; currently, the latest publicly available version (ChatGPT 3.5) also is unable to analyze clinical images.^3,4

Reddit is an online social media forum that allows users to post questions and photographs to which anyone can reply and offer advice. Patients may find comfort in online communities where they can connect with others facing similar challenges related to their diagnosis. Within these communities, the responses often share users’ own lived experiences and offer support based on what has and has not worked for them. Prior research found that users intentionally seeking health information via Reddit are likely to implement the advice they receive even without verification of its credibility, suggesting a trust and receptibility to ideas offered on the platform.⁵ Furthermore, a study analyzing the dermatologic content of 17 dermatology related subreddits that had 1000 or more subscribers found that 70.6% of posts fell under the category of “seeking health/cosmetic advice.”⁶ Reddit users thus are vulnerable to receiving advice based on personal bias and exposing their health information to the public.

We hypothesized that ChatGPT would provide users with guidance that was more closely aligned with typical dermatologists’ advice due to its thorough analysis and compilation of diverse sources and recommendations available on the internet. We expected Reddit to yield recommendations of lesser quality and a diminished safety score, primarily due to the absence of credibility-vetting mechanisms and the influence of personal biases within the advice shared.

User-submitted posts to large dermatologic community Reddit forums representing a few of the most common skin conditions (r/eczema, r/acne, r/Folliculitis, r/SebDerm, r/Hidradenitis, r/keratosis, and r/Psoriasis) were retrospectively reviewed from January 2024 to March 2024. The most popular posts that did not include photographs were included in our study. Posts with photographs were excluded, as clinical images were not able to be uploaded to the publicly available ChatGPT 3.5. We collected real user questions about common skin conditions from Reddit forums and then asked ChatGPT to answer those same questions. We compared ChatGPT’s responses to the most upvoted Reddit comments to see how they matched up (eTable).

Each ChatGPT response and the top-rated Reddit comment were independently evaluated by a board certified dermatologist (S.A.) and a dermatology resident (A.H.K.). The quality of the ChatGPT and Reddit responses were determined by scoring the accuracy, appropriateness, safety consideration, and specificity on a 5-point Likert scale (1=low, 5=high). The 2 evaluators’ mean scores for each of the 4 categories were calculated based on adequate interrater reliability, which was tested using Cohen’s κ coefficient. Related-samples sign tests were used to compare ChatGPT and Reddit responses for each of the 4 categories. Analysis was completed using SPSS statistics software version 29.0 (IBM). The evaluators also were asked to provide qualitative feedback on the strengths and weaknesses of each response.

Our retrospective review yielded 20 total questions: 5 (25%) on atopic dermatitis, 4 (20%) on acne, 4 (20%) on hidradenitis suppurativa, 4 (20%) on psoriasis, 1 (5%) on folliculitis, 1 (5%) on keratosis pilaris, and 1 (5%) on seborrheic dermatitis. The number of posts was limited to 20 due to the extensive time required for grading each response. These 20 questions were selected from a larger pool of eligible posts based on factors such as clarity and relevance to common skin conditions. With regard to the types of questions that were asked, 6 (30%) were related to general management of a diagnosis, 5 (25%) were on treatment recommendations for symptom relief, 3 (15%) were on optimal utilization of current treatment regimens, 2 (10%) were on prescription side effects, 2 (10%) were on diagnosis presentation, 1 (5%) was on potential triggers of the diagnosis, and 1 (5%) was on natural treatment recommendations.

Mean (SD) evaluator scores for accuracy were significantly higher among ChatGPT responses compared with Reddit (4.63 [0.60] vs 2.60 [0.98])(P<.001). ChatGPT responses also were significantly higher for appropriateness compared with Reddit (4.55 [0.71] vs 2.58 [1.02])(P<.001) and safety consideration (4.88 [0.56] vs 2.80[0.97])(P <.001). There was no significant difference in mean specificity scores between ChatGPT and Reddit (4.25[1.02] vs 3.80 [0.70])(P=.096)(Figure).

For the Reddit responses, the weighted Cohen’s κ coefficient between the 2 evaluators was 0.200 (95% CI, –.089 to .489) for accuracy, 0.255 (95% CI, .014-.497) for appropriateness, 0.385 (95% CI, .176-.594) for safety consideration, and –0.024 (95% CI, –.177 to .129) for specificity. For the ChatGPT responses, the weighted Cohen’s κ coefficient between the 2 evaluators was 0.426 (95% CI, .122-.730) for accuracy, 0.571 (95% CI, .294-.849) for appropriateness, 0.655 (95% CI, .632-.678) for safety consideration, and 0.313 (95% CI, .043-.584) for specificity.

The strengths and weaknesses of the responses also were qualitatively analyzed. One commonly observed strength was ChatGPT’s frequent and appropriate recommendation for users to consult a dermatologist. In the case of atopic dermatitis—one of the more frequently asked about conditions—ChatGPT consistently emphasized evidence-based strategies such as gentle skin care and moisturization, reflecting alignment with clinical guidelines. Additionally, a common weakness of both ChatGPT and Reddit responses generally was the lack of personalized guidance and comprehensive discussion of the risks and benefits of specific treatments. It also was noted that neither platform consistently explored differential diagnoses—for example, distinguishing atopic dermatitis from conditions such as allergic contact dermatitis—limiting the diagnostic depth of the responses.

ChatGPT and Reddit can provide patients with quick and accessible health information for various dermatologic concerns. The results of our study demonstrated a significantly higher level of accuracy, appropriateness, and safety of responses generated by ChatGPT compared with human-generated responses on Reddit (P<.001). Both platforms offered similarly specific responses to user inquiries, demonstrating ChatGPT’s ability to comprehend user questions and draw from publicly available texts and Reddit users’ contributing insights based on their own first-hand experiences.

Reddit’s dermatologic forums often feature personal anecdotes and unique treatments described by individual users. Although specific to particular dermatologic concerns, such advice lacks an evidence-based standard of care. With the noted inherent trust of patients seeking guidance within Reddit communities, patients may follow unhelpful or potentially dangerous medical advice.⁵ A study examining 300 user-submitted posts on popular Reddit dermatology forums during the COVID-19 pandemic found that the mean scores for top-rated comments’ potential to be misleading or dangerous was 2.33 out of 5 on a Likert scale (95% CI, 2.18- 2.48).⁷ Dermatologists should be aware of the potential risks associated with dermatologic advice offered on Reddit and should caution patients against relying solely on this information without consulting a qualified dermatologist first.

Reddit’s open-forum design provides licensed dermatologists with the opportunity to disseminate evidence based information regarding dermatologic conditions. Currently, there is a subreddit (r/AskDocs) that allows users to post medical questions that can be answered by moderator-verified physicians. Participation from dermatologists in online communities such as this can improve the quality of dermatologic information shared online, combat misinformation, and promote safe skin care practices.

ChatGPT offers more accurate, appropriate, and safe information compared to Reddit responses, but its answers lack personalization. In a clinical setting, a personalized treatment plan from a physician can be tailored with a comprehensive discussion of the risks and benefits. Further, clinical settings allow for diagnosis and confirmation via biopsy and meticulous history taking to ensure that the diagnosis and treatment plan are accurate. While ChatGPT may be an option for seeking basic advice on dermatologic conditions, a licensed dermatologist should always be consulted for proper medical advice. Services such as telehealth may be another option to for patients with limited access to care.

Since ChatGPT 3.5 does not support the ability to upload images, our study acknowledges a limitation regarding the inclusion of Reddit posts containing photographs. Images can improve the response quality from both Reddit users and ChatGPT. While the updated ChatGPT 4o is capable of processing images, it requires a monthly subscription fee. The free version was chosen for use in this study, as this may reflect the most likely version that patients of low socioeconomic status would utilize to access dermatologic care; however, there is potential for growth and improvement of ChatGPT’s capability in providing medical advice.

This study compared the strengths and limitations of ChatGPT’s and Reddit’s responses to common dermatologic inquiries. ChatGPT and Reddit both show potential to be helpful sources of dermatologic health information; however, their current versions have many limitations and require caution and careful examination by patients of the guidance provided. Clinicians should be aware of these limitations when advising patients and emphasize the importance of consulting a licensed dermatologist for personalized, evidence-based care. For the best medical advice, it is always advisable to consult with a licensed dermatologist.

To the Editor:

Online resources that are convenient and affordable play a crucial role in mitigating health inequality and improving patient access to health care information; however, the benefits are limited by the quality of information available, as medical misinformation can lead to patients engaging in harmful practices, making dangerous decisions, and even avoiding safe and effective treatments. In this study, we aimed to assess and compare the quality of patient guidance on dermatologic care generated by ChatGPT vs Reddit based on accuracy, appropriateness, and safety. It is essential to assess the quality and reliability of online health information to support patients in making informed decisions about their health.

The emergence and advancement of artificial intelligence and large language models such as ChatGPT present a new method for patients to access health care advice. ChatGPT can engage in conversation by accessing information from existing publicly available data on the internet, including books and websites, up to the year 2023 and providing humanlike responses with context.¹ ChatGPT’s access to a breadth of online evidence-based literature ensures the dissemination of quality information that is quick and without inherent bias, offering the potential to more closely align with health care professionals. ChatGPT’s use in dermatology by patients has shown efficacy, with a 98.87% approval rate by dermatologists scoring its ability to recommend appropriate medication for common dermatologic conditions.² However, ChatGPT has limitations when providing health care advice and has been observed to misunderstand health care standards, lack personalization, and offer incorrect references; currently, the latest publicly available version (ChatGPT 3.5) also is unable to analyze clinical images.^3,4

Reddit is an online social media forum that allows users to post questions and photographs to which anyone can reply and offer advice. Patients may find comfort in online communities where they can connect with others facing similar challenges related to their diagnosis. Within these communities, the responses often share users’ own lived experiences and offer support based on what has and has not worked for them. Prior research found that users intentionally seeking health information via Reddit are likely to implement the advice they receive even without verification of its credibility, suggesting a trust and receptibility to ideas offered on the platform.⁵ Furthermore, a study analyzing the dermatologic content of 17 dermatology related subreddits that had 1000 or more subscribers found that 70.6% of posts fell under the category of “seeking health/cosmetic advice.”⁶ Reddit users thus are vulnerable to receiving advice based on personal bias and exposing their health information to the public.

We hypothesized that ChatGPT would provide users with guidance that was more closely aligned with typical dermatologists’ advice due to its thorough analysis and compilation of diverse sources and recommendations available on the internet. We expected Reddit to yield recommendations of lesser quality and a diminished safety score, primarily due to the absence of credibility-vetting mechanisms and the influence of personal biases within the advice shared.

User-submitted posts to large dermatologic community Reddit forums representing a few of the most common skin conditions (r/eczema, r/acne, r/Folliculitis, r/SebDerm, r/Hidradenitis, r/keratosis, and r/Psoriasis) were retrospectively reviewed from January 2024 to March 2024. The most popular posts that did not include photographs were included in our study. Posts with photographs were excluded, as clinical images were not able to be uploaded to the publicly available ChatGPT 3.5. We collected real user questions about common skin conditions from Reddit forums and then asked ChatGPT to answer those same questions. We compared ChatGPT’s responses to the most upvoted Reddit comments to see how they matched up (eTable).

Each ChatGPT response and the top-rated Reddit comment were independently evaluated by a board certified dermatologist (S.A.) and a dermatology resident (A.H.K.). The quality of the ChatGPT and Reddit responses were determined by scoring the accuracy, appropriateness, safety consideration, and specificity on a 5-point Likert scale (1=low, 5=high). The 2 evaluators’ mean scores for each of the 4 categories were calculated based on adequate interrater reliability, which was tested using Cohen’s κ coefficient. Related-samples sign tests were used to compare ChatGPT and Reddit responses for each of the 4 categories. Analysis was completed using SPSS statistics software version 29.0 (IBM). The evaluators also were asked to provide qualitative feedback on the strengths and weaknesses of each response.

Our retrospective review yielded 20 total questions: 5 (25%) on atopic dermatitis, 4 (20%) on acne, 4 (20%) on hidradenitis suppurativa, 4 (20%) on psoriasis, 1 (5%) on folliculitis, 1 (5%) on keratosis pilaris, and 1 (5%) on seborrheic dermatitis. The number of posts was limited to 20 due to the extensive time required for grading each response. These 20 questions were selected from a larger pool of eligible posts based on factors such as clarity and relevance to common skin conditions. With regard to the types of questions that were asked, 6 (30%) were related to general management of a diagnosis, 5 (25%) were on treatment recommendations for symptom relief, 3 (15%) were on optimal utilization of current treatment regimens, 2 (10%) were on prescription side effects, 2 (10%) were on diagnosis presentation, 1 (5%) was on potential triggers of the diagnosis, and 1 (5%) was on natural treatment recommendations.

Mean (SD) evaluator scores for accuracy were significantly higher among ChatGPT responses compared with Reddit (4.63 [0.60] vs 2.60 [0.98])(P<.001). ChatGPT responses also were significantly higher for appropriateness compared with Reddit (4.55 [0.71] vs 2.58 [1.02])(P<.001) and safety consideration (4.88 [0.56] vs 2.80[0.97])(P <.001). There was no significant difference in mean specificity scores between ChatGPT and Reddit (4.25[1.02] vs 3.80 [0.70])(P=.096)(Figure).

For the Reddit responses, the weighted Cohen’s κ coefficient between the 2 evaluators was 0.200 (95% CI, –.089 to .489) for accuracy, 0.255 (95% CI, .014-.497) for appropriateness, 0.385 (95% CI, .176-.594) for safety consideration, and –0.024 (95% CI, –.177 to .129) for specificity. For the ChatGPT responses, the weighted Cohen’s κ coefficient between the 2 evaluators was 0.426 (95% CI, .122-.730) for accuracy, 0.571 (95% CI, .294-.849) for appropriateness, 0.655 (95% CI, .632-.678) for safety consideration, and 0.313 (95% CI, .043-.584) for specificity.

The strengths and weaknesses of the responses also were qualitatively analyzed. One commonly observed strength was ChatGPT’s frequent and appropriate recommendation for users to consult a dermatologist. In the case of atopic dermatitis—one of the more frequently asked about conditions—ChatGPT consistently emphasized evidence-based strategies such as gentle skin care and moisturization, reflecting alignment with clinical guidelines. Additionally, a common weakness of both ChatGPT and Reddit responses generally was the lack of personalized guidance and comprehensive discussion of the risks and benefits of specific treatments. It also was noted that neither platform consistently explored differential diagnoses—for example, distinguishing atopic dermatitis from conditions such as allergic contact dermatitis—limiting the diagnostic depth of the responses.

ChatGPT and Reddit can provide patients with quick and accessible health information for various dermatologic concerns. The results of our study demonstrated a significantly higher level of accuracy, appropriateness, and safety of responses generated by ChatGPT compared with human-generated responses on Reddit (P<.001). Both platforms offered similarly specific responses to user inquiries, demonstrating ChatGPT’s ability to comprehend user questions and draw from publicly available texts and Reddit users’ contributing insights based on their own first-hand experiences.

Reddit’s dermatologic forums often feature personal anecdotes and unique treatments described by individual users. Although specific to particular dermatologic concerns, such advice lacks an evidence-based standard of care. With the noted inherent trust of patients seeking guidance within Reddit communities, patients may follow unhelpful or potentially dangerous medical advice.⁵ A study examining 300 user-submitted posts on popular Reddit dermatology forums during the COVID-19 pandemic found that the mean scores for top-rated comments’ potential to be misleading or dangerous was 2.33 out of 5 on a Likert scale (95% CI, 2.18- 2.48).⁷ Dermatologists should be aware of the potential risks associated with dermatologic advice offered on Reddit and should caution patients against relying solely on this information without consulting a qualified dermatologist first.

Reddit’s open-forum design provides licensed dermatologists with the opportunity to disseminate evidence based information regarding dermatologic conditions. Currently, there is a subreddit (r/AskDocs) that allows users to post medical questions that can be answered by moderator-verified physicians. Participation from dermatologists in online communities such as this can improve the quality of dermatologic information shared online, combat misinformation, and promote safe skin care practices.

ChatGPT offers more accurate, appropriate, and safe information compared to Reddit responses, but its answers lack personalization. In a clinical setting, a personalized treatment plan from a physician can be tailored with a comprehensive discussion of the risks and benefits. Further, clinical settings allow for diagnosis and confirmation via biopsy and meticulous history taking to ensure that the diagnosis and treatment plan are accurate. While ChatGPT may be an option for seeking basic advice on dermatologic conditions, a licensed dermatologist should always be consulted for proper medical advice. Services such as telehealth may be another option to for patients with limited access to care.

Since ChatGPT 3.5 does not support the ability to upload images, our study acknowledges a limitation regarding the inclusion of Reddit posts containing photographs. Images can improve the response quality from both Reddit users and ChatGPT. While the updated ChatGPT 4o is capable of processing images, it requires a monthly subscription fee. The free version was chosen for use in this study, as this may reflect the most likely version that patients of low socioeconomic status would utilize to access dermatologic care; however, there is potential for growth and improvement of ChatGPT’s capability in providing medical advice.

This study compared the strengths and limitations of ChatGPT’s and Reddit’s responses to common dermatologic inquiries. ChatGPT and Reddit both show potential to be helpful sources of dermatologic health information; however, their current versions have many limitations and require caution and careful examination by patients of the guidance provided. Clinicians should be aware of these limitations when advising patients and emphasize the importance of consulting a licensed dermatologist for personalized, evidence-based care. For the best medical advice, it is always advisable to consult with a licensed dermatologist.

A 90-year-old man presented for evaluation of a large basal cell carcinoma (BCC) involving the nasal region. The lesion was a 7×4-cm pink, crusted, verrucous plaque covering the majority of the nose and extending onto the malar cheeks that originally had been biopsied 26 years prior, and repeat biopsy was performed 3 years prior. Results from both biopsies were consistent with BCC. The patient had avoided treatment for many years due to fear of losing his nose.

Given the size and location of the tumor, surgical intervention posed major challenges for both functional and cosmetic outcomes. After careful consideration and discussion of treatment options, which included Mohs micrographic surgery (MMS), wide local excision, radiation therapy, and systemic therapy, the decision was made to start the patient on vismodegib 150 mg once daily as well as L-carnitine 330 mg twice daily to help with muscle cramps. A baseline complete metabolic panel with an estimated glomerular filtration rate was unremarkable.

By the patient’s first follow-up visit after 2 months of therapy, he had experienced marked clinical improvement with notable regression of the tumor (Figure 1). He reported no adverse effects (eg, muscle cramps, dysgeusia, hair loss, nausea, vomiting, diarrhea). At subsequent follow-up visits, the patient continued to demonstrate clinical improvement. His only adverse effect was a 6-kg weight loss over the prior 6 months of initiating therapy despite no changes in taste or appetite. His dose of vismodegib was decreased to an alternative regimen of 150 mg daily for the first 2 weeks of each month with a drug holiday the rest of the month. Since that time, his weight has stabilized and he has continued with treatment.

