Article

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

Case Presentation: A 65-year-old male veteran presented to the Veterans Affairs Boston Healthcare System (VABHS) emergency department with progressive fatigue, dyspnea on exertion, lightheadedness, and falls over the last month. New bilateral lower extremity numbness up to his knees developed in the week prior to admission and prompted him to seek care. Additional history included 2 episodes of transient loss of consciousness resulting in falls and a week of diarrhea, which had resolved. His medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis, seizure disorder, vitiligo, treated hepatitis C virus (HCV) infection, alcohol use disorder in remission, diabetes mellitus, posttraumatic stress disorder, and traumatic brain injury. His medications included levothyroxine and carbamazepine. He previously worked as a barber but recently had stopped due to cognitive impairment. On initial evaluation, the patient's vital signs included a temperature of 36.3 °C, heart rate of 77 beats per minute, blood pressure of 139/83 mm Hg, respiratory rate of 18 breaths per minute, and 99% oxygen saturation while breathing ambient air. Physical examination was notable for a frail-appearing man in no acute distress. His conjunctivae were pale, and cardiac auscultation revealed a normal heart rate and irregularly irregular heart rhythm. A neurologic examination revealed decreased vibratory sensation in both feet, delayed and minimal speech, and a blunted affect. His skin was warm and dry with patchy hypopigmentation across the face and forehead. Laboratory results are shown in the Table. Testing 2 years previously found the patient's hemoglobin to be 11.4 g/dL and serum creatinine to be 1.7 mg/dL. A peripheral blood smear showed anisocytosis, hypochromia, decreased platelets, ovalocytes, elliptocytes, and rare teardrop cells, with no schistocytes present. Chest radiography and computed tomography of the head were unremarkable. An abdominal ultrasound revealed a complex hypoechoic mass with peripheral rim vascularity in the right hepatic lobe measuring 3.9 cm × 3.6 cm × 3.9 cm.

Lindsey Ulin, MD, Chief Medical Resident, VABHS and Brigham and Women’s Hospital (BWH):

To build the initial differential diagnosis, we are joined today by 3 internal medicine residents who were not involved in the care of this patient. Dr. Hickey, Dr. Ross and Dr. Manivannan, how did you approach this case?

Meghan Hickey, MD, Senior Internal Medicine Resident, VABHS and Boston Medical Center (BMC):

The constellation of fatigue, weakness, blunted affect, and delayed, minimal speech suggested central nervous system involvement, which I sought to unify with hemolytic anemia and his liver mass. The first diagnosis I considered was Wilson disease; however, this genetic disorder of copper metabolism often presents with liver failure or cirrhosis in young or middle-aged women, so this presentation would be atypical. Next, given the hypopigmentation was reported only on sun-exposed areas of the patient’s face, I considered possibilities other than vitiligo to avoid diagnostic anchoring. One such alternate diagnosis is porphyria cutanea tarda (PCT), which presents in middle-aged and older adults with a photosensitive dermatitis that can include acute sensory deficits. Manifestations of PCT can be triggered by alcohol consumption, though his alcohol use disorder was thought to be in remission, as well as HCV, for which he previously received treatment. However, anemia is uncommon in PCT, so the patient’s low hemoglobin would not be explained by this diagnosis. Lastly, I considered thrombotic thrombocytopenic purpura (TTP) given his anemia, thrombocytopenia, and neurologic symptoms; however, the patient did not have fever or a clear inciting cause, his renal dysfunction was relatively mild, and the peripheral blood smear revealed no schistocytes, which should be present in TTP.

Caroline Ross, MD, and Alan Manivannan, MD; Senior Internal Medicine Residents, VABHS and BMC:

We noted several salient features in the history and physical examination. First, we sought to explain the bilateral lower extremity numbness and decreased vibratory sensation in the feet leading to falls. We also considered his anemia and thrombocytopenia with signs of hemolysis including elevated lactate dehydrogenase (LDH), low haptoglobin, and elevated total bilirubin; however, with normal coagulation parameters. These results initially raised our concern for a thrombotic microangiopathy (TMA) such as TTP. However, the peripheral smear lacked schistocytes, making this less likely. The combination of his neurologic symptoms and TMA-like laboratory findings but without schistocytes raised our concern for vitamin B12 deficiency. Vitamin B12 deficiency can cause a pseudo-TMA picture with laboratory finding similar to TTP; however, schistocytes are typically absent. We also considered the possibility of hepatocellular carcinoma (HCC) with bone marrow infiltration leading to anemia given the finding of a liver mass on his abdominal ultrasound and low reticulocyte index. However, this would not explain his hemolysis. We also considered chronic disseminated intravascular coagulation in the setting of a malignancy as a contributor, but again, the smear lacked schistocytes and his coagulation parameters were normal. Finally, we considered a primary bone marrow process such as myelodysplastic syndrome due to the bicytopenia with poor bone marrow response and smear with tear drop cells and elliptocytes. However, we felt this was less likely as this would not explain his hemolytic anemia.

Dr. Ulin:

To refine the differential diagnosis, we are joined by an expert clinician who was also not involved in the care of this patient to describe his approach to this case. Dr. Orlander, can you walk us through your clinical reasoning?

Jay Orlander, MD, MPH: Professor of Medicine, Section of General Internal Medicine, Boston University Chobanian & Avedisian School of Medicine, Associate Chief, Medical Service, VABHS:

I will first comment on the hepatic mass. The hypoechoic liver mass with peripheral vascularity suggests a growing tumor. The patient has a history of substance use disorder with alcohol and treated HCV. He remains at increased risk for HCC even after prior successful HCV treatment and has 2 of 4 known risk factors for developing HCC— diabetes mellitus and alcohol use—the other 2 being underlying metabolic dysfunctionassociated steatotic liver disease (MASLD) and the presence of hepatic fibrosis, which we have not yet assessed. Worsening liver function can lead to cognitive issues and alcohol to peripheral neuropathy, but his story is not consistent with this. For his liver mass, I recommend a nonurgent magnetic resonance image for further evaluation.

Next, let’s consider his markedly elevated thyrotropin (TSH). Cognitive impairment along with lethargy, fatigue, and decreased exercise tolerance can be prominent features in severe hypothyroidism, but this diagnosis would not explain his hematologic findings.¹

I view the principal finding of his laboratory testing as being that his bone marrow is failing to maintain adequate blood elements. He has a markedly low hematocrit along with low platelets and low-normal white blood cell counts. There is an absence of schistocytes on the blood smear, and after correcting his reticulocyte count for his degree of anemia (observed reticulocyte percentage [0.8%] x observed hematocrit [15.3%] / expected hematocrit [40%]), results in a reticulocyte index of 0.12, which is low. This suggests