Comment

Vismodegib was the first Hedgehog (Hh) inhibitor approved by the US Food and Drug Administration for management of selected locally advanced and metastatic BCC in adults.^1,2 Genetic alterations in the Hh signaling pathway resulting in proliferation of basal cells are present in nearly all BCCs.² In normal function, when the Hh ligand is absent at the patched (PTCH1) receptor, smoothened (SMO) is inhibited. When Hh ligand binds PTCH1, SMO is activated with downstream effects of triggering cell survival and proliferation in the nucleus via GLI. Loss of function mutations at the PTCH1 receptor or SMO-activating mutations lead to the same downstream effects, even when Hh ligand is absent.¹ This allows for unregulated tumor growth.

Vismodegib is a small-molecule SMO inhibitor that blocks aberrant activation of the Hh signaling pathway, thereby slowing the growth of BCCs (Figure 2).^3,4 Vismodegib and sonidegib have been used to treat patients with basal cell nevus syndrome as well as metastatic or locally advanced BCCs. At least 50% of advanced BCCs develop resistance to vismodegib, commonly via acquiring mutations in SMO.⁴

Basal cell carcinoma can be classified as low or high risk based on risk for recurrence. First-line treatments for low-risk BCC are surgical excision, electrodessication and curettage, and MMS.⁴ Second-line treatment includes radiation therapy. High-risk tumors include those involving anatomic locations of Area H near the eyelids, nose, ears, hands, feet, or genitals in addition to tumors with an aggressive histologic subtype.^4,5 First-line treatments for high-risk BCC are MMS or surgical excision. Second-line treatments are radiation therapy or systemic therapy, such as vismodegib.⁴

Although Hh inhibitors are not a first-line treatment, our case highlights vismodegib’s effectiveness in the management of a large unresectable BCC on the nose of an elderly patient. Our patient opted out of surgical first-line options due to functional and cosmetic concerns.⁴ He also declined radiation treatment due to financial cost and difficulty with transportation. The patient chose to pursue systemic vismodegib therapy through shared decision-making with dermatology. Vismodegib treatment alone granted our patient a highly remarkable result.

There are limited clinical data on the effectiveness and safety profile of vismodegib in elderly patients, even though this is a high-risk population for BCC.⁶ In a study that categorized responses to vismodegib in 13 patients with canthal BCC, 5 experienced a complete clinical response (defined as complete regression of the tumor), and 8 achieved partial clinical response (defined as regression but not to the extent of a complete response).⁷ Our patient’s successful response is notable, as it reinforces vismodegib’s effectiveness as a treatment option for BCC in a sensitive facial area. In addition, our patient’s minimal adverse effect profile is evidence in support of establishing visogemib’s role as a viable treatment option in advanced BCC in the elderly.

Alternative dosing regimens of vismodegib involve the use of drug holidays.⁸ Utilizing a regimen of 1 week with and 3 weeks without vismodegib for 5 to 14 cycles has led to the resolution of BCC with decreased adverse effects.⁸ Furthermore, the MIKIE study demonstrated the efficacy of 2 dosing regimens: 12 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 12 weeks of vismodegib 150 mg and 24 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 8 weeks of vismodegib 150 mg.⁹ Both regimens appeared viable to treat BCC in patients who were at risk for treatment discontinuation due to adverse effects.¹⁰

One adverse effect associated with vismodegib is muscle cramps, which are a potential cause of treatment discontinuation. The mechanism by which vismodegib causes cramps is not fully understood but is attributed to contractions from Ca²⁺ influx into muscle cells and a lack of adenosine triphosphate to allow muscle relaxation.¹¹ This is due to vismodegib’s inhibition of the SMO signaling pathway and activation of the SMO–Ca2+/ AMP-related kinase axis.¹² L-carnitine can be used as an adjuvant with vismodegib to address this adverse effect. L-carnitine is found in muscle cells, where its role is to produce energy by utilizing fatty acids.¹³ It is hypothesized that L-carnitine helps prevent cramps through production of adenosine triphosphate via fatty acid Β-oxidation that aids in stabilizing the sarcolemma and promoting muscle relaxation in skeletal muscle.^13,14 Evidence suggests that making L-carnitine a common adjuvant to vismodegib can aid in preventing this adverse effect.

Vismodegib can be an effective treatment option for large nasal BCCs that are difficult to resect. Our case demonstrates both clinical efficacy and a favorable safety profile in an elderly patient. Further studies and long-term follow-up are warranted to establish the role of vismodegib in the evolving landscape of BCC management.

A 90-year-old man presented for evaluation of a large basal cell carcinoma (BCC) involving the nasal region. The lesion was a 7×4-cm pink, crusted, verrucous plaque covering the majority of the nose and extending onto the malar cheeks that originally had been biopsied 26 years prior, and repeat biopsy was performed 3 years prior. Results from both biopsies were consistent with BCC. The patient had avoided treatment for many years due to fear of losing his nose.

Given the size and location of the tumor, surgical intervention posed major challenges for both functional and cosmetic outcomes. After careful consideration and discussion of treatment options, which included Mohs micrographic surgery (MMS), wide local excision, radiation therapy, and systemic therapy, the decision was made to start the patient on vismodegib 150 mg once daily as well as L-carnitine 330 mg twice daily to help with muscle cramps. A baseline complete metabolic panel with an estimated glomerular filtration rate was unremarkable.

By the patient’s first follow-up visit after 2 months of therapy, he had experienced marked clinical improvement with notable regression of the tumor (Figure 1). He reported no adverse effects (eg, muscle cramps, dysgeusia, hair loss, nausea, vomiting, diarrhea). At subsequent follow-up visits, the patient continued to demonstrate clinical improvement. His only adverse effect was a 6-kg weight loss over the prior 6 months of initiating therapy despite no changes in taste or appetite. His dose of vismodegib was decreased to an alternative regimen of 150 mg daily for the first 2 weeks of each month with a drug holiday the rest of the month. Since that time, his weight has stabilized and he has continued with treatment.

Comment

Vismodegib was the first Hedgehog (Hh) inhibitor approved by the US Food and Drug Administration for management of selected locally advanced and metastatic BCC in adults.^1,2 Genetic alterations in the Hh signaling pathway resulting in proliferation of basal cells are present in nearly all BCCs.² In normal function, when the Hh ligand is absent at the patched (PTCH1) receptor, smoothened (SMO) is inhibited. When Hh ligand binds PTCH1, SMO is activated with downstream effects of triggering cell survival and proliferation in the nucleus via GLI. Loss of function mutations at the PTCH1 receptor or SMO-activating mutations lead to the same downstream effects, even when Hh ligand is absent.¹ This allows for unregulated tumor growth.

Vismodegib is a small-molecule SMO inhibitor that blocks aberrant activation of the Hh signaling pathway, thereby slowing the growth of BCCs (Figure 2).^3,4 Vismodegib and sonidegib have been used to treat patients with basal cell nevus syndrome as well as metastatic or locally advanced BCCs. At least 50% of advanced BCCs develop resistance to vismodegib, commonly via acquiring mutations in SMO.⁴

Basal cell carcinoma can be classified as low or high risk based on risk for recurrence. First-line treatments for low-risk BCC are surgical excision, electrodessication and curettage, and MMS.⁴ Second-line treatment includes radiation therapy. High-risk tumors include those involving anatomic locations of Area H near the eyelids, nose, ears, hands, feet, or genitals in addition to tumors with an aggressive histologic subtype.^4,5 First-line treatments for high-risk BCC are MMS or surgical excision. Second-line treatments are radiation therapy or systemic therapy, such as vismodegib.⁴

Although Hh inhibitors are not a first-line treatment, our case highlights vismodegib’s effectiveness in the management of a large unresectable BCC on the nose of an elderly patient. Our patient opted out of surgical first-line options due to functional and cosmetic concerns.⁴ He also declined radiation treatment due to financial cost and difficulty with transportation. The patient chose to pursue systemic vismodegib therapy through shared decision-making with dermatology. Vismodegib treatment alone granted our patient a highly remarkable result.

There are limited clinical data on the effectiveness and safety profile of vismodegib in elderly patients, even though this is a high-risk population for BCC.⁶ In a study that categorized responses to vismodegib in 13 patients with canthal BCC, 5 experienced a complete clinical response (defined as complete regression of the tumor), and 8 achieved partial clinical response (defined as regression but not to the extent of a complete response).⁷ Our patient’s successful response is notable, as it reinforces vismodegib’s effectiveness as a treatment option for BCC in a sensitive facial area. In addition, our patient’s minimal adverse effect profile is evidence in support of establishing visogemib’s role as a viable treatment option in advanced BCC in the elderly.

Alternative dosing regimens of vismodegib involve the use of drug holidays.⁸ Utilizing a regimen of 1 week with and 3 weeks without vismodegib for 5 to 14 cycles has led to the resolution of BCC with decreased adverse effects.⁸ Furthermore, the MIKIE study demonstrated the efficacy of 2 dosing regimens: 12 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 12 weeks of vismodegib 150 mg and 24 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 8 weeks of vismodegib 150 mg.⁹ Both regimens appeared viable to treat BCC in patients who were at risk for treatment discontinuation due to adverse effects.¹⁰

One adverse effect associated with vismodegib is muscle cramps, which are a potential cause of treatment discontinuation. The mechanism by which vismodegib causes cramps is not fully understood but is attributed to contractions from Ca²⁺ influx into muscle cells and a lack of adenosine triphosphate to allow muscle relaxation.¹¹ This is due to vismodegib’s inhibition of the SMO signaling pathway and activation of the SMO–Ca2+/ AMP-related kinase axis.¹² L-carnitine can be used as an adjuvant with vismodegib to address this adverse effect. L-carnitine is found in muscle cells, where its role is to produce energy by utilizing fatty acids.¹³ It is hypothesized that L-carnitine helps prevent cramps through production of adenosine triphosphate via fatty acid Β-oxidation that aids in stabilizing the sarcolemma and promoting muscle relaxation in skeletal muscle.^13,14 Evidence suggests that making L-carnitine a common adjuvant to vismodegib can aid in preventing this adverse effect.

Vismodegib can be an effective treatment option for large nasal BCCs that are difficult to resect. Our case demonstrates both clinical efficacy and a favorable safety profile in an elderly patient. Further studies and long-term follow-up are warranted to establish the role of vismodegib in the evolving landscape of BCC management.

A 90-year-old man presented for evaluation of a large basal cell carcinoma (BCC) involving the nasal region. The lesion was a 7×4-cm pink, crusted, verrucous plaque covering the majority of the nose and extending onto the malar cheeks that originally had been biopsied 26 years prior, and repeat biopsy was performed 3 years prior. Results from both biopsies were consistent with BCC. The patient had avoided treatment for many years due to fear of losing his nose.

Given the size and location of the tumor, surgical intervention posed major challenges for both functional and cosmetic outcomes. After careful consideration and discussion of treatment options, which included Mohs micrographic surgery (MMS), wide local excision, radiation therapy, and systemic therapy, the decision was made to start the patient on vismodegib 150 mg once daily as well as L-carnitine 330 mg twice daily to help with muscle cramps. A baseline complete metabolic panel with an estimated glomerular filtration rate was unremarkable.

By the patient’s first follow-up visit after 2 months of therapy, he had experienced marked clinical improvement with notable regression of the tumor (Figure 1). He reported no adverse effects (eg, muscle cramps, dysgeusia, hair loss, nausea, vomiting, diarrhea). At subsequent follow-up visits, the patient continued to demonstrate clinical improvement. His only adverse effect was a 6-kg weight loss over the prior 6 months of initiating therapy despite no changes in taste or appetite. His dose of vismodegib was decreased to an alternative regimen of 150 mg daily for the first 2 weeks of each month with a drug holiday the rest of the month. Since that time, his weight has stabilized and he has continued with treatment.

Comment

Vismodegib was the first Hedgehog (Hh) inhibitor approved by the US Food and Drug Administration for management of selected locally advanced and metastatic BCC in adults.^1,2 Genetic alterations in the Hh signaling pathway resulting in proliferation of basal cells are present in nearly all BCCs.² In normal function, when the Hh ligand is absent at the patched (PTCH1) receptor, smoothened (SMO) is inhibited. When Hh ligand binds PTCH1, SMO is activated with downstream effects of triggering cell survival and proliferation in the nucleus via GLI. Loss of function mutations at the PTCH1 receptor or SMO-activating mutations lead to the same downstream effects, even when Hh ligand is absent.¹ This allows for unregulated tumor growth.

Vismodegib is a small-molecule SMO inhibitor that blocks aberrant activation of the Hh signaling pathway, thereby slowing the growth of BCCs (Figure 2).^3,4 Vismodegib and sonidegib have been used to treat patients with basal cell nevus syndrome as well as metastatic or locally advanced BCCs. At least 50% of advanced BCCs develop resistance to vismodegib, commonly via acquiring mutations in SMO.⁴

Basal cell carcinoma can be classified as low or high risk based on risk for recurrence. First-line treatments for low-risk BCC are surgical excision, electrodessication and curettage, and MMS.⁴ Second-line treatment includes radiation therapy. High-risk tumors include those involving anatomic locations of Area H near the eyelids, nose, ears, hands, feet, or genitals in addition to tumors with an aggressive histologic subtype.^4,5 First-line treatments for high-risk BCC are MMS or surgical excision. Second-line treatments are radiation therapy or systemic therapy, such as vismodegib.⁴

Although Hh inhibitors are not a first-line treatment, our case highlights vismodegib’s effectiveness in the management of a large unresectable BCC on the nose of an elderly patient. Our patient opted out of surgical first-line options due to functional and cosmetic concerns.⁴ He also declined radiation treatment due to financial cost and difficulty with transportation. The patient chose to pursue systemic vismodegib therapy through shared decision-making with dermatology. Vismodegib treatment alone granted our patient a highly remarkable result.

There are limited clinical data on the effectiveness and safety profile of vismodegib in elderly patients, even though this is a high-risk population for BCC.⁶ In a study that categorized responses to vismodegib in 13 patients with canthal BCC, 5 experienced a complete clinical response (defined as complete regression of the tumor), and 8 achieved partial clinical response (defined as regression but not to the extent of a complete response).⁷ Our patient’s successful response is notable, as it reinforces vismodegib’s effectiveness as a treatment option for BCC in a sensitive facial area. In addition, our patient’s minimal adverse effect profile is evidence in support of establishing visogemib’s role as a viable treatment option in advanced BCC in the elderly.

Alternative dosing regimens of vismodegib involve the use of drug holidays.⁸ Utilizing a regimen of 1 week with and 3 weeks without vismodegib for 5 to 14 cycles has led to the resolution of BCC with decreased adverse effects.⁸ Furthermore, the MIKIE study demonstrated the efficacy of 2 dosing regimens: 12 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 12 weeks of vismodegib 150 mg and 24 weeks of vismodegib 150 mg followed by 3 cycles of 8 placebo weeks and 8 weeks of vismodegib 150 mg.⁹ Both regimens appeared viable to treat BCC in patients who were at risk for treatment discontinuation due to adverse effects.¹⁰

One adverse effect associated with vismodegib is muscle cramps, which are a potential cause of treatment discontinuation. The mechanism by which vismodegib causes cramps is not fully understood but is attributed to contractions from Ca²⁺ influx into muscle cells and a lack of adenosine triphosphate to allow muscle relaxation.¹¹ This is due to vismodegib’s inhibition of the SMO signaling pathway and activation of the SMO–Ca2+/ AMP-related kinase axis.¹² L-carnitine can be used as an adjuvant with vismodegib to address this adverse effect. L-carnitine is found in muscle cells, where its role is to produce energy by utilizing fatty acids.¹³ It is hypothesized that L-carnitine helps prevent cramps through production of adenosine triphosphate via fatty acid Β-oxidation that aids in stabilizing the sarcolemma and promoting muscle relaxation in skeletal muscle.^13,14 Evidence suggests that making L-carnitine a common adjuvant to vismodegib can aid in preventing this adverse effect.

Vismodegib can be an effective treatment option for large nasal BCCs that are difficult to resect. Our case demonstrates both clinical efficacy and a favorable safety profile in an elderly patient. Further studies and long-term follow-up are warranted to establish the role of vismodegib in the evolving landscape of BCC management.

THE DIAGNOSIS: Syphilis

The differential diagnosis of oral lesions can be complex; in our patient, we considered conditions such as pyogenic granuloma, herpes simplex virus, and syphilis, despite the presence of pain. Immunohistochemical staining for spirochete antigens was positive, and serologic confirmation through a positive rapid plasma reagin (RPR) test confirmed the diagnosis of primary syphilis. The patient was promptly referred back to the primary care physician for treatment with intramuscular penicillin, leading to resolution of the lesion. At 3 months’ follow-up in our clinic, the lesion was fully resolved.

A primary syphilitic chancre is the initial lesion caused by Treponema pallidum, typically manifesting as a painless ulcer at the infection site, usually in the genital area; however, chancres also may manifest in other locations (eg, the anus or oral cavity) due to direct contact with infectious lesions on another individual. Our case represents an atypical presentation of an oral syphilitic chancre.

Syphilis is a sexually transmitted infection with various clinical manifestations. It is crucial to consider syphilis in the differential diagnosis of ulcerative lesions even when pain is present, especially in high-risk individuals such as those who engage in unprotected sex.^1,2 Oral syphilitic chancres have been documented in the medical literature for more than a century, underscoring the importance of maintaining a high index of suspicion for diagnosis and a low threshold for obtaining an RPR test to facilitate early detection and treatment.^2,3 Notably, the prevalence of syphilis is higher in men who have sex with men, particularly among those who engage in unprotected oral and anal sex. Increased screening and early treatment are essential to control the spread of disease within all populations. Doxycycline postexposure prophylaxis (doxyPEP) is used as a preventive measure for syphilis, chlamydia, and gonorrhea.⁴ This regimen consists of 200 mg of doxycycline taken within 24 hours but no later than 72 hours after unprotected anal, vaginal, or oral sex.

Our case highlights the importance of considering the differential diagnosis of oral ulcers, particularly in high-risk populations such as men who have sex with men. Prompt diagnosis, effective treatment, and preventive strategies such as doxyPEP are essential for controlling syphilis. Comprehensive patient education and regular follow-up appointments are critical components of successful management.

The United States has experienced a considerable rise in primary and congenital syphilis cases, with an 80% increase between 2018 and 2022.⁶ Serologic testing is the primary method for diagnosing, staging, and managing syphilis. Sexually active patients with suspected syphilis or unexplained symptoms should undergo testing. Prompt diagnosis and treatment can prevent systemic complications, including ocular involvement and permanent blindness.

Syphilis is transmitted through direct contact with a syphilitic ulcer or saliva or blood from an infected individual. Oral syphilitic ulcers can develop on the lips, tongue, oral mucosa, and tonsils. Chancres can range from a few millimeters to several centimeters, with an incubation period of 10 to 90 days (average, 21 days). The chancre lasts 3 to 6 weeks and heals spontaneously. Without treatment, primary syphilis can progress to secondary syphilis, characterized by a papulosquamous eruption and mucosal involvement, and potentially tertiary syphilis, which can affect the central nervous system, heart, bones, and skin.⁷

Immunocompromised patients, especially those diagnosed with HIV, face increased risks including altered clinical presentations (eg, multiple or deep chancres), delayed healing, overlapping stages of disease, and increased severity of organ involvement. All sexually active individuals should be screened for syphilis every 3 to 6 months, particularly those with unexplained oral ulcers.

Serologic testing is fundamental for syphilis diagnosis and management. Nontreponemal tests such as RPR and treponemal tests such as the fluorescent treponemal antibody absorption test provide comprehensive diagnostic information. Early diagnosis and empiric treatment are crucial in suspected cases. Ocular screening is recommended for suspected or confirmed syphilis cases.⁷

Management of syphilis includes treating all sexual partners and providing thorough patient education on the disease. Monitoring for the Jarisch-Herxheimer reaction—an acute febrile reaction following penicillin therapy—is important, especially in pregnant patients.5 Serologic evaluation at 6 and 12 months posttreatment is recommended, with more frequent evaluations if follow-up is uncertain, particularly for those with inconsistent access to health care or in whom reinfection is suspected. Guidelines from the Centers for Disease Control and Prevention advocate for intramuscular penicillin G benzathine as the preferred treatment, with specific dosing for adults and children.⁷ Due to the ongoing bicillin shortage, alternatives such as extencilline have temporarily been allowed for use in the United States.⁸

The rising incidence of syphilis in the United States underscores the critical need for enhanced public health initiatives focusing on education, screening, and early intervention. Comprehensive sexual education that includes information about syphilis and other sexually transmitted infections, proper use of prophylactic measures such as condoms, and the benefits of doxyPEP can considerably reduce transmission rates. Health care providers should routinely discuss these preventive measures with their patients, especially those in high-risk groups.

Our case highlights the importance of considering syphilis in the differential diagnosis of oral ulcers, particularly in high-risk populations. Timely diagnosis, effective treatment, and preventive measures such as doxyPEP are essential for managing and controlling syphilis. The rising incidence of syphilis in the United States warrants increased screening, patient education, and public health interventions to address this notable health challenge. The syphilis crisis calls for coordinated efforts from health care providers, public health officials, and community leaders to curb the spread of this infection and protect public health.

THE DIAGNOSIS: Syphilis

The differential diagnosis of oral lesions can be complex; in our patient, we considered conditions such as pyogenic granuloma, herpes simplex virus, and syphilis, despite the presence of pain. Immunohistochemical staining for spirochete antigens was positive, and serologic confirmation through a positive rapid plasma reagin (RPR) test confirmed the diagnosis of primary syphilis. The patient was promptly referred back to the primary care physician for treatment with intramuscular penicillin, leading to resolution of the lesion. At 3 months’ follow-up in our clinic, the lesion was fully resolved.

A primary syphilitic chancre is the initial lesion caused by Treponema pallidum, typically manifesting as a painless ulcer at the infection site, usually in the genital area; however, chancres also may manifest in other locations (eg, the anus or oral cavity) due to direct contact with infectious lesions on another individual. Our case represents an atypical presentation of an oral syphilitic chancre.

Syphilis is a sexually transmitted infection with various clinical manifestations. It is crucial to consider syphilis in the differential diagnosis of ulcerative lesions even when pain is present, especially in high-risk individuals such as those who engage in unprotected sex.^1,2 Oral syphilitic chancres have been documented in the medical literature for more than a century, underscoring the importance of maintaining a high index of suspicion for diagnosis and a low threshold for obtaining an RPR test to facilitate early detection and treatment.^2,3 Notably, the prevalence of syphilis is higher in men who have sex with men, particularly among those who engage in unprotected oral and anal sex. Increased screening and early treatment are essential to control the spread of disease within all populations. Doxycycline postexposure prophylaxis (doxyPEP) is used as a preventive measure for syphilis, chlamydia, and gonorrhea.⁴ This regimen consists of 200 mg of doxycycline taken within 24 hours but no later than 72 hours after unprotected anal, vaginal, or oral sex.

Our case highlights the importance of considering the differential diagnosis of oral ulcers, particularly in high-risk populations such as men who have sex with men. Prompt diagnosis, effective treatment, and preventive strategies such as doxyPEP are essential for controlling syphilis. Comprehensive patient education and regular follow-up appointments are critical components of successful management.

The United States has experienced a considerable rise in primary and congenital syphilis cases, with an 80% increase between 2018 and 2022.⁶ Serologic testing is the primary method for diagnosing, staging, and managing syphilis. Sexually active patients with suspected syphilis or unexplained symptoms should undergo testing. Prompt diagnosis and treatment can prevent systemic complications, including ocular involvement and permanent blindness.

Syphilis is transmitted through direct contact with a syphilitic ulcer or saliva or blood from an infected individual. Oral syphilitic ulcers can develop on the lips, tongue, oral mucosa, and tonsils. Chancres can range from a few millimeters to several centimeters, with an incubation period of 10 to 90 days (average, 21 days). The chancre lasts 3 to 6 weeks and heals spontaneously. Without treatment, primary syphilis can progress to secondary syphilis, characterized by a papulosquamous eruption and mucosal involvement, and potentially tertiary syphilis, which can affect the central nervous system, heart, bones, and skin.⁷

Immunocompromised patients, especially those diagnosed with HIV, face increased risks including altered clinical presentations (eg, multiple or deep chancres), delayed healing, overlapping stages of disease, and increased severity of organ involvement. All sexually active individuals should be screened for syphilis every 3 to 6 months, particularly those with unexplained oral ulcers.

Serologic testing is fundamental for syphilis diagnosis and management. Nontreponemal tests such as RPR and treponemal tests such as the fluorescent treponemal antibody absorption test provide comprehensive diagnostic information. Early diagnosis and empiric treatment are crucial in suspected cases. Ocular screening is recommended for suspected or confirmed syphilis cases.⁷

Management of syphilis includes treating all sexual partners and providing thorough patient education on the disease. Monitoring for the Jarisch-Herxheimer reaction—an acute febrile reaction following penicillin therapy—is important, especially in pregnant patients.5 Serologic evaluation at 6 and 12 months posttreatment is recommended, with more frequent evaluations if follow-up is uncertain, particularly for those with inconsistent access to health care or in whom reinfection is suspected. Guidelines from the Centers for Disease Control and Prevention advocate for intramuscular penicillin G benzathine as the preferred treatment, with specific dosing for adults and children.⁷ Due to the ongoing bicillin shortage, alternatives such as extencilline have temporarily been allowed for use in the United States.⁸

The rising incidence of syphilis in the United States underscores the critical need for enhanced public health initiatives focusing on education, screening, and early intervention. Comprehensive sexual education that includes information about syphilis and other sexually transmitted infections, proper use of prophylactic measures such as condoms, and the benefits of doxyPEP can considerably reduce transmission rates. Health care providers should routinely discuss these preventive measures with their patients, especially those in high-risk groups.

Our case highlights the importance of considering syphilis in the differential diagnosis of oral ulcers, particularly in high-risk populations. Timely diagnosis, effective treatment, and preventive measures such as doxyPEP are essential for managing and controlling syphilis. The rising incidence of syphilis in the United States warrants increased screening, patient education, and public health interventions to address this notable health challenge. The syphilis crisis calls for coordinated efforts from health care providers, public health officials, and community leaders to curb the spread of this infection and protect public health.

THE DIAGNOSIS: Syphilis

The differential diagnosis of oral lesions can be complex; in our patient, we considered conditions such as pyogenic granuloma, herpes simplex virus, and syphilis, despite the presence of pain. Immunohistochemical staining for spirochete antigens was positive, and serologic confirmation through a positive rapid plasma reagin (RPR) test confirmed the diagnosis of primary syphilis. The patient was promptly referred back to the primary care physician for treatment with intramuscular penicillin, leading to resolution of the lesion. At 3 months’ follow-up in our clinic, the lesion was fully resolved.

A primary syphilitic chancre is the initial lesion caused by Treponema pallidum, typically manifesting as a painless ulcer at the infection site, usually in the genital area; however, chancres also may manifest in other locations (eg, the anus or oral cavity) due to direct contact with infectious lesions on another individual. Our case represents an atypical presentation of an oral syphilitic chancre.

Syphilis is a sexually transmitted infection with various clinical manifestations. It is crucial to consider syphilis in the differential diagnosis of ulcerative lesions even when pain is present, especially in high-risk individuals such as those who engage in unprotected sex.^1,2 Oral syphilitic chancres have been documented in the medical literature for more than a century, underscoring the importance of maintaining a high index of suspicion for diagnosis and a low threshold for obtaining an RPR test to facilitate early detection and treatment.^2,3 Notably, the prevalence of syphilis is higher in men who have sex with men, particularly among those who engage in unprotected oral and anal sex. Increased screening and early treatment are essential to control the spread of disease within all populations. Doxycycline postexposure prophylaxis (doxyPEP) is used as a preventive measure for syphilis, chlamydia, and gonorrhea.⁴ This regimen consists of 200 mg of doxycycline taken within 24 hours but no later than 72 hours after unprotected anal, vaginal, or oral sex.

Our case highlights the importance of considering the differential diagnosis of oral ulcers, particularly in high-risk populations such as men who have sex with men. Prompt diagnosis, effective treatment, and preventive strategies such as doxyPEP are essential for controlling syphilis. Comprehensive patient education and regular follow-up appointments are critical components of successful management.

The United States has experienced a considerable rise in primary and congenital syphilis cases, with an 80% increase between 2018 and 2022.⁶ Serologic testing is the primary method for diagnosing, staging, and managing syphilis. Sexually active patients with suspected syphilis or unexplained symptoms should undergo testing. Prompt diagnosis and treatment can prevent systemic complications, including ocular involvement and permanent blindness.

Syphilis is transmitted through direct contact with a syphilitic ulcer or saliva or blood from an infected individual. Oral syphilitic ulcers can develop on the lips, tongue, oral mucosa, and tonsils. Chancres can range from a few millimeters to several centimeters, with an incubation period of 10 to 90 days (average, 21 days). The chancre lasts 3 to 6 weeks and heals spontaneously. Without treatment, primary syphilis can progress to secondary syphilis, characterized by a papulosquamous eruption and mucosal involvement, and potentially tertiary syphilis, which can affect the central nervous system, heart, bones, and skin.⁷

Immunocompromised patients, especially those diagnosed with HIV, face increased risks including altered clinical presentations (eg, multiple or deep chancres), delayed healing, overlapping stages of disease, and increased severity of organ involvement. All sexually active individuals should be screened for syphilis every 3 to 6 months, particularly those with unexplained oral ulcers.

Serologic testing is fundamental for syphilis diagnosis and management. Nontreponemal tests such as RPR and treponemal tests such as the fluorescent treponemal antibody absorption test provide comprehensive diagnostic information. Early diagnosis and empiric treatment are crucial in suspected cases. Ocular screening is recommended for suspected or confirmed syphilis cases.⁷

Management of syphilis includes treating all sexual partners and providing thorough patient education on the disease. Monitoring for the Jarisch-Herxheimer reaction—an acute febrile reaction following penicillin therapy—is important, especially in pregnant patients.5 Serologic evaluation at 6 and 12 months posttreatment is recommended, with more frequent evaluations if follow-up is uncertain, particularly for those with inconsistent access to health care or in whom reinfection is suspected. Guidelines from the Centers for Disease Control and Prevention advocate for intramuscular penicillin G benzathine as the preferred treatment, with specific dosing for adults and children.⁷ Due to the ongoing bicillin shortage, alternatives such as extencilline have temporarily been allowed for use in the United States.⁸

The rising incidence of syphilis in the United States underscores the critical need for enhanced public health initiatives focusing on education, screening, and early intervention. Comprehensive sexual education that includes information about syphilis and other sexually transmitted infections, proper use of prophylactic measures such as condoms, and the benefits of doxyPEP can considerably reduce transmission rates. Health care providers should routinely discuss these preventive measures with their patients, especially those in high-risk groups.

Our case highlights the importance of considering syphilis in the differential diagnosis of oral ulcers, particularly in high-risk populations. Timely diagnosis, effective treatment, and preventive measures such as doxyPEP are essential for managing and controlling syphilis. The rising incidence of syphilis in the United States warrants increased screening, patient education, and public health interventions to address this notable health challenge. The syphilis crisis calls for coordinated efforts from health care providers, public health officials, and community leaders to curb the spread of this infection and protect public health.

THE DIAGNOSIS: Bullous Hemorrhagic Dermatosis

Biopsy results showed an intraepidermal blister with a floor composed of maturing epidermis. The roof of the blister was composed of necrotic keratinocytes with overlying orthokeratosis, and the cavity was filled with a moderate amount of fibrin and dead cells with neutrophils. Direct immunofluorescence (DIF) using specific antihuman IgG, IgM, IgA, C3, and fibrin was negative. Aerobic, anaerobic, and fungal cultures also were negative. With these histopathologic findings, medication exposure, and timing of bullae onset, our patient was diagnosed with bullous hemorrhagic dermatosis (BHD) secondary to enoxaparin administration. Enoxaparin was continued due to increased risk for coagulopathy, and there was complete resolution of the bullae after 5 weeks with no residual symptoms.

Bullous hemorrhagic dermatosis is a rare eruption that can occur after administration of heparin and low-molecular-weight heparin, with enoxaparin being the most commonly implicated drug.¹ The lesions typically are seen in elderly men in the seventh decade of life and appear within a median of 7 days after drug exposure. The time course for the postexposure eruption can vary from 2 to 21 days, with reports of skin lesions appearing up to 4 months after exposure.^1,2 hemorrhagic bullae (Figure) typically on the arms and legs, though lesions also can develop on the trunk. The lesions can occur in distant areas from the injection site, suggesting BHD may be a systemic reaction, although the etiology is poorly understood.¹

Another heparin reaction that can manifest similarly to BHD is heparin-induced skin necrosis.³ Patients with this condition also may have associated heparin-induced thrombocytopenia upon laboratory investigation and have a more aggressive clinical course than BHD. Biopsy can help differentiate BHD and early heparin-induced skin necrosis if the clinical manifestation is unclear. Histopathologically, BHD typically has intraepidermal bullae filled with blood, whereas heparin-induced skin necrosis has dermal thrombi.^1,4 Treatment of both conditions differs in whether to discontinue anticoagulants: heparin-induced skin necrosis requires discontinuation of the medication, while BHD does not.^2,3

In patients with BHD, the lesions are self-resolving, and treatment is supportive, although whether enoxaparin is discontinued varies among physicians.² Lesions typically resolve within 2 weeks of onset, although it is unclear whether continuing anticoagulants delays resolution.¹ Discontinuing anticoagulants in certain patients can be life-threatening due to complex comorbidities (eg, risk for venous thromboembolism or pulmonary embolism from prolonged hospitalization or severe trauma) and is not necessary for the resolution of BHD.

In addition to BHD and heparin-induced skin necrosis, our differential diagnosis included bullous pemphigoid, coma blisters, and Vibrio vulnificus infection. Although bullous pemphigoid can manifest with tense bullae that are pauci-inflammatory on histology, DIF would show linear IgG and C3 deposition at the dermal-epidermal junction. In our patient, DIF was negative and favored another etiology for the lesions. Coma blisters can occur in areas of sustained pressure and typically develop in patients with a prolonged hospitalization or those who are sedentary for long periods of time. The distribution of bullae on our patient’s bilateral pretibial shins made this diagnosis unlikely. Vibrio vulnificus infection can manifest as hemorrhagic bullae, though typically after a break in the skin exposed to brackish water. Vibrio vulnificus infection can be life-threatening, resulting in septicemia and increased mortality, and a thorough patient history is important for diagnosis.⁵

THE DIAGNOSIS: Bullous Hemorrhagic Dermatosis

Biopsy results showed an intraepidermal blister with a floor composed of maturing epidermis. The roof of the blister was composed of necrotic keratinocytes with overlying orthokeratosis, and the cavity was filled with a moderate amount of fibrin and dead cells with neutrophils. Direct immunofluorescence (DIF) using specific antihuman IgG, IgM, IgA, C3, and fibrin was negative. Aerobic, anaerobic, and fungal cultures also were negative. With these histopathologic findings, medication exposure, and timing of bullae onset, our patient was diagnosed with bullous hemorrhagic dermatosis (BHD) secondary to enoxaparin administration. Enoxaparin was continued due to increased risk for coagulopathy, and there was complete resolution of the bullae after 5 weeks with no residual symptoms.

Bullous hemorrhagic dermatosis is a rare eruption that can occur after administration of heparin and low-molecular-weight heparin, with enoxaparin being the most commonly implicated drug.¹ The lesions typically are seen in elderly men in the seventh decade of life and appear within a median of 7 days after drug exposure. The time course for the postexposure eruption can vary from 2 to 21 days, with reports of skin lesions appearing up to 4 months after exposure.^1,2 hemorrhagic bullae (Figure) typically on the arms and legs, though lesions also can develop on the trunk. The lesions can occur in distant areas from the injection site, suggesting BHD may be a systemic reaction, although the etiology is poorly understood.¹

Another heparin reaction that can manifest similarly to BHD is heparin-induced skin necrosis.³ Patients with this condition also may have associated heparin-induced thrombocytopenia upon laboratory investigation and have a more aggressive clinical course than BHD. Biopsy can help differentiate BHD and early heparin-induced skin necrosis if the clinical manifestation is unclear. Histopathologically, BHD typically has intraepidermal bullae filled with blood, whereas heparin-induced skin necrosis has dermal thrombi.^1,4 Treatment of both conditions differs in whether to discontinue anticoagulants: heparin-induced skin necrosis requires discontinuation of the medication, while BHD does not.^2,3

In patients with BHD, the lesions are self-resolving, and treatment is supportive, although whether enoxaparin is discontinued varies among physicians.² Lesions typically resolve within 2 weeks of onset, although it is unclear whether continuing anticoagulants delays resolution.¹ Discontinuing anticoagulants in certain patients can be life-threatening due to complex comorbidities (eg, risk for venous thromboembolism or pulmonary embolism from prolonged hospitalization or severe trauma) and is not necessary for the resolution of BHD.

In addition to BHD and heparin-induced skin necrosis, our differential diagnosis included bullous pemphigoid, coma blisters, and Vibrio vulnificus infection. Although bullous pemphigoid can manifest with tense bullae that are pauci-inflammatory on histology, DIF would show linear IgG and C3 deposition at the dermal-epidermal junction. In our patient, DIF was negative and favored another etiology for the lesions. Coma blisters can occur in areas of sustained pressure and typically develop in patients with a prolonged hospitalization or those who are sedentary for long periods of time. The distribution of bullae on our patient’s bilateral pretibial shins made this diagnosis unlikely. Vibrio vulnificus infection can manifest as hemorrhagic bullae, though typically after a break in the skin exposed to brackish water. Vibrio vulnificus infection can be life-threatening, resulting in septicemia and increased mortality, and a thorough patient history is important for diagnosis.⁵

THE DIAGNOSIS: Bullous Hemorrhagic Dermatosis

Biopsy results showed an intraepidermal blister with a floor composed of maturing epidermis. The roof of the blister was composed of necrotic keratinocytes with overlying orthokeratosis, and the cavity was filled with a moderate amount of fibrin and dead cells with neutrophils. Direct immunofluorescence (DIF) using specific antihuman IgG, IgM, IgA, C3, and fibrin was negative. Aerobic, anaerobic, and fungal cultures also were negative. With these histopathologic findings, medication exposure, and timing of bullae onset, our patient was diagnosed with bullous hemorrhagic dermatosis (BHD) secondary to enoxaparin administration. Enoxaparin was continued due to increased risk for coagulopathy, and there was complete resolution of the bullae after 5 weeks with no residual symptoms.

Bullous hemorrhagic dermatosis is a rare eruption that can occur after administration of heparin and low-molecular-weight heparin, with enoxaparin being the most commonly implicated drug.¹ The lesions typically are seen in elderly men in the seventh decade of life and appear within a median of 7 days after drug exposure. The time course for the postexposure eruption can vary from 2 to 21 days, with reports of skin lesions appearing up to 4 months after exposure.^1,2 hemorrhagic bullae (Figure) typically on the arms and legs, though lesions also can develop on the trunk. The lesions can occur in distant areas from the injection site, suggesting BHD may be a systemic reaction, although the etiology is poorly understood.¹

Another heparin reaction that can manifest similarly to BHD is heparin-induced skin necrosis.³ Patients with this condition also may have associated heparin-induced thrombocytopenia upon laboratory investigation and have a more aggressive clinical course than BHD. Biopsy can help differentiate BHD and early heparin-induced skin necrosis if the clinical manifestation is unclear. Histopathologically, BHD typically has intraepidermal bullae filled with blood, whereas heparin-induced skin necrosis has dermal thrombi.^1,4 Treatment of both conditions differs in whether to discontinue anticoagulants: heparin-induced skin necrosis requires discontinuation of the medication, while BHD does not.^2,3

In patients with BHD, the lesions are self-resolving, and treatment is supportive, although whether enoxaparin is discontinued varies among physicians.² Lesions typically resolve within 2 weeks of onset, although it is unclear whether continuing anticoagulants delays resolution.¹ Discontinuing anticoagulants in certain patients can be life-threatening due to complex comorbidities (eg, risk for venous thromboembolism or pulmonary embolism from prolonged hospitalization or severe trauma) and is not necessary for the resolution of BHD.

In addition to BHD and heparin-induced skin necrosis, our differential diagnosis included bullous pemphigoid, coma blisters, and Vibrio vulnificus infection. Although bullous pemphigoid can manifest with tense bullae that are pauci-inflammatory on histology, DIF would show linear IgG and C3 deposition at the dermal-epidermal junction. In our patient, DIF was negative and favored another etiology for the lesions. Coma blisters can occur in areas of sustained pressure and typically develop in patients with a prolonged hospitalization or those who are sedentary for long periods of time. The distribution of bullae on our patient’s bilateral pretibial shins made this diagnosis unlikely. Vibrio vulnificus infection can manifest as hemorrhagic bullae, though typically after a break in the skin exposed to brackish water. Vibrio vulnificus infection can be life-threatening, resulting in septicemia and increased mortality, and a thorough patient history is important for diagnosis.⁵

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Excessive alcohol use is one of the leading preventable causes of death in the United States, responsible for about 178,000 deaths annually and an average of 488 daily deaths in 2020 and 2021.¹Alcohol-related deaths increased by 49% between 2006 and 2019.² This trend continued during the COVID-19 pandemic, with death certificates that listed alcohol increasing by > 25% from 2019 to 2020, and another 10% in 2021.³ This increase of alcohol-related deaths includes those as a direct result of chronic alcohol use, such as alcoholic cardiomyopathy, alcoholic hepatitis and cirrhosis, and alcohol-induced pancreatitis, as well as a result of acute use such as alcohol poisoning, suicide by exposure to alcohol, and alcohol-impaired driving fatalities.⁴

Excessive alcohol consumption poses other serious risks, including cases when intake is abruptly reduced without proper management. Alcohol withdrawal syndrome (AWS) can vary in severity, with potentially life-threatening complications such as hallucinations, seizures, and delirium tremens.⁵

These risks highlight the importance of professional intervention and support, not only to mitigate risks associated with AWS, but provide a pathway towards recovery from alcohol use disorder (AUD).

According to the 2022 National Survey on Drug Use and Health, 28.8 million US adults had AUD in the prior year, yet only 7.6% of these individuals received treatment and an even smaller group (2.2%) received medication-assisted treatment for alcohol.^6,7 This is despite American Psychiatric Association guidelines for the pharmacological treatment of patients with AUD, including the use of naltrexone, acamprosate, disulfiram, topiramate, or gabapentin, depending on therapy goals, past medication trials, medication contraindications, and patient preference.⁸ Several of these medications are approved by the US Food and Drug Administration (FDA) for the treatment of AUD and have support for effectiveness from randomized controlled trials and meta-analyses.^9-11

Clinical practice guidelines for the management of substance use disorders (SUDs) from the US Department of Veterans Affairs (VA) and US Department of Defense have strong recommendations for naltrexone and topiramate as first-line pharmacotherapies for moderate to severe AUD. Acamprosate and disulfiram are weak recommendations as alternative options. Gabapentin is a weak recommendation for cases where first-line treatments are contraindicated or ineffective. The guidelines emphasize the importance of a comprehensive approach to AUD treatment, including psychosocial interventions in addition to pharmacotherapy.¹²

A 2023 national survey found veterans reported higher alcohol consumption than nonveterans.¹³ At the end of fiscal year 2023, > 4.4 million veterans—6% of Veterans Health Administration patients—had been diagnosed with AUD.14 However, > 87% of these patients nationally, and 88% of Veterans Integrated Service Network (VISN) 21 patients, were not receiving naltrexone, acamprosate, disulfiram, or topiramate as part of their treatment. The VA Academic Detailing Service (ADS) now includes AUD pharmacotherapy as a campaign focus, highlighting its importance. The ADS is a pharmacy educational outreach program that uses unbiased clinical guidelines to promote aligning prescribing behavior with best practices. Academic detailing methods include speaking with health care practitioners (HCPs), and direct-to-consumer (DTC) patient education.

ADS campaigns include DTC educational handouts. Past ADS projects and research using DTC have demonstrated a significant improvement in outcomes and positively influencing patients’ pharmacotherapy treatment. ^15,16 A VA quality improvement project found a positive correlation between the initiation of AUD pharmacotherapy and engagement with mental health care following the distribution of AUD DTC patient education. ¹⁷ This project aimed to apply the same principles of prior research to explore the use of DTC across multiple facilities within VISN 21 to increase AUD pharmacotherapy. VISN 21 includes VA facilities and clinics across the Pacific Islands, Nevada, and California and serves about 350,000 veterans.

METHODS

A prospective cohort of VISN 21 veterans with or at high risk for AUD was identified using the VA ADS AUD Dashboard. The cohort included those not on acamprosate, disulfiram, naltrexone, topiramate, or gabapentin for treatment of AUD and had an elevated Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score of ≥ 6 (high risk) with an AUD diagnosis or ≥ 8 (severe risk) without a diagnosis. The AUDIT-C scores used in the dashboard are supported by the VA AUD clinician guide as the minimum scores when AUD pharmacotherapy should be offered to patients.¹⁸ Prescriptions filled outside the VA were not included in this dashboard.

Data and patient information were collected using the VA Corporate Data Warehouse. To be eligible, veterans needed a valid mailing address within the VISN 21 region and a primary care, mental health, or SUD clinician prescriber visit scheduled between October 1, 2023, and January 31, 2024. Veterans were excluded if they were in hospice, had a 1-year mortality risk score > 50% based on their Care Assessment Need (CAN) score, or facility leadership opted out of project involvement. Patients with both severe renal and hepatic impairments were excluded because they were ineligible for AUD pharmacotherapy. However, veterans with either renal or hepatic impairment (but not both) were included, as they could be potential candidates for ≥ 1 AUD pharmacotherapy option.

Initial correspondence with facilities was initiated through local academic detailers. A local champion was identified for the 1 facility without an academic detailer. Facilities could opt in or out of the project. Approval was provided by the local pharmacy and therapeutics committee, pharmacy, primary care, or psychiatry leadership. Approval process and clinician involvement varied by site.

Education

The selected AUD patient education was designed and approved by the national VA ADS (eappendix). The DTC patient education provided general knowledge about alcohol, including what constitutes a standard amount of alcohol, what is considered heavy drinking, risks of heavy drinking, creating a plan with a clinician to reduce and manage withdrawal symptoms, and additional resources. The DTC was accompanied by a cover letter that included a local facility contact number.

A centralized mailing facility was used for all materials. VA Northern California Health Care System provided the funding to cover the cost of postage. The list of veterans to be contacted was updated on a rolling basis and DTC education was mailed 2 weeks prior to their scheduled prescriber visit.

The eligible cohort of 1260 veterans received DTC education. A comparator group of 2048 veterans that did not receive DTC education was obtained retrospectively by using the same inclusion and exclusion criteria with a scheduled primary care, mental health, or SUD HCP visit from October 1, 2022, to January 31, 2023. The outcomes assessed were within 30 days of the scheduled visit, with the primary outcome as the initiation of AUD-related pharmacotherapy and the secondary outcome as the placement of a consultation for mental health or SUD services. Any consultations sent to Behavioral Health, Addiction, Mental Health, Psychiatric, and SUD services following the HCP visit, within the specified time frame, were used for the secondary outcome.

Matching and Analysis

A 1-to-1 nearest neighbor propensity score (PS) matching without replacement was used to pair the 1260 veterans from the intervention group with similarly scored comparator group veterans for a PS-matched final dataset of 2520 veterans. The PS model was a multivariate logistic regression with the outcome being exposure and comparator group status. Baseline characteristics used in the PS model were age, birth sex, race, facility of care, baseline AUDIT-C score, and days between project start and scheduled appointment. Covariate imbalance for the PS-matched sample was assessed to ensure the standardized mean difference for all covariates fell under a 0.1 threshold (Figure).¹⁹

A frequency table was provided to compare the discrete distributions of the baseline characteristics in the intervention and comparator groups. Logistic regression analysis was performed to evaluate the association between DTC education exposure and pharmacotherapy initiation, while controlling for potential confounders. Univariate and multivariate P value results for each variable included in the model were reported along with the multivariate odds ratios (ORs) and their associated 95% CIs. Logistic regression analyses were run for both outcomes. Each model included the exposure and comparator group status as well as the baseline characteristics included in the PS model. Statistical significance was set at P < .05. All statistical analyses were performed with R version 4.2.1.

RESULTS

Two of 7 VISN 21 sites did not participate, and 3 had restrictions on participation. DTC education was mailed about 2 weeks prior to scheduled visit for 1260 veterans; 53.6% identified as White, 37.6% were aged 41 to 60 years, and 79.2% had an AUDIT-C ≥ 8 (Table 1). Of those mailed education, there were 173 no-show appointments (13.7%). Thirty-two veterans (2.5%) in the DTC group and 33 veterans (2.6%) in the comparator group received an AUD-related pharmacotherapy prescription (P = .88) (Table 2). One hundred seventy-one veterans (13.6%) in the DTC group and 160 veterans (12.7%) in the comparator group had a consult placed for mental health or SUD services within 30 days of their appointment (P = .59) (Table 3).

DISCUSSION

This project did not yield statistically significant differences in either the primary or secondary outcomes within the 30-day follow-up window and found limited impact from the DTC educational outreach to veterans. The percentage of veterans that received AUD-related pharmacotherapy or consultations for mental health or SUD services was similarly low in the DTC and comparator groups. These findings suggest that although DTC education may raise awareness, it may not be sufficient on its own to drive changes in prescribing behavior or referral patterns without system-level support.

Addiction is a complex disease faced with stigma and requiring readiness by both the HCP and patient to move forward in support and treatment. The consequences of stigma can be severe: the more stigma perceived by a person with AUD, the less likely they are to seek treatment.²⁰ Stigma may exist even within HCPs and may lead to compromised care including shortened visits, less engagement, and less empathy.¹⁹ Cultural attitude towards alcohol use and intoxication can also be influenced through a wide range of sources including social media, movies, music, and television. Studies have shown targeted alcohol marketing may result in the development of positive beliefs about drinking and expand environments where alcohol use is socially acceptable and encouraged.²¹ These factors can impact drinking behavior, including the onset of drinking, binge drinking, and increased alcohol consumption.²²

Three VISN 21 sites in this study had restrictions on or excluded primary care from participation. Leadership at some of these facilities were concerned that primary care teams did not have the bandwidth to take on additional items and/or there was variable primary care readiness for initiating AUD pharmacotherapy. Further attempts should be made to integrate primary care into the process of initiating AUD treatment as significant research suggests that integrated care models for AUD may be associated with improved process and outcome measures of care.²³

There are several differences between this quality improvement project and prior research investigating the impact of DTC education for other conditions, such as the EMPOWER randomized controlled trial and VISN 22 project, which both demonstrated effectiveness of DTC education for reducing benzodiazepine use in geriatric veterans. ^15,16 These studies focused on reducing or stopping pharmacotherapy use, whereas this project sought to promote the initiation of AUD pharmacotherapy. These studies evaluated outcomes at least 6 months postindex date, whereas this project evaluated outcomes within 30 days postappointment. Furthermore, the educational content varied significantly. Other projects provided patients with information focused on specific medications and interventions, such as benzodiazepine tapering, while this project mailed general information on heavy drinking, its risks, and strategies for cutting back, without mentioning pharmacotherapy. The DTC material used in this project was chosen because it was a preapproved national VA ADS resource, which expedited the project timeline by avoiding the need for additional approvals at each participating site. These differences may impact the observed effectiveness of DTC education in this project, especially regarding the primary outcome.

Strengths and Limitations

This quality improvement project sent a large sample of veterans DTC education in a clinical setting across multiple sites. Additionally, PS matching methods were used to balance covariates between the comparator and DTC education group, thereby simulating a randomized controlled trial and reducing selection bias. The project brought attention to the VISN 21 AUD treatment rates, stimulated conversation across sites about available treatments and resources for AUD, and sparked collaboration between academic detailing, mental health, and primary care services. The time frame for visits was selected during the winter; the National Institute on Alcohol Abuse and Alcoholism notes this is a time when people may be more likely to engage in excessive alcohol consumption than at other times of the year.²⁴

The 30-day time frame for outcomes may have been too short to observe changes in prescribing or referral patterns. Additionally, the comparator group was comprised of veterans seen from October 1, 2022, to January 31, 2023, where seasonal timing may have influenced alcohol consumption behaviors and skewed the results. There were also no-show appointments in the DTC education group (13.7%), though it is likely some patients rescheduled and still received AUD pharmacotherapy within 30 days of the original appointment. Finally, it was not possible to confirm whether a patient opened and read the education that was mailed to them. This may be another reason to explore electronic distribution of DTC education. This all may have contributed to the lack of statistically significant differences in both the primary and secondary outcomes.

There was a high level of variability between facility participation in the project. Two of 7 sites did not participate, and 3 sites restricted primary care engagement. This represents a significant limitation, particularly for the secondary outcome of placing consultations for MH or SUD services. Facilities that only included mental health or SUD HCPs may have resulted in lower consultation rates due to their inherent specialization, reducing the likelihood of self-referrals.

The project may overestimate prescribed AUD pharmacotherapy in the primary outcome due to potential misclassification of medications. While the project adhered to the national VA ADS AUD dashboard’s definition of AUD pharmacotherapy, including acamprosate, disulfiram, naltrexone, topiramate, and gabapentin, some of these medications have multiple indications. For example, gabapentin is commonly prescribed for peripheral neuropathy, and topiramate is used to treat migraines and seizures. The multipurpose use adds uncertainty about whether they were prescribed specifically for AUD treatment, especially in cases where the HCP is responsible for treating a broad range of disease states, as in primary care.

CONCLUSIONS

Results of this quality improvement project did not show a statistically significant difference between patients sent DTC education and the comparator group for the initiation of AUD pharmacotherapy or placement of a consult to mental health or SUD services within 30 days of their scheduled visit. Future studies may seek to implement stricter criteria to confirm the intended use of topiramate and gabapentin, such as looking for keywords in the prescription instructions for use, performing chart reviews, and/or only including these medications if prescribed by a mental health or SUD HCP. Alternatively, future studies may consider limiting the analysis to only FDA-approved AUD medications: acamprosate, disulfiram, and naltrexone. It is vital to continue to enhance primary care HCP readiness to treat AUD, given the existing relationships and trust they often have with patients. Electronic methods for distributing DTC education could also be advantageous, as these methods may have the ability to track whether a message has been opened and read. Despite a lack of statistical significance, this project sparked crucial conversations and collaboration around AUD, available treatments, and addressing potential barriers to connecting patients to care within VISN 21.

Excessive alcohol use is one of the leading preventable causes of death in the United States, responsible for about 178,000 deaths annually and an average of 488 daily deaths in 2020 and 2021.¹Alcohol-related deaths increased by 49% between 2006 and 2019.² This trend continued during the COVID-19 pandemic, with death certificates that listed alcohol increasing by > 25% from 2019 to 2020, and another 10% in 2021.³ This increase of alcohol-related deaths includes those as a direct result of chronic alcohol use, such as alcoholic cardiomyopathy, alcoholic hepatitis and cirrhosis, and alcohol-induced pancreatitis, as well as a result of acute use such as alcohol poisoning, suicide by exposure to alcohol, and alcohol-impaired driving fatalities.⁴

Excessive alcohol consumption poses other serious risks, including cases when intake is abruptly reduced without proper management. Alcohol withdrawal syndrome (AWS) can vary in severity, with potentially life-threatening complications such as hallucinations, seizures, and delirium tremens.⁵

These risks highlight the importance of professional intervention and support, not only to mitigate risks associated with AWS, but provide a pathway towards recovery from alcohol use disorder (AUD).

According to the 2022 National Survey on Drug Use and Health, 28.8 million US adults had AUD in the prior year, yet only 7.6% of these individuals received treatment and an even smaller group (2.2%) received medication-assisted treatment for alcohol.^6,7 This is despite American Psychiatric Association guidelines for the pharmacological treatment of patients with AUD, including the use of naltrexone, acamprosate, disulfiram, topiramate, or gabapentin, depending on therapy goals, past medication trials, medication contraindications, and patient preference.⁸ Several of these medications are approved by the US Food and Drug Administration (FDA) for the treatment of AUD and have support for effectiveness from randomized controlled trials and meta-analyses.^9-11

Clinical practice guidelines for the management of substance use disorders (SUDs) from the US Department of Veterans Affairs (VA) and US Department of Defense have strong recommendations for naltrexone and topiramate as first-line pharmacotherapies for moderate to severe AUD. Acamprosate and disulfiram are weak recommendations as alternative options. Gabapentin is a weak recommendation for cases where first-line treatments are contraindicated or ineffective. The guidelines emphasize the importance of a comprehensive approach to AUD treatment, including psychosocial interventions in addition to pharmacotherapy.¹²

A 2023 national survey found veterans reported higher alcohol consumption than nonveterans.¹³ At the end of fiscal year 2023, > 4.4 million veterans—6% of Veterans Health Administration patients—had been diagnosed with AUD.14 However, > 87% of these patients nationally, and 88% of Veterans Integrated Service Network (VISN) 21 patients, were not receiving naltrexone, acamprosate, disulfiram, or topiramate as part of their treatment. The VA Academic Detailing Service (ADS) now includes AUD pharmacotherapy as a campaign focus, highlighting its importance. The ADS is a pharmacy educational outreach program that uses unbiased clinical guidelines to promote aligning prescribing behavior with best practices. Academic detailing methods include speaking with health care practitioners (HCPs), and direct-to-consumer (DTC) patient education.

ADS campaigns include DTC educational handouts. Past ADS projects and research using DTC have demonstrated a significant improvement in outcomes and positively influencing patients’ pharmacotherapy treatment. ^15,16 A VA quality improvement project found a positive correlation between the initiation of AUD pharmacotherapy and engagement with mental health care following the distribution of AUD DTC patient education. ¹⁷ This project aimed to apply the same principles of prior research to explore the use of DTC across multiple facilities within VISN 21 to increase AUD pharmacotherapy. VISN 21 includes VA facilities and clinics across the Pacific Islands, Nevada, and California and serves about 350,000 veterans.

METHODS

A prospective cohort of VISN 21 veterans with or at high risk for AUD was identified using the VA ADS AUD Dashboard. The cohort included those not on acamprosate, disulfiram, naltrexone, topiramate, or gabapentin for treatment of AUD and had an elevated Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score of ≥ 6 (high risk) with an AUD diagnosis or ≥ 8 (severe risk) without a diagnosis. The AUDIT-C scores used in the dashboard are supported by the VA AUD clinician guide as the minimum scores when AUD pharmacotherapy should be offered to patients.¹⁸ Prescriptions filled outside the VA were not included in this dashboard.

Data and patient information were collected using the VA Corporate Data Warehouse. To be eligible, veterans needed a valid mailing address within the VISN 21 region and a primary care, mental health, or SUD clinician prescriber visit scheduled between October 1, 2023, and January 31, 2024. Veterans were excluded if they were in hospice, had a 1-year mortality risk score > 50% based on their Care Assessment Need (CAN) score, or facility leadership opted out of project involvement. Patients with both severe renal and hepatic impairments were excluded because they were ineligible for AUD pharmacotherapy. However, veterans with either renal or hepatic impairment (but not both) were included, as they could be potential candidates for ≥ 1 AUD pharmacotherapy option.

Initial correspondence with facilities was initiated through local academic detailers. A local champion was identified for the 1 facility without an academic detailer. Facilities could opt in or out of the project. Approval was provided by the local pharmacy and therapeutics committee, pharmacy, primary care, or psychiatry leadership. Approval process and clinician involvement varied by site.

Education

The selected AUD patient education was designed and approved by the national VA ADS (eappendix). The DTC patient education provided general knowledge about alcohol, including what constitutes a standard amount of alcohol, what is considered heavy drinking, risks of heavy drinking, creating a plan with a clinician to reduce and manage withdrawal symptoms, and additional resources. The DTC was accompanied by a cover letter that included a local facility contact number.

A centralized mailing facility was used for all materials. VA Northern California Health Care System provided the funding to cover the cost of postage. The list of veterans to be contacted was updated on a rolling basis and DTC education was mailed 2 weeks prior to their scheduled prescriber visit.

The eligible cohort of 1260 veterans received DTC education. A comparator group of 2048 veterans that did not receive DTC education was obtained retrospectively by using the same inclusion and exclusion criteria with a scheduled primary care, mental health, or SUD HCP visit from October 1, 2022, to January 31, 2023. The outcomes assessed were within 30 days of the scheduled visit, with the primary outcome as the initiation of AUD-related pharmacotherapy and the secondary outcome as the placement of a consultation for mental health or SUD services. Any consultations sent to Behavioral Health, Addiction, Mental Health, Psychiatric, and SUD services following the HCP visit, within the specified time frame, were used for the secondary outcome.

Matching and Analysis

A 1-to-1 nearest neighbor propensity score (PS) matching without replacement was used to pair the 1260 veterans from the intervention group with similarly scored comparator group veterans for a PS-matched final dataset of 2520 veterans. The PS model was a multivariate logistic regression with the outcome being exposure and comparator group status. Baseline characteristics used in the PS model were age, birth sex, race, facility of care, baseline AUDIT-C score, and days between project start and scheduled appointment. Covariate imbalance for the PS-matched sample was assessed to ensure the standardized mean difference for all covariates fell under a 0.1 threshold (Figure).¹⁹

A frequency table was provided to compare the discrete distributions of the baseline characteristics in the intervention and comparator groups. Logistic regression analysis was performed to evaluate the association between DTC education exposure and pharmacotherapy initiation, while controlling for potential confounders. Univariate and multivariate P value results for each variable included in the model were reported along with the multivariate odds ratios (ORs) and their associated 95% CIs. Logistic regression analyses were run for both outcomes. Each model included the exposure and comparator group status as well as the baseline characteristics included in the PS model. Statistical significance was set at P < .05. All statistical analyses were performed with R version 4.2.1.

RESULTS

Two of 7 VISN 21 sites did not participate, and 3 had restrictions on participation. DTC education was mailed about 2 weeks prior to scheduled visit for 1260 veterans; 53.6% identified as White, 37.6% were aged 41 to 60 years, and 79.2% had an AUDIT-C ≥ 8 (Table 1). Of those mailed education, there were 173 no-show appointments (13.7%). Thirty-two veterans (2.5%) in the DTC group and 33 veterans (2.6%) in the comparator group received an AUD-related pharmacotherapy prescription (P = .88) (Table 2). One hundred seventy-one veterans (13.6%) in the DTC group and 160 veterans (12.7%) in the comparator group had a consult placed for mental health or SUD services within 30 days of their appointment (P = .59) (Table 3).

DISCUSSION

This project did not yield statistically significant differences in either the primary or secondary outcomes within the 30-day follow-up window and found limited impact from the DTC educational outreach to veterans. The percentage of veterans that received AUD-related pharmacotherapy or consultations for mental health or SUD services was similarly low in the DTC and comparator groups. These findings suggest that although DTC education may raise awareness, it may not be sufficient on its own to drive changes in prescribing behavior or referral patterns without system-level support.

Addiction is a complex disease faced with stigma and requiring readiness by both the HCP and patient to move forward in support and treatment. The consequences of stigma can be severe: the more stigma perceived by a person with AUD, the less likely they are to seek treatment.²⁰ Stigma may exist even within HCPs and may lead to compromised care including shortened visits, less engagement, and less empathy.¹⁹ Cultural attitude towards alcohol use and intoxication can also be influenced through a wide range of sources including social media, movies, music, and television. Studies have shown targeted alcohol marketing may result in the development of positive beliefs about drinking and expand environments where alcohol use is socially acceptable and encouraged.²¹ These factors can impact drinking behavior, including the onset of drinking, binge drinking, and increased alcohol consumption.²²

Three VISN 21 sites in this study had restrictions on or excluded primary care from participation. Leadership at some of these facilities were concerned that primary care teams did not have the bandwidth to take on additional items and/or there was variable primary care readiness for initiating AUD pharmacotherapy. Further attempts should be made to integrate primary care into the process of initiating AUD treatment as significant research suggests that integrated care models for AUD may be associated with improved process and outcome measures of care.²³

There are several differences between this quality improvement project and prior research investigating the impact of DTC education for other conditions, such as the EMPOWER randomized controlled trial and VISN 22 project, which both demonstrated effectiveness of DTC education for reducing benzodiazepine use in geriatric veterans. ^15,16 These studies focused on reducing or stopping pharmacotherapy use, whereas this project sought to promote the initiation of AUD pharmacotherapy. These studies evaluated outcomes at least 6 months postindex date, whereas this project evaluated outcomes within 30 days postappointment. Furthermore, the educational content varied significantly. Other projects provided patients with information focused on specific medications and interventions, such as benzodiazepine tapering, while this project mailed general information on heavy drinking, its risks, and strategies for cutting back, without mentioning pharmacotherapy. The DTC material used in this project was chosen because it was a preapproved national VA ADS resource, which expedited the project timeline by avoiding the need for additional approvals at each participating site. These differences may impact the observed effectiveness of DTC education in this project, especially regarding the primary outcome.

Strengths and Limitations

This quality improvement project sent a large sample of veterans DTC education in a clinical setting across multiple sites. Additionally, PS matching methods were used to balance covariates between the comparator and DTC education group, thereby simulating a randomized controlled trial and reducing selection bias. The project brought attention to the VISN 21 AUD treatment rates, stimulated conversation across sites about available treatments and resources for AUD, and sparked collaboration between academic detailing, mental health, and primary care services. The time frame for visits was selected during the winter; the National Institute on Alcohol Abuse and Alcoholism notes this is a time when people may be more likely to engage in excessive alcohol consumption than at other times of the year.²⁴

The 30-day time frame for outcomes may have been too short to observe changes in prescribing or referral patterns. Additionally, the comparator group was comprised of veterans seen from October 1, 2022, to January 31, 2023, where seasonal timing may have influenced alcohol consumption behaviors and skewed the results. There were also no-show appointments in the DTC education group (13.7%), though it is likely some patients rescheduled and still received AUD pharmacotherapy within 30 days of the original appointment. Finally, it was not possible to confirm whether a patient opened and read the education that was mailed to them. This may be another reason to explore electronic distribution of DTC education. This all may have contributed to the lack of statistically significant differences in both the primary and secondary outcomes.

There was a high level of variability between facility participation in the project. Two of 7 sites did not participate, and 3 sites restricted primary care engagement. This represents a significant limitation, particularly for the secondary outcome of placing consultations for MH or SUD services. Facilities that only included mental health or SUD HCPs may have resulted in lower consultation rates due to their inherent specialization, reducing the likelihood of self-referrals.

The project may overestimate prescribed AUD pharmacotherapy in the primary outcome due to potential misclassification of medications. While the project adhered to the national VA ADS AUD dashboard’s definition of AUD pharmacotherapy, including acamprosate, disulfiram, naltrexone, topiramate, and gabapentin, some of these medications have multiple indications. For example, gabapentin is commonly prescribed for peripheral neuropathy, and topiramate is used to treat migraines and seizures. The multipurpose use adds uncertainty about whether they were prescribed specifically for AUD treatment, especially in cases where the HCP is responsible for treating a broad range of disease states, as in primary care.

CONCLUSIONS

Results of this quality improvement project did not show a statistically significant difference between patients sent DTC education and the comparator group for the initiation of AUD pharmacotherapy or placement of a consult to mental health or SUD services within 30 days of their scheduled visit. Future studies may seek to implement stricter criteria to confirm the intended use of topiramate and gabapentin, such as looking for keywords in the prescription instructions for use, performing chart reviews, and/or only including these medications if prescribed by a mental health or SUD HCP. Alternatively, future studies may consider limiting the analysis to only FDA-approved AUD medications: acamprosate, disulfiram, and naltrexone. It is vital to continue to enhance primary care HCP readiness to treat AUD, given the existing relationships and trust they often have with patients. Electronic methods for distributing DTC education could also be advantageous, as these methods may have the ability to track whether a message has been opened and read. Despite a lack of statistical significance, this project sparked crucial conversations and collaboration around AUD, available treatments, and addressing potential barriers to connecting patients to care within VISN 21.

Excessive alcohol use is one of the leading preventable causes of death in the United States, responsible for about 178,000 deaths annually and an average of 488 daily deaths in 2020 and 2021.¹Alcohol-related deaths increased by 49% between 2006 and 2019.² This trend continued during the COVID-19 pandemic, with death certificates that listed alcohol increasing by > 25% from 2019 to 2020, and another 10% in 2021.³ This increase of alcohol-related deaths includes those as a direct result of chronic alcohol use, such as alcoholic cardiomyopathy, alcoholic hepatitis and cirrhosis, and alcohol-induced pancreatitis, as well as a result of acute use such as alcohol poisoning, suicide by exposure to alcohol, and alcohol-impaired driving fatalities.⁴

Excessive alcohol consumption poses other serious risks, including cases when intake is abruptly reduced without proper management. Alcohol withdrawal syndrome (AWS) can vary in severity, with potentially life-threatening complications such as hallucinations, seizures, and delirium tremens.⁵

These risks highlight the importance of professional intervention and support, not only to mitigate risks associated with AWS, but provide a pathway towards recovery from alcohol use disorder (AUD).

According to the 2022 National Survey on Drug Use and Health, 28.8 million US adults had AUD in the prior year, yet only 7.6% of these individuals received treatment and an even smaller group (2.2%) received medication-assisted treatment for alcohol.^6,7 This is despite American Psychiatric Association guidelines for the pharmacological treatment of patients with AUD, including the use of naltrexone, acamprosate, disulfiram, topiramate, or gabapentin, depending on therapy goals, past medication trials, medication contraindications, and patient preference.⁸ Several of these medications are approved by the US Food and Drug Administration (FDA) for the treatment of AUD and have support for effectiveness from randomized controlled trials and meta-analyses.^9-11

Clinical practice guidelines for the management of substance use disorders (SUDs) from the US Department of Veterans Affairs (VA) and US Department of Defense have strong recommendations for naltrexone and topiramate as first-line pharmacotherapies for moderate to severe AUD. Acamprosate and disulfiram are weak recommendations as alternative options. Gabapentin is a weak recommendation for cases where first-line treatments are contraindicated or ineffective. The guidelines emphasize the importance of a comprehensive approach to AUD treatment, including psychosocial interventions in addition to pharmacotherapy.¹²

A 2023 national survey found veterans reported higher alcohol consumption than nonveterans.¹³ At the end of fiscal year 2023, > 4.4 million veterans—6% of Veterans Health Administration patients—had been diagnosed with AUD.14 However, > 87% of these patients nationally, and 88% of Veterans Integrated Service Network (VISN) 21 patients, were not receiving naltrexone, acamprosate, disulfiram, or topiramate as part of their treatment. The VA Academic Detailing Service (ADS) now includes AUD pharmacotherapy as a campaign focus, highlighting its importance. The ADS is a pharmacy educational outreach program that uses unbiased clinical guidelines to promote aligning prescribing behavior with best practices. Academic detailing methods include speaking with health care practitioners (HCPs), and direct-to-consumer (DTC) patient education.

ADS campaigns include DTC educational handouts. Past ADS projects and research using DTC have demonstrated a significant improvement in outcomes and positively influencing patients’ pharmacotherapy treatment. ^15,16 A VA quality improvement project found a positive correlation between the initiation of AUD pharmacotherapy and engagement with mental health care following the distribution of AUD DTC patient education. ¹⁷ This project aimed to apply the same principles of prior research to explore the use of DTC across multiple facilities within VISN 21 to increase AUD pharmacotherapy. VISN 21 includes VA facilities and clinics across the Pacific Islands, Nevada, and California and serves about 350,000 veterans.

METHODS

A prospective cohort of VISN 21 veterans with or at high risk for AUD was identified using the VA ADS AUD Dashboard. The cohort included those not on acamprosate, disulfiram, naltrexone, topiramate, or gabapentin for treatment of AUD and had an elevated Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score of ≥ 6 (high risk) with an AUD diagnosis or ≥ 8 (severe risk) without a diagnosis. The AUDIT-C scores used in the dashboard are supported by the VA AUD clinician guide as the minimum scores when AUD pharmacotherapy should be offered to patients.¹⁸ Prescriptions filled outside the VA were not included in this dashboard.

Data and patient information were collected using the VA Corporate Data Warehouse. To be eligible, veterans needed a valid mailing address within the VISN 21 region and a primary care, mental health, or SUD clinician prescriber visit scheduled between October 1, 2023, and January 31, 2024. Veterans were excluded if they were in hospice, had a 1-year mortality risk score > 50% based on their Care Assessment Need (CAN) score, or facility leadership opted out of project involvement. Patients with both severe renal and hepatic impairments were excluded because they were ineligible for AUD pharmacotherapy. However, veterans with either renal or hepatic impairment (but not both) were included, as they could be potential candidates for ≥ 1 AUD pharmacotherapy option.

Initial correspondence with facilities was initiated through local academic detailers. A local champion was identified for the 1 facility without an academic detailer. Facilities could opt in or out of the project. Approval was provided by the local pharmacy and therapeutics committee, pharmacy, primary care, or psychiatry leadership. Approval process and clinician involvement varied by site.

Education

The selected AUD patient education was designed and approved by the national VA ADS (eappendix). The DTC patient education provided general knowledge about alcohol, including what constitutes a standard amount of alcohol, what is considered heavy drinking, risks of heavy drinking, creating a plan with a clinician to reduce and manage withdrawal symptoms, and additional resources. The DTC was accompanied by a cover letter that included a local facility contact number.

A centralized mailing facility was used for all materials. VA Northern California Health Care System provided the funding to cover the cost of postage. The list of veterans to be contacted was updated on a rolling basis and DTC education was mailed 2 weeks prior to their scheduled prescriber visit.

The eligible cohort of 1260 veterans received DTC education. A comparator group of 2048 veterans that did not receive DTC education was obtained retrospectively by using the same inclusion and exclusion criteria with a scheduled primary care, mental health, or SUD HCP visit from October 1, 2022, to January 31, 2023. The outcomes assessed were within 30 days of the scheduled visit, with the primary outcome as the initiation of AUD-related pharmacotherapy and the secondary outcome as the placement of a consultation for mental health or SUD services. Any consultations sent to Behavioral Health, Addiction, Mental Health, Psychiatric, and SUD services following the HCP visit, within the specified time frame, were used for the secondary outcome.

Matching and Analysis

A 1-to-1 nearest neighbor propensity score (PS) matching without replacement was used to pair the 1260 veterans from the intervention group with similarly scored comparator group veterans for a PS-matched final dataset of 2520 veterans. The PS model was a multivariate logistic regression with the outcome being exposure and comparator group status. Baseline characteristics used in the PS model were age, birth sex, race, facility of care, baseline AUDIT-C score, and days between project start and scheduled appointment. Covariate imbalance for the PS-matched sample was assessed to ensure the standardized mean difference for all covariates fell under a 0.1 threshold (Figure).¹⁹

A frequency table was provided to compare the discrete distributions of the baseline characteristics in the intervention and comparator groups. Logistic regression analysis was performed to evaluate the association between DTC education exposure and pharmacotherapy initiation, while controlling for potential confounders. Univariate and multivariate P value results for each variable included in the model were reported along with the multivariate odds ratios (ORs) and their associated 95% CIs. Logistic regression analyses were run for both outcomes. Each model included the exposure and comparator group status as well as the baseline characteristics included in the PS model. Statistical significance was set at P < .05. All statistical analyses were performed with R version 4.2.1.

RESULTS

Two of 7 VISN 21 sites did not participate, and 3 had restrictions on participation. DTC education was mailed about 2 weeks prior to scheduled visit for 1260 veterans; 53.6% identified as White, 37.6% were aged 41 to 60 years, and 79.2% had an AUDIT-C ≥ 8 (Table 1). Of those mailed education, there were 173 no-show appointments (13.7%). Thirty-two veterans (2.5%) in the DTC group and 33 veterans (2.6%) in the comparator group received an AUD-related pharmacotherapy prescription (P = .88) (Table 2). One hundred seventy-one veterans (13.6%) in the DTC group and 160 veterans (12.7%) in the comparator group had a consult placed for mental health or SUD services within 30 days of their appointment (P = .59) (Table 3).

DISCUSSION

This project did not yield statistically significant differences in either the primary or secondary outcomes within the 30-day follow-up window and found limited impact from the DTC educational outreach to veterans. The percentage of veterans that received AUD-related pharmacotherapy or consultations for mental health or SUD services was similarly low in the DTC and comparator groups. These findings suggest that although DTC education may raise awareness, it may not be sufficient on its own to drive changes in prescribing behavior or referral patterns without system-level support.

Addiction is a complex disease faced with stigma and requiring readiness by both the HCP and patient to move forward in support and treatment. The consequences of stigma can be severe: the more stigma perceived by a person with AUD, the less likely they are to seek treatment.²⁰ Stigma may exist even within HCPs and may lead to compromised care including shortened visits, less engagement, and less empathy.¹⁹ Cultural attitude towards alcohol use and intoxication can also be influenced through a wide range of sources including social media, movies, music, and television. Studies have shown targeted alcohol marketing may result in the development of positive beliefs about drinking and expand environments where alcohol use is socially acceptable and encouraged.²¹ These factors can impact drinking behavior, including the onset of drinking, binge drinking, and increased alcohol consumption.²²

Three VISN 21 sites in this study had restrictions on or excluded primary care from participation. Leadership at some of these facilities were concerned that primary care teams did not have the bandwidth to take on additional items and/or there was variable primary care readiness for initiating AUD pharmacotherapy. Further attempts should be made to integrate primary care into the process of initiating AUD treatment as significant research suggests that integrated care models for AUD may be associated with improved process and outcome measures of care.²³

There are several differences between this quality improvement project and prior research investigating the impact of DTC education for other conditions, such as the EMPOWER randomized controlled trial and VISN 22 project, which both demonstrated effectiveness of DTC education for reducing benzodiazepine use in geriatric veterans. ^15,16 These studies focused on reducing or stopping pharmacotherapy use, whereas this project sought to promote the initiation of AUD pharmacotherapy. These studies evaluated outcomes at least 6 months postindex date, whereas this project evaluated outcomes within 30 days postappointment. Furthermore, the educational content varied significantly. Other projects provided patients with information focused on specific medications and interventions, such as benzodiazepine tapering, while this project mailed general information on heavy drinking, its risks, and strategies for cutting back, without mentioning pharmacotherapy. The DTC material used in this project was chosen because it was a preapproved national VA ADS resource, which expedited the project timeline by avoiding the need for additional approvals at each participating site. These differences may impact the observed effectiveness of DTC education in this project, especially regarding the primary outcome.

Strengths and Limitations

This quality improvement project sent a large sample of veterans DTC education in a clinical setting across multiple sites. Additionally, PS matching methods were used to balance covariates between the comparator and DTC education group, thereby simulating a randomized controlled trial and reducing selection bias. The project brought attention to the VISN 21 AUD treatment rates, stimulated conversation across sites about available treatments and resources for AUD, and sparked collaboration between academic detailing, mental health, and primary care services. The time frame for visits was selected during the winter; the National Institute on Alcohol Abuse and Alcoholism notes this is a time when people may be more likely to engage in excessive alcohol consumption than at other times of the year.²⁴

The 30-day time frame for outcomes may have been too short to observe changes in prescribing or referral patterns. Additionally, the comparator group was comprised of veterans seen from October 1, 2022, to January 31, 2023, where seasonal timing may have influenced alcohol consumption behaviors and skewed the results. There were also no-show appointments in the DTC education group (13.7%), though it is likely some patients rescheduled and still received AUD pharmacotherapy within 30 days of the original appointment. Finally, it was not possible to confirm whether a patient opened and read the education that was mailed to them. This may be another reason to explore electronic distribution of DTC education. This all may have contributed to the lack of statistically significant differences in both the primary and secondary outcomes.

There was a high level of variability between facility participation in the project. Two of 7 sites did not participate, and 3 sites restricted primary care engagement. This represents a significant limitation, particularly for the secondary outcome of placing consultations for MH or SUD services. Facilities that only included mental health or SUD HCPs may have resulted in lower consultation rates due to their inherent specialization, reducing the likelihood of self-referrals.

The project may overestimate prescribed AUD pharmacotherapy in the primary outcome due to potential misclassification of medications. While the project adhered to the national VA ADS AUD dashboard’s definition of AUD pharmacotherapy, including acamprosate, disulfiram, naltrexone, topiramate, and gabapentin, some of these medications have multiple indications. For example, gabapentin is commonly prescribed for peripheral neuropathy, and topiramate is used to treat migraines and seizures. The multipurpose use adds uncertainty about whether they were prescribed specifically for AUD treatment, especially in cases where the HCP is responsible for treating a broad range of disease states, as in primary care.

CONCLUSIONS

Results of this quality improvement project did not show a statistically significant difference between patients sent DTC education and the comparator group for the initiation of AUD pharmacotherapy or placement of a consult to mental health or SUD services within 30 days of their scheduled visit. Future studies may seek to implement stricter criteria to confirm the intended use of topiramate and gabapentin, such as looking for keywords in the prescription instructions for use, performing chart reviews, and/or only including these medications if prescribed by a mental health or SUD HCP. Alternatively, future studies may consider limiting the analysis to only FDA-approved AUD medications: acamprosate, disulfiram, and naltrexone. It is vital to continue to enhance primary care HCP readiness to treat AUD, given the existing relationships and trust they often have with patients. Electronic methods for distributing DTC education could also be advantageous, as these methods may have the ability to track whether a message has been opened and read. Despite a lack of statistical significance, this project sparked crucial conversations and collaboration around AUD, available treatments, and addressing potential barriers to connecting patients to care within VISN 21.

THE DIAGNOSIS: Apocrine Hidrocystoma

Histology for all 3 lesions demonstrated similar cystic structures lined by a dual layer of epithelial cells, with the outermost layer composed of flattened myoepithelial cells and the inner layer composed of cells with apocrine features (Figure 1). Based on these findings, a diagnosis of apocrine hidrocystoma was made. The patient underwent successful surgical excision shortly thereafter without recurrence at follow-up 1 year later. 

Apocrine hidrocystomas are rare benign cystic lesions that are considered to be adenomatous proliferations of apocrine glands. They typically manifest as solitary asymptomatic lesions measuring 3 to 15 mm.¹ They tend to appear on the face, usually in the periorbital region, but also have been described on the neck, scalp, trunk, arms, and legs.^2-4 Multiple apocrine hidrocystomas can be a marker of 2 rare inherited disorders: Gorlin-Goltz syndrome and Schopf-Schulz-Passarge syndrome.⁵ Apocrine hidrocystomas may be flesh colored or may have a blue, black, or brown appearance due to the Tyndall effect, in which light with shorter wavelengths is scattered by the contents of the lesions.² Histologically, apocrine hidrocystomas are cysts lined by a dual layer of epithelial cells. The inner layer is composed of cells with apocrine features, and the outer layer is composed of flattened myoepithelial cells. Due to their range of colors and predilection for sun-exposed surfaces, apocrine hidrocystomas may be mistaken for various malignant neoplasms, including melanoma.^6,7

The differential diagnosis for our patient included agminated blue nevi, melanoma, pigmented basal cell carcinoma (BCC), and seborrheic keratosis. A blue nevus is a dermal melanocytic lesion that manifests as a well-demarcated, blue to blue-black papule that typically appears on the face, scalp, arms, legs, lower back, and buttocks. Although there are several histologic subtypes, the common blue nevus usually manifests as a solitary lesion measuring less than 1 cm, often developing during childhood to young adulthood.⁸ Histologically, common blue nevi are characterized by a dermal proliferation of deeply pigmented bipolar spindled melanocytes embedded in thickened collagen bundles, often with scattered epithelioid melanophages, and no conspicuous mitotic activity (Figure 2).⁹ There are other types of blue nevi, including cellular blue nevi, which tend to be larger and manifest commonly on the buttocks and sacrococcygeal region in early adulthood.⁹ Histologically, cellular blue nevi contain oval to spindled melanocytes with scattered melanophages forming a well-demarcated nodule typically in the reticular dermis. There may be bulbous extension into the subcutaneous adipose tissue. Occasional mitoses may be seen.^9,10 Melanoma can arise from common or cellular blue nevi, though it more frequently occurs with cellular blue nevi. Other subtypes of blue nevi have been described, including the sclerosing, plaque-type, combined, hypomelanotic/amelanotic, and pigmented epithelioid melanocytoma.¹¹ However, they typically have features of the common blue nevus or cellular blue nevus, such as oval/spindle cell morphology, some degree of melanin, and biphasic architecture, but are classified according to their dominant histologic characteristics. 

Given the location of our patient’s lesions on the scalp and his extensive history of sun exposure, malignancy was high in the differential. Multiple synchronous primary melanomas including nodular melanoma, blue nevus–like metastatic melanoma, and metastatic melanoma were considered. The leg and the scalp have the highest reported incidence of cutaneous metastases of melanoma, with many cases presenting as dermal or subcutaneous nodules and eruptive blue nevus–like papules, similar to our patient’s clinical presentation.^12,13 Nodular melanoma (NM) is one of 4 major types of melanoma, accounting for approximately 15% to 30% of cases in the United States.¹⁴ Nodular melanoma typically manifests as a smooth, raised, symmetric, well-circumscribed lesion with variable pigmentation, from very dark to amelanotic. Histologically, NM is defined as a dermal mass, either in isolation or with an epidermal component, not to exceed 3 rete ridges beyond the dermal component.¹⁵ Tumor cells have a high cell density with pleomorphism, usually with atypical epithelioid cells with vesicular nuclei and irregular cytoplasm, and occasionally spindle cells (Figure 2).¹⁶ Mitoses and necrosis are frequent. Scalp location independently is responsible for worse survival, both overall and melanoma specific.¹⁷ Nodular melanoma tends to have greater Breslow thickness at diagnosis than other melanoma subtypes and often carries a worse prognosis. 

Malignant melanomas that develop from or in conjunction with or bear histologic resemblance to blue nevi are termed blue nevus–like melanoma or blue nevus–associated melanoma. These malignancies are exceedingly rare, accounting for only 0.3% of melanomas in one Turkey-based multicenter study.¹⁸ The histologic criteria for diagnosing blue nevus–like melanoma are poorly defined, and terminology of these lesions has led to some debate in naming conventions.¹⁹ Nevertheless, unlike blue nevus, blue nevus–like melanoma demonstrates histologic features of malignancy, including pleomorphism, prominent nucleoli, mitotic activity, vascular invasion, and potential necrosis.¹⁰ The lack of an inflammatory infiltrate, surrounding fibrosis, junctional activity, and pre-existing nevus can help distinguish cutaneous melanoma metastases from primary nodular melanoma. Immunohistochemical stains such as S100, Melan-A/MART1, or SOX-10 can help confirm melanocytic lineage.¹² 

Pigmented BCC is a clinical and histologic variant of BCC characterized by increased melanin pigmentation due to melanocytes admixed with tumor cells. Dermoscopically, the pigment can have a maple leaf–like appearance with spoke-wheel areas, in-focus dots, and concentric structures at the dermoepidermal junction, which is more characteristic of superficial and infiltrating BCC.²⁰ In nodular BCC, the pigment occurs as blue-gray ovoid nests and globules in deeper layers of the dermis.²⁰ 

Seborrheic keratoses (SKs) can vary widely in clinical appearance, with pigmentation ranging from flesh colored to yellow to brown to black. Melanoacanthomas are acanthotic SKs that are highly pigmented due to intermixed epidermal melanocytes and subepidermal melanophages.²¹ Dermoscopy can help distinguish cutaneous malignancies from SKs, which often demonstrate fissures and ridges, comedolike openings, and milialike cysts. Biopsy sometimes is required to assess for malignancy, as was the case in our patient. The classic histologic features of SKs include acanthosis, papillomatosis, and hyperkeratosis.²² 

This case highlights the need to consider apocrine hidrocystoma, along with malignancy, in the differential diagnosis of pigmented cystic masses of the face and scalp. Because apocrine hidrocystomas are benign, they do not need to be treated but often are surgically excised for cosmesis or complete histopathologic examination. Destruction via electrodessication, carbon dioxide ablation, trichloroacetic acid chemical ablation, botulinum toxin injection, and anticholinergic creams sometimes is used, especially for cosmetic treatment of multiple small lesions.⁵ Our patient was treated with surgical excision with no evidence of recurrence on follow-up 1 year later. 

THE DIAGNOSIS: Apocrine Hidrocystoma

Histology for all 3 lesions demonstrated similar cystic structures lined by a dual layer of epithelial cells, with the outermost layer composed of flattened myoepithelial cells and the inner layer composed of cells with apocrine features (Figure 1). Based on these findings, a diagnosis of apocrine hidrocystoma was made. The patient underwent successful surgical excision shortly thereafter without recurrence at follow-up 1 year later. 

Apocrine hidrocystomas are rare benign cystic lesions that are considered to be adenomatous proliferations of apocrine glands. They typically manifest as solitary asymptomatic lesions measuring 3 to 15 mm.¹ They tend to appear on the face, usually in the periorbital region, but also have been described on the neck, scalp, trunk, arms, and legs.^2-4 Multiple apocrine hidrocystomas can be a marker of 2 rare inherited disorders: Gorlin-Goltz syndrome and Schopf-Schulz-Passarge syndrome.⁵ Apocrine hidrocystomas may be flesh colored or may have a blue, black, or brown appearance due to the Tyndall effect, in which light with shorter wavelengths is scattered by the contents of the lesions.² Histologically, apocrine hidrocystomas are cysts lined by a dual layer of epithelial cells. The inner layer is composed of cells with apocrine features, and the outer layer is composed of flattened myoepithelial cells. Due to their range of colors and predilection for sun-exposed surfaces, apocrine hidrocystomas may be mistaken for various malignant neoplasms, including melanoma.^6,7

The differential diagnosis for our patient included agminated blue nevi, melanoma, pigmented basal cell carcinoma (BCC), and seborrheic keratosis. A blue nevus is a dermal melanocytic lesion that manifests as a well-demarcated, blue to blue-black papule that typically appears on the face, scalp, arms, legs, lower back, and buttocks. Although there are several histologic subtypes, the common blue nevus usually manifests as a solitary lesion measuring less than 1 cm, often developing during childhood to young adulthood.⁸ Histologically, common blue nevi are characterized by a dermal proliferation of deeply pigmented bipolar spindled melanocytes embedded in thickened collagen bundles, often with scattered epithelioid melanophages, and no conspicuous mitotic activity (Figure 2).⁹ There are other types of blue nevi, including cellular blue nevi, which tend to be larger and manifest commonly on the buttocks and sacrococcygeal region in early adulthood.⁹ Histologically, cellular blue nevi contain oval to spindled melanocytes with scattered melanophages forming a well-demarcated nodule typically in the reticular dermis. There may be bulbous extension into the subcutaneous adipose tissue. Occasional mitoses may be seen.^9,10 Melanoma can arise from common or cellular blue nevi, though it more frequently occurs with cellular blue nevi. Other subtypes of blue nevi have been described, including the sclerosing, plaque-type, combined, hypomelanotic/amelanotic, and pigmented epithelioid melanocytoma.¹¹ However, they typically have features of the common blue nevus or cellular blue nevus, such as oval/spindle cell morphology, some degree of melanin, and biphasic architecture, but are classified according to their dominant histologic characteristics. 

Given the location of our patient’s lesions on the scalp and his extensive history of sun exposure, malignancy was high in the differential. Multiple synchronous primary melanomas including nodular melanoma, blue nevus–like metastatic melanoma, and metastatic melanoma were considered. The leg and the scalp have the highest reported incidence of cutaneous metastases of melanoma, with many cases presenting as dermal or subcutaneous nodules and eruptive blue nevus–like papules, similar to our patient’s clinical presentation.^12,13 Nodular melanoma (NM) is one of 4 major types of melanoma, accounting for approximately 15% to 30% of cases in the United States.¹⁴ Nodular melanoma typically manifests as a smooth, raised, symmetric, well-circumscribed lesion with variable pigmentation, from very dark to amelanotic. Histologically, NM is defined as a dermal mass, either in isolation or with an epidermal component, not to exceed 3 rete ridges beyond the dermal component.¹⁵ Tumor cells have a high cell density with pleomorphism, usually with atypical epithelioid cells with vesicular nuclei and irregular cytoplasm, and occasionally spindle cells (Figure 2).¹⁶ Mitoses and necrosis are frequent. Scalp location independently is responsible for worse survival, both overall and melanoma specific.¹⁷ Nodular melanoma tends to have greater Breslow thickness at diagnosis than other melanoma subtypes and often carries a worse prognosis. 

Malignant melanomas that develop from or in conjunction with or bear histologic resemblance to blue nevi are termed blue nevus–like melanoma or blue nevus–associated melanoma. These malignancies are exceedingly rare, accounting for only 0.3% of melanomas in one Turkey-based multicenter study.¹⁸ The histologic criteria for diagnosing blue nevus–like melanoma are poorly defined, and terminology of these lesions has led to some debate in naming conventions.¹⁹ Nevertheless, unlike blue nevus, blue nevus–like melanoma demonstrates histologic features of malignancy, including pleomorphism, prominent nucleoli, mitotic activity, vascular invasion, and potential necrosis.¹⁰ The lack of an inflammatory infiltrate, surrounding fibrosis, junctional activity, and pre-existing nevus can help distinguish cutaneous melanoma metastases from primary nodular melanoma. Immunohistochemical stains such as S100, Melan-A/MART1, or SOX-10 can help confirm melanocytic lineage.¹² 

Pigmented BCC is a clinical and histologic variant of BCC characterized by increased melanin pigmentation due to melanocytes admixed with tumor cells. Dermoscopically, the pigment can have a maple leaf–like appearance with spoke-wheel areas, in-focus dots, and concentric structures at the dermoepidermal junction, which is more characteristic of superficial and infiltrating BCC.²⁰ In nodular BCC, the pigment occurs as blue-gray ovoid nests and globules in deeper layers of the dermis.²⁰ 

Seborrheic keratoses (SKs) can vary widely in clinical appearance, with pigmentation ranging from flesh colored to yellow to brown to black. Melanoacanthomas are acanthotic SKs that are highly pigmented due to intermixed epidermal melanocytes and subepidermal melanophages.²¹ Dermoscopy can help distinguish cutaneous malignancies from SKs, which often demonstrate fissures and ridges, comedolike openings, and milialike cysts. Biopsy sometimes is required to assess for malignancy, as was the case in our patient. The classic histologic features of SKs include acanthosis, papillomatosis, and hyperkeratosis.²² 

This case highlights the need to consider apocrine hidrocystoma, along with malignancy, in the differential diagnosis of pigmented cystic masses of the face and scalp. Because apocrine hidrocystomas are benign, they do not need to be treated but often are surgically excised for cosmesis or complete histopathologic examination. Destruction via electrodessication, carbon dioxide ablation, trichloroacetic acid chemical ablation, botulinum toxin injection, and anticholinergic creams sometimes is used, especially for cosmetic treatment of multiple small lesions.⁵ Our patient was treated with surgical excision with no evidence of recurrence on follow-up 1 year later. 

THE DIAGNOSIS: Apocrine Hidrocystoma

Histology for all 3 lesions demonstrated similar cystic structures lined by a dual layer of epithelial cells, with the outermost layer composed of flattened myoepithelial cells and the inner layer composed of cells with apocrine features (Figure 1). Based on these findings, a diagnosis of apocrine hidrocystoma was made. The patient underwent successful surgical excision shortly thereafter without recurrence at follow-up 1 year later. 

Apocrine hidrocystomas are rare benign cystic lesions that are considered to be adenomatous proliferations of apocrine glands. They typically manifest as solitary asymptomatic lesions measuring 3 to 15 mm.¹ They tend to appear on the face, usually in the periorbital region, but also have been described on the neck, scalp, trunk, arms, and legs.^2-4 Multiple apocrine hidrocystomas can be a marker of 2 rare inherited disorders: Gorlin-Goltz syndrome and Schopf-Schulz-Passarge syndrome.⁵ Apocrine hidrocystomas may be flesh colored or may have a blue, black, or brown appearance due to the Tyndall effect, in which light with shorter wavelengths is scattered by the contents of the lesions.² Histologically, apocrine hidrocystomas are cysts lined by a dual layer of epithelial cells. The inner layer is composed of cells with apocrine features, and the outer layer is composed of flattened myoepithelial cells. Due to their range of colors and predilection for sun-exposed surfaces, apocrine hidrocystomas may be mistaken for various malignant neoplasms, including melanoma.^6,7

The differential diagnosis for our patient included agminated blue nevi, melanoma, pigmented basal cell carcinoma (BCC), and seborrheic keratosis. A blue nevus is a dermal melanocytic lesion that manifests as a well-demarcated, blue to blue-black papule that typically appears on the face, scalp, arms, legs, lower back, and buttocks. Although there are several histologic subtypes, the common blue nevus usually manifests as a solitary lesion measuring less than 1 cm, often developing during childhood to young adulthood.⁸ Histologically, common blue nevi are characterized by a dermal proliferation of deeply pigmented bipolar spindled melanocytes embedded in thickened collagen bundles, often with scattered epithelioid melanophages, and no conspicuous mitotic activity (Figure 2).⁹ There are other types of blue nevi, including cellular blue nevi, which tend to be larger and manifest commonly on the buttocks and sacrococcygeal region in early adulthood.⁹ Histologically, cellular blue nevi contain oval to spindled melanocytes with scattered melanophages forming a well-demarcated nodule typically in the reticular dermis. There may be bulbous extension into the subcutaneous adipose tissue. Occasional mitoses may be seen.^9,10 Melanoma can arise from common or cellular blue nevi, though it more frequently occurs with cellular blue nevi. Other subtypes of blue nevi have been described, including the sclerosing, plaque-type, combined, hypomelanotic/amelanotic, and pigmented epithelioid melanocytoma.¹¹ However, they typically have features of the common blue nevus or cellular blue nevus, such as oval/spindle cell morphology, some degree of melanin, and biphasic architecture, but are classified according to their dominant histologic characteristics. 

Given the location of our patient’s lesions on the scalp and his extensive history of sun exposure, malignancy was high in the differential. Multiple synchronous primary melanomas including nodular melanoma, blue nevus–like metastatic melanoma, and metastatic melanoma were considered. The leg and the scalp have the highest reported incidence of cutaneous metastases of melanoma, with many cases presenting as dermal or subcutaneous nodules and eruptive blue nevus–like papules, similar to our patient’s clinical presentation.^12,13 Nodular melanoma (NM) is one of 4 major types of melanoma, accounting for approximately 15% to 30% of cases in the United States.¹⁴ Nodular melanoma typically manifests as a smooth, raised, symmetric, well-circumscribed lesion with variable pigmentation, from very dark to amelanotic. Histologically, NM is defined as a dermal mass, either in isolation or with an epidermal component, not to exceed 3 rete ridges beyond the dermal component.¹⁵ Tumor cells have a high cell density with pleomorphism, usually with atypical epithelioid cells with vesicular nuclei and irregular cytoplasm, and occasionally spindle cells (Figure 2).¹⁶ Mitoses and necrosis are frequent. Scalp location independently is responsible for worse survival, both overall and melanoma specific.¹⁷ Nodular melanoma tends to have greater Breslow thickness at diagnosis than other melanoma subtypes and often carries a worse prognosis. 

Malignant melanomas that develop from or in conjunction with or bear histologic resemblance to blue nevi are termed blue nevus–like melanoma or blue nevus–associated melanoma. These malignancies are exceedingly rare, accounting for only 0.3% of melanomas in one Turkey-based multicenter study.¹⁸ The histologic criteria for diagnosing blue nevus–like melanoma are poorly defined, and terminology of these lesions has led to some debate in naming conventions.¹⁹ Nevertheless, unlike blue nevus, blue nevus–like melanoma demonstrates histologic features of malignancy, including pleomorphism, prominent nucleoli, mitotic activity, vascular invasion, and potential necrosis.¹⁰ The lack of an inflammatory infiltrate, surrounding fibrosis, junctional activity, and pre-existing nevus can help distinguish cutaneous melanoma metastases from primary nodular melanoma. Immunohistochemical stains such as S100, Melan-A/MART1, or SOX-10 can help confirm melanocytic lineage.¹² 

Pigmented BCC is a clinical and histologic variant of BCC characterized by increased melanin pigmentation due to melanocytes admixed with tumor cells. Dermoscopically, the pigment can have a maple leaf–like appearance with spoke-wheel areas, in-focus dots, and concentric structures at the dermoepidermal junction, which is more characteristic of superficial and infiltrating BCC.²⁰ In nodular BCC, the pigment occurs as blue-gray ovoid nests and globules in deeper layers of the dermis.²⁰ 

Seborrheic keratoses (SKs) can vary widely in clinical appearance, with pigmentation ranging from flesh colored to yellow to brown to black. Melanoacanthomas are acanthotic SKs that are highly pigmented due to intermixed epidermal melanocytes and subepidermal melanophages.²¹ Dermoscopy can help distinguish cutaneous malignancies from SKs, which often demonstrate fissures and ridges, comedolike openings, and milialike cysts. Biopsy sometimes is required to assess for malignancy, as was the case in our patient. The classic histologic features of SKs include acanthosis, papillomatosis, and hyperkeratosis.²² 

This case highlights the need to consider apocrine hidrocystoma, along with malignancy, in the differential diagnosis of pigmented cystic masses of the face and scalp. Because apocrine hidrocystomas are benign, they do not need to be treated but often are surgically excised for cosmesis or complete histopathologic examination. Destruction via electrodessication, carbon dioxide ablation, trichloroacetic acid chemical ablation, botulinum toxin injection, and anticholinergic creams sometimes is used, especially for cosmetic treatment of multiple small lesions.⁵ Our patient was treated with surgical excision with no evidence of recurrence on follow-up 1 year later. 

To the Editor:

A 34-year-old Brazilian woman presented to the dermatology department with pruritic lesions on the neck and chest that had been present since adolescence. She reported a family history of Darier disease in her father. Physical examination revealed erythematous follicular papules on the neck, inframammary region, and abdomen (Figure 1A), as well as longitudinal bandlike leukonychia and distal nail splits on the fingernails (Figure 1B). Histopathology of a lesion on the back revealed compact hyperkeratosis and parakeratosis above an acantholytic cleft accompanied by dyskeratotic keratinocytes, including some corps ronds and grains, which supported the clinical impression of Darier disease (Figure 2). The typical clinical presentation along with the family history and histopathology confirmed the diagnosis. After therapeutic failure with topical corticosteroids and oral antibiotics for 3 months, low-dose oral naltrexone (4.5 mg/d) as monotherapy noticeably improved the lesions and pruritus within 2 months, with near-complete regression at 6 months, achieving disease stability (Figures 1C and 1D). The patient remained stable with no recurrence after 1 year of follow-up.

Darier disease is an autosomal-dominant genodermatosis caused by a mutation in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum calcium ATPase, leading to defective intracellular calcium signaling and alterations in epidermal adhesion and keratinization.¹ Darier disease typically begins in adolescence and is aggravated by exposure to heat and friction. It is characterized by seborrheic distribution of painful and pruritic red-brown keratotic papules. Nail manifestations include longitudinal ridges—erythronychia and/or leukonychia—and grooves that end in a V-shaped notch. The differential diagnosis includes Hailey-Hailey disease, psoriasis, and pityriasis rubra pilaris.^1,2 The diagnosis is clinical and is confirmed by histopathology, which reveals suprabasal cleavage, acantholytic dyskeratosis, corps ronds, and grains. Treatment options are limited and include corticosteroids, oral and/or topical antibiotics, and systemic retinoids.²

 

Oral naltrexone has been used in Darier disease based on its observed effectiveness in Hailey-Hailey disease, considering the histopathologic similarities and alterations in calcium homeostasis in both conditions. Low-dose oral naltrexone (1-5 mg/d) increases the expression of opioid receptors (δ, μ, κ), enhancing its immunomodulatory and antinociceptive effects. The δ opioid receptor regulates the expression of desmoglein, improving epidermal differentiation and wound healing.³ Activation of the δ and μ receptors increases intracellular calcium through the inositol phosphate pathway, which contributes to calcium homeostasis.⁴ Naltrexone blocks the nonopioid toll-like receptor 4 found in keratinocytes and macrophages, exerting an anti-inflammatory effect by reducing proinflammatory cytokines.³ Adverse events associated with low-dose naltrexone are minimal, mostly mild, and often related to sleep disorders^3,5; however, patients should undergo screening for prior opioid dependence, recent opioid usage, and signs of opioid withdrawal before initiating naltrexone treatment.⁵

Boehmer et al⁶ used naltrexone (4.5 mg/d) and oral magnesium (200 mg/d) in 6 patients with inconsistent results, except for 1 case that concurrently used acitretin (25 mg/d) with satisfactory improvement. Pessoa et al⁷ added naltrexone (4.5 mg/d) to oral isotretinoin (0.5 mg/kg/d) in 1 patient, resulting in notable improvement of lesions within 3 months. 

In our patient with Darier disease, low-dose naltrexone demonstrated a substantial response as monotherapy after 2 months of treatment and nearly complete regression of lesions within 6 months, with no reported side effects after 1 year of follow-up. The use of low-dose naltrexone could be a promising and safe treatment option as monotherapy or in combination with conventional therapy for Darier disease; however, further studies are needed.

To the Editor:

A 34-year-old Brazilian woman presented to the dermatology department with pruritic lesions on the neck and chest that had been present since adolescence. She reported a family history of Darier disease in her father. Physical examination revealed erythematous follicular papules on the neck, inframammary region, and abdomen (Figure 1A), as well as longitudinal bandlike leukonychia and distal nail splits on the fingernails (Figure 1B). Histopathology of a lesion on the back revealed compact hyperkeratosis and parakeratosis above an acantholytic cleft accompanied by dyskeratotic keratinocytes, including some corps ronds and grains, which supported the clinical impression of Darier disease (Figure 2). The typical clinical presentation along with the family history and histopathology confirmed the diagnosis. After therapeutic failure with topical corticosteroids and oral antibiotics for 3 months, low-dose oral naltrexone (4.5 mg/d) as monotherapy noticeably improved the lesions and pruritus within 2 months, with near-complete regression at 6 months, achieving disease stability (Figures 1C and 1D). The patient remained stable with no recurrence after 1 year of follow-up.

Darier disease is an autosomal-dominant genodermatosis caused by a mutation in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum calcium ATPase, leading to defective intracellular calcium signaling and alterations in epidermal adhesion and keratinization.¹ Darier disease typically begins in adolescence and is aggravated by exposure to heat and friction. It is characterized by seborrheic distribution of painful and pruritic red-brown keratotic papules. Nail manifestations include longitudinal ridges—erythronychia and/or leukonychia—and grooves that end in a V-shaped notch. The differential diagnosis includes Hailey-Hailey disease, psoriasis, and pityriasis rubra pilaris.^1,2 The diagnosis is clinical and is confirmed by histopathology, which reveals suprabasal cleavage, acantholytic dyskeratosis, corps ronds, and grains. Treatment options are limited and include corticosteroids, oral and/or topical antibiotics, and systemic retinoids.²

 

Oral naltrexone has been used in Darier disease based on its observed effectiveness in Hailey-Hailey disease, considering the histopathologic similarities and alterations in calcium homeostasis in both conditions. Low-dose oral naltrexone (1-5 mg/d) increases the expression of opioid receptors (δ, μ, κ), enhancing its immunomodulatory and antinociceptive effects. The δ opioid receptor regulates the expression of desmoglein, improving epidermal differentiation and wound healing.³ Activation of the δ and μ receptors increases intracellular calcium through the inositol phosphate pathway, which contributes to calcium homeostasis.⁴ Naltrexone blocks the nonopioid toll-like receptor 4 found in keratinocytes and macrophages, exerting an anti-inflammatory effect by reducing proinflammatory cytokines.³ Adverse events associated with low-dose naltrexone are minimal, mostly mild, and often related to sleep disorders^3,5; however, patients should undergo screening for prior opioid dependence, recent opioid usage, and signs of opioid withdrawal before initiating naltrexone treatment.⁵

Boehmer et al⁶ used naltrexone (4.5 mg/d) and oral magnesium (200 mg/d) in 6 patients with inconsistent results, except for 1 case that concurrently used acitretin (25 mg/d) with satisfactory improvement. Pessoa et al⁷ added naltrexone (4.5 mg/d) to oral isotretinoin (0.5 mg/kg/d) in 1 patient, resulting in notable improvement of lesions within 3 months. 

In our patient with Darier disease, low-dose naltrexone demonstrated a substantial response as monotherapy after 2 months of treatment and nearly complete regression of lesions within 6 months, with no reported side effects after 1 year of follow-up. The use of low-dose naltrexone could be a promising and safe treatment option as monotherapy or in combination with conventional therapy for Darier disease; however, further studies are needed.

To the Editor:

A 34-year-old Brazilian woman presented to the dermatology department with pruritic lesions on the neck and chest that had been present since adolescence. She reported a family history of Darier disease in her father. Physical examination revealed erythematous follicular papules on the neck, inframammary region, and abdomen (Figure 1A), as well as longitudinal bandlike leukonychia and distal nail splits on the fingernails (Figure 1B). Histopathology of a lesion on the back revealed compact hyperkeratosis and parakeratosis above an acantholytic cleft accompanied by dyskeratotic keratinocytes, including some corps ronds and grains, which supported the clinical impression of Darier disease (Figure 2). The typical clinical presentation along with the family history and histopathology confirmed the diagnosis. After therapeutic failure with topical corticosteroids and oral antibiotics for 3 months, low-dose oral naltrexone (4.5 mg/d) as monotherapy noticeably improved the lesions and pruritus within 2 months, with near-complete regression at 6 months, achieving disease stability (Figures 1C and 1D). The patient remained stable with no recurrence after 1 year of follow-up.

Darier disease is an autosomal-dominant genodermatosis caused by a mutation in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum calcium ATPase, leading to defective intracellular calcium signaling and alterations in epidermal adhesion and keratinization.¹ Darier disease typically begins in adolescence and is aggravated by exposure to heat and friction. It is characterized by seborrheic distribution of painful and pruritic red-brown keratotic papules. Nail manifestations include longitudinal ridges—erythronychia and/or leukonychia—and grooves that end in a V-shaped notch. The differential diagnosis includes Hailey-Hailey disease, psoriasis, and pityriasis rubra pilaris.^1,2 The diagnosis is clinical and is confirmed by histopathology, which reveals suprabasal cleavage, acantholytic dyskeratosis, corps ronds, and grains. Treatment options are limited and include corticosteroids, oral and/or topical antibiotics, and systemic retinoids.²

 

Oral naltrexone has been used in Darier disease based on its observed effectiveness in Hailey-Hailey disease, considering the histopathologic similarities and alterations in calcium homeostasis in both conditions. Low-dose oral naltrexone (1-5 mg/d) increases the expression of opioid receptors (δ, μ, κ), enhancing its immunomodulatory and antinociceptive effects. The δ opioid receptor regulates the expression of desmoglein, improving epidermal differentiation and wound healing.³ Activation of the δ and μ receptors increases intracellular calcium through the inositol phosphate pathway, which contributes to calcium homeostasis.⁴ Naltrexone blocks the nonopioid toll-like receptor 4 found in keratinocytes and macrophages, exerting an anti-inflammatory effect by reducing proinflammatory cytokines.³ Adverse events associated with low-dose naltrexone are minimal, mostly mild, and often related to sleep disorders^3,5; however, patients should undergo screening for prior opioid dependence, recent opioid usage, and signs of opioid withdrawal before initiating naltrexone treatment.⁵

Boehmer et al⁶ used naltrexone (4.5 mg/d) and oral magnesium (200 mg/d) in 6 patients with inconsistent results, except for 1 case that concurrently used acitretin (25 mg/d) with satisfactory improvement. Pessoa et al⁷ added naltrexone (4.5 mg/d) to oral isotretinoin (0.5 mg/kg/d) in 1 patient, resulting in notable improvement of lesions within 3 months. 

In our patient with Darier disease, low-dose naltrexone demonstrated a substantial response as monotherapy after 2 months of treatment and nearly complete regression of lesions within 6 months, with no reported side effects after 1 year of follow-up. The use of low-dose naltrexone could be a promising and safe treatment option as monotherapy or in combination with conventional therapy for Darier disease; however, further studies are needed.

Peer-review, evidence-based, detailed gene/drug clinical practice guidelines suggest that genetic variations can impact how individuals metabolize medications, which is sometimes included in medication prescribing information.^1-3 Pharmacogenomic testing identifies genetic markers so medication selection and dosing can be tailored to each individual by identifying whether a specific medication is likely to be safe and effective prior to prescribing.⁴

Pharmacogenomics can be a valuable tool for personalizing medicine but has had suboptimal implementation since its discovery. The US Department of Veterans Affairs (VA) health care system reviewed the implementation of the Pharmacogenomic Testing for Veterans (PHASER) program. This review identified clinician barriers pre- and post-PHASER program implementation; staffing issues, competing clinical priorities, and inadequate PHASER program resources were the most frequently reported barriers to implementation of pharmacogenomic testing.⁵

Another evaluation of the implementation of the PHASER program that surveyed VA patients found that patients could be separated into 3 groups. Acceptors of pharmacogenomic testing emphasized potential health benefits of testing. Patients that declined testing often cited concerns for genetic information affecting insurance coverage, being misused, or being susceptible to data breach. The third group—identified as contemplators—reported the need for clinician outreach to impact their decision on whether or not to receive pharmacogenomic testing.⁶ These studies suggest that removing barriers by providing ample pharmacogenomics resources to clinicians, in addition to detailed training on how to offer and follow up with patients regarding pharmacogenomic testing, is crucial to successful implementation of the PHASER program.

PHASER

In 2019, the VA began working with Sanford Health to establish the PHASER program and offer pharmacogenomic testing. PHASER has since expanded to 25 VA medical centers, including the VA Central Ohio Healthcare System (VACOHCS).^7,8 Pharmacogenomic testing through PHASER is conducted using a standardized laboratory panel that includes 12 different medication classes.⁹ The drug classes include certain anti-infective, anticoagulant, antiplatelet, cardiovascular, cholesterol, gastrointestinal, mental health, neurological, oncology, pain, transplant, and other miscellaneous medications. Medications are correlated to each class and assessed for therapeutic impacts based on gene panel results.

Clinical recommendations for medication-gene interactions can range from monitoring for increased risk of adverse effects or therapeutic failure to recommending avoiding a medication. For example, patients who test positive for the HLA-B gene have significantly increased risk of hypersensitivity to abacavir, an HIV treatment.¹⁰

Similarly, patients who cannot adequately metabolize cytochrome P450 2C19 should consider avoiding clopidogrel as they are unlikely to convert clopidogrel to its active prodrug, which reduces its effectiveness.¹¹ Pharmacists can play a critical role educating patients about pharmacogenomic testing, especially within hematology and oncology.¹² Patients can benefit from this testing even if they are not currently taking medications with known concerns as they could be prescribed in the future. The SLCO1B1 gene-drug test, for example, can identify risk for statin-associated muscle symptoms.¹³

Clinical pharmacist practitioners (CPPs) can increase access to genetic testing because they interact with patients in a variety of settings and can order this laboratory test.^12,14 Recent research has demonstrated that most VA patients carry ≥ 1 genetic variant that may influence medication decisions and that half of veterans are prescribed a medication with known gene-drug interactions.¹⁵ CPP ordering of pharmacogenomic tests at the VACOHCS outpatient clinic was evaluated through collection of baseline data from March 8, 2023, to September 8, 2023. A goal was identified to increase orders by 50% for a patient care quality improvement initiative and use CPPs to increase access to pharmacogenomic testing. The purpose of this quality improvement initiative was to expand access to pharmacogenomic testing through process implementation and improvement within CPP-led clinic settings.

Gap Analysis

Lean Six Sigma A3 methodology was used to identify ways to increase the use of pharmacogenomic testing for veterans at VACOHCS and develop an improved process for increased ordering of pharmacogenomic testing. Lean Six Sigma A3 methodology is a stepwise approach to process improvement that helps identify gaps in efficiency, sustainable changes, and eliminate waste.¹⁶ Baseline data were collected from March 8, 2023, to September 8, 2023, to determine the frequency of CPPs ordering pharmacogenomic laboratory panels during clinic appointments. The ordering of pharmacogenomic panels was monitored by the VACOHCS PHASER coordinator.

CPPs were surveyed to identify perceived barriers to PHASER implementation. A gap analysis was conducted using Lean Six Sigma A3 methodology. Gap analyses use lean tools such as a Fishbone Diagram to illustrate and identify the gap between current state and ideal state. (Figure 1).The following barriers were identified: lack of clinician education materials, lack of a standardized patient screening process, time constraints on patient education and ordering, higher priority clinical needs, forgetting to order, lack of comfort with pharmacogenomics ordering and education, lack of support for the initiative, and increased workload and burnout. Among these perceived barriers, higher priority clinical needs, forgetting to order, and time constraints ranked highest in importance among CPPs. 

In line with Lean Six Sigma A3 methodology, several tests of change were used to improve pharmacogenomic testing ordering. These changes focused on increasing patient and clinician awareness, facilitating discussion, educating clinicians, and simplifying documentation to ease time constraints. Several strategies were employed postimplementation (Figure 2). Prefilled templates simplified documentation. These templates helped identify patients without pharmacogenomic testing, provided reminders, and saved documentation time during visits. CPPs also received training and materials on PHASER ordering and documentation within encounter notes. Additionally, patient-directed advertisements were displayed in CPP examination rooms to help inspire and facilitate discussion between veterans and CPPs.

Process Improvement Data

The quality improvement project goal was to increase PHASER orders by 50% after 3 months. PHASER orders increased from 87 at baseline (March 8, 2023, to September 8, 2023) to 196 during the intervention (November 16, 2023, to February 16, 2024), a 125% increase. Changes were consistent and sustained with 65 orders the first month, 67 orders the second month, and 64 orders the third month.

Discussion

Using Lean Six Sigma A3 methodology for a quality improvement process to increase PHASER orders by CPPs revealed barriers and guided potential solutions to overcome these barriers. Interventions included additional CPP training and ordering, tools for easier identification of potential patients, documentation best practices, patient-directed advertisements to facilitate conversations. These interventions required about 8 hours for preparation, distribution, development, and interpretation of surveys, education, and documentation materials. The financial impact of these interventions was already included in allotted office materials budgeted and provided. Additional funding was not needed to provide patient-directed advertisements or education materials. The VACOHCS pharmacogenomics CPP discusses PHASER test results with patients at a separate appointment.

Future directions include educating other CPPs to assist in discussing results with veterans. Overall, the changes implemented to improve the PHASER ordering process were low effort and exemplify the ease of streamlining future initiatives, allowing for sustained optimal implementation of pharmacogenomic testing.

Conclusions

A quality improvement initiative resulted in increased PHASER orders and a clearly defined process, allowing for a continued increase and sustained support. Perceived barriers were identified, and the changes implemented were often low effort but exhibited a sustained impact. The insights gleaned from this process will shape future process development initiatives and continue to sustain pharmacogenomic testing ordering by CPPs. This process will be extended to other VACOHCS clinical departments to further support increased access to pharmacogenomic testing, reduce medication trial and error, and reduce hospitalizations from adverse effects for veterans.

Peer-review, evidence-based, detailed gene/drug clinical practice guidelines suggest that genetic variations can impact how individuals metabolize medications, which is sometimes included in medication prescribing information.^1-3 Pharmacogenomic testing identifies genetic markers so medication selection and dosing can be tailored to each individual by identifying whether a specific medication is likely to be safe and effective prior to prescribing.⁴

Pharmacogenomics can be a valuable tool for personalizing medicine but has had suboptimal implementation since its discovery. The US Department of Veterans Affairs (VA) health care system reviewed the implementation of the Pharmacogenomic Testing for Veterans (PHASER) program. This review identified clinician barriers pre- and post-PHASER program implementation; staffing issues, competing clinical priorities, and inadequate PHASER program resources were the most frequently reported barriers to implementation of pharmacogenomic testing.⁵

Another evaluation of the implementation of the PHASER program that surveyed VA patients found that patients could be separated into 3 groups. Acceptors of pharmacogenomic testing emphasized potential health benefits of testing. Patients that declined testing often cited concerns for genetic information affecting insurance coverage, being misused, or being susceptible to data breach. The third group—identified as contemplators—reported the need for clinician outreach to impact their decision on whether or not to receive pharmacogenomic testing.⁶ These studies suggest that removing barriers by providing ample pharmacogenomics resources to clinicians, in addition to detailed training on how to offer and follow up with patients regarding pharmacogenomic testing, is crucial to successful implementation of the PHASER program.

PHASER

In 2019, the VA began working with Sanford Health to establish the PHASER program and offer pharmacogenomic testing. PHASER has since expanded to 25 VA medical centers, including the VA Central Ohio Healthcare System (VACOHCS).^7,8 Pharmacogenomic testing through PHASER is conducted using a standardized laboratory panel that includes 12 different medication classes.⁹ The drug classes include certain anti-infective, anticoagulant, antiplatelet, cardiovascular, cholesterol, gastrointestinal, mental health, neurological, oncology, pain, transplant, and other miscellaneous medications. Medications are correlated to each class and assessed for therapeutic impacts based on gene panel results.

Clinical recommendations for medication-gene interactions can range from monitoring for increased risk of adverse effects or therapeutic failure to recommending avoiding a medication. For example, patients who test positive for the HLA-B gene have significantly increased risk of hypersensitivity to abacavir, an HIV treatment.¹⁰

Similarly, patients who cannot adequately metabolize cytochrome P450 2C19 should consider avoiding clopidogrel as they are unlikely to convert clopidogrel to its active prodrug, which reduces its effectiveness.¹¹ Pharmacists can play a critical role educating patients about pharmacogenomic testing, especially within hematology and oncology.¹² Patients can benefit from this testing even if they are not currently taking medications with known concerns as they could be prescribed in the future. The SLCO1B1 gene-drug test, for example, can identify risk for statin-associated muscle symptoms.¹³

Clinical pharmacist practitioners (CPPs) can increase access to genetic testing because they interact with patients in a variety of settings and can order this laboratory test.^12,14 Recent research has demonstrated that most VA patients carry ≥ 1 genetic variant that may influence medication decisions and that half of veterans are prescribed a medication with known gene-drug interactions.¹⁵ CPP ordering of pharmacogenomic tests at the VACOHCS outpatient clinic was evaluated through collection of baseline data from March 8, 2023, to September 8, 2023. A goal was identified to increase orders by 50% for a patient care quality improvement initiative and use CPPs to increase access to pharmacogenomic testing. The purpose of this quality improvement initiative was to expand access to pharmacogenomic testing through process implementation and improvement within CPP-led clinic settings.

Gap Analysis

Lean Six Sigma A3 methodology was used to identify ways to increase the use of pharmacogenomic testing for veterans at VACOHCS and develop an improved process for increased ordering of pharmacogenomic testing. Lean Six Sigma A3 methodology is a stepwise approach to process improvement that helps identify gaps in efficiency, sustainable changes, and eliminate waste.¹⁶ Baseline data were collected from March 8, 2023, to September 8, 2023, to determine the frequency of CPPs ordering pharmacogenomic laboratory panels during clinic appointments. The ordering of pharmacogenomic panels was monitored by the VACOHCS PHASER coordinator.

CPPs were surveyed to identify perceived barriers to PHASER implementation. A gap analysis was conducted using Lean Six Sigma A3 methodology. Gap analyses use lean tools such as a Fishbone Diagram to illustrate and identify the gap between current state and ideal state. (Figure 1).The following barriers were identified: lack of clinician education materials, lack of a standardized patient screening process, time constraints on patient education and ordering, higher priority clinical needs, forgetting to order, lack of comfort with pharmacogenomics ordering and education, lack of support for the initiative, and increased workload and burnout. Among these perceived barriers, higher priority clinical needs, forgetting to order, and time constraints ranked highest in importance among CPPs. 

In line with Lean Six Sigma A3 methodology, several tests of change were used to improve pharmacogenomic testing ordering. These changes focused on increasing patient and clinician awareness, facilitating discussion, educating clinicians, and simplifying documentation to ease time constraints. Several strategies were employed postimplementation (Figure 2). Prefilled templates simplified documentation. These templates helped identify patients without pharmacogenomic testing, provided reminders, and saved documentation time during visits. CPPs also received training and materials on PHASER ordering and documentation within encounter notes. Additionally, patient-directed advertisements were displayed in CPP examination rooms to help inspire and facilitate discussion between veterans and CPPs.

Process Improvement Data

The quality improvement project goal was to increase PHASER orders by 50% after 3 months. PHASER orders increased from 87 at baseline (March 8, 2023, to September 8, 2023) to 196 during the intervention (November 16, 2023, to February 16, 2024), a 125% increase. Changes were consistent and sustained with 65 orders the first month, 67 orders the second month, and 64 orders the third month.

Discussion

Using Lean Six Sigma A3 methodology for a quality improvement process to increase PHASER orders by CPPs revealed barriers and guided potential solutions to overcome these barriers. Interventions included additional CPP training and ordering, tools for easier identification of potential patients, documentation best practices, patient-directed advertisements to facilitate conversations. These interventions required about 8 hours for preparation, distribution, development, and interpretation of surveys, education, and documentation materials. The financial impact of these interventions was already included in allotted office materials budgeted and provided. Additional funding was not needed to provide patient-directed advertisements or education materials. The VACOHCS pharmacogenomics CPP discusses PHASER test results with patients at a separate appointment.

Future directions include educating other CPPs to assist in discussing results with veterans. Overall, the changes implemented to improve the PHASER ordering process were low effort and exemplify the ease of streamlining future initiatives, allowing for sustained optimal implementation of pharmacogenomic testing.

Conclusions

A quality improvement initiative resulted in increased PHASER orders and a clearly defined process, allowing for a continued increase and sustained support. Perceived barriers were identified, and the changes implemented were often low effort but exhibited a sustained impact. The insights gleaned from this process will shape future process development initiatives and continue to sustain pharmacogenomic testing ordering by CPPs. This process will be extended to other VACOHCS clinical departments to further support increased access to pharmacogenomic testing, reduce medication trial and error, and reduce hospitalizations from adverse effects for veterans.

Peer-review, evidence-based, detailed gene/drug clinical practice guidelines suggest that genetic variations can impact how individuals metabolize medications, which is sometimes included in medication prescribing information.^1-3 Pharmacogenomic testing identifies genetic markers so medication selection and dosing can be tailored to each individual by identifying whether a specific medication is likely to be safe and effective prior to prescribing.⁴

Pharmacogenomics can be a valuable tool for personalizing medicine but has had suboptimal implementation since its discovery. The US Department of Veterans Affairs (VA) health care system reviewed the implementation of the Pharmacogenomic Testing for Veterans (PHASER) program. This review identified clinician barriers pre- and post-PHASER program implementation; staffing issues, competing clinical priorities, and inadequate PHASER program resources were the most frequently reported barriers to implementation of pharmacogenomic testing.⁵

Another evaluation of the implementation of the PHASER program that surveyed VA patients found that patients could be separated into 3 groups. Acceptors of pharmacogenomic testing emphasized potential health benefits of testing. Patients that declined testing often cited concerns for genetic information affecting insurance coverage, being misused, or being susceptible to data breach. The third group—identified as contemplators—reported the need for clinician outreach to impact their decision on whether or not to receive pharmacogenomic testing.⁶ These studies suggest that removing barriers by providing ample pharmacogenomics resources to clinicians, in addition to detailed training on how to offer and follow up with patients regarding pharmacogenomic testing, is crucial to successful implementation of the PHASER program.

PHASER

In 2019, the VA began working with Sanford Health to establish the PHASER program and offer pharmacogenomic testing. PHASER has since expanded to 25 VA medical centers, including the VA Central Ohio Healthcare System (VACOHCS).^7,8 Pharmacogenomic testing through PHASER is conducted using a standardized laboratory panel that includes 12 different medication classes.⁹ The drug classes include certain anti-infective, anticoagulant, antiplatelet, cardiovascular, cholesterol, gastrointestinal, mental health, neurological, oncology, pain, transplant, and other miscellaneous medications. Medications are correlated to each class and assessed for therapeutic impacts based on gene panel results.

Clinical recommendations for medication-gene interactions can range from monitoring for increased risk of adverse effects or therapeutic failure to recommending avoiding a medication. For example, patients who test positive for the HLA-B gene have significantly increased risk of hypersensitivity to abacavir, an HIV treatment.¹⁰

Similarly, patients who cannot adequately metabolize cytochrome P450 2C19 should consider avoiding clopidogrel as they are unlikely to convert clopidogrel to its active prodrug, which reduces its effectiveness.¹¹ Pharmacists can play a critical role educating patients about pharmacogenomic testing, especially within hematology and oncology.¹² Patients can benefit from this testing even if they are not currently taking medications with known concerns as they could be prescribed in the future. The SLCO1B1 gene-drug test, for example, can identify risk for statin-associated muscle symptoms.¹³

Clinical pharmacist practitioners (CPPs) can increase access to genetic testing because they interact with patients in a variety of settings and can order this laboratory test.^12,14 Recent research has demonstrated that most VA patients carry ≥ 1 genetic variant that may influence medication decisions and that half of veterans are prescribed a medication with known gene-drug interactions.¹⁵ CPP ordering of pharmacogenomic tests at the VACOHCS outpatient clinic was evaluated through collection of baseline data from March 8, 2023, to September 8, 2023. A goal was identified to increase orders by 50% for a patient care quality improvement initiative and use CPPs to increase access to pharmacogenomic testing. The purpose of this quality improvement initiative was to expand access to pharmacogenomic testing through process implementation and improvement within CPP-led clinic settings.

Gap Analysis

Lean Six Sigma A3 methodology was used to identify ways to increase the use of pharmacogenomic testing for veterans at VACOHCS and develop an improved process for increased ordering of pharmacogenomic testing. Lean Six Sigma A3 methodology is a stepwise approach to process improvement that helps identify gaps in efficiency, sustainable changes, and eliminate waste.¹⁶ Baseline data were collected from March 8, 2023, to September 8, 2023, to determine the frequency of CPPs ordering pharmacogenomic laboratory panels during clinic appointments. The ordering of pharmacogenomic panels was monitored by the VACOHCS PHASER coordinator.

CPPs were surveyed to identify perceived barriers to PHASER implementation. A gap analysis was conducted using Lean Six Sigma A3 methodology. Gap analyses use lean tools such as a Fishbone Diagram to illustrate and identify the gap between current state and ideal state. (Figure 1).The following barriers were identified: lack of clinician education materials, lack of a standardized patient screening process, time constraints on patient education and ordering, higher priority clinical needs, forgetting to order, lack of comfort with pharmacogenomics ordering and education, lack of support for the initiative, and increased workload and burnout. Among these perceived barriers, higher priority clinical needs, forgetting to order, and time constraints ranked highest in importance among CPPs. 

In line with Lean Six Sigma A3 methodology, several tests of change were used to improve pharmacogenomic testing ordering. These changes focused on increasing patient and clinician awareness, facilitating discussion, educating clinicians, and simplifying documentation to ease time constraints. Several strategies were employed postimplementation (Figure 2). Prefilled templates simplified documentation. These templates helped identify patients without pharmacogenomic testing, provided reminders, and saved documentation time during visits. CPPs also received training and materials on PHASER ordering and documentation within encounter notes. Additionally, patient-directed advertisements were displayed in CPP examination rooms to help inspire and facilitate discussion between veterans and CPPs.

Process Improvement Data

The quality improvement project goal was to increase PHASER orders by 50% after 3 months. PHASER orders increased from 87 at baseline (March 8, 2023, to September 8, 2023) to 196 during the intervention (November 16, 2023, to February 16, 2024), a 125% increase. Changes were consistent and sustained with 65 orders the first month, 67 orders the second month, and 64 orders the third month.

Discussion

Using Lean Six Sigma A3 methodology for a quality improvement process to increase PHASER orders by CPPs revealed barriers and guided potential solutions to overcome these barriers. Interventions included additional CPP training and ordering, tools for easier identification of potential patients, documentation best practices, patient-directed advertisements to facilitate conversations. These interventions required about 8 hours for preparation, distribution, development, and interpretation of surveys, education, and documentation materials. The financial impact of these interventions was already included in allotted office materials budgeted and provided. Additional funding was not needed to provide patient-directed advertisements or education materials. The VACOHCS pharmacogenomics CPP discusses PHASER test results with patients at a separate appointment.

Future directions include educating other CPPs to assist in discussing results with veterans. Overall, the changes implemented to improve the PHASER ordering process were low effort and exemplify the ease of streamlining future initiatives, allowing for sustained optimal implementation of pharmacogenomic testing.

Conclusions

A quality improvement initiative resulted in increased PHASER orders and a clearly defined process, allowing for a continued increase and sustained support. Perceived barriers were identified, and the changes implemented were often low effort but exhibited a sustained impact. The insights gleaned from this process will shape future process development initiatives and continue to sustain pharmacogenomic testing ordering by CPPs. This process will be extended to other VACOHCS clinical departments to further support increased access to pharmacogenomic testing, reduce medication trial and error, and reduce hospitalizations from adverse effects for veterans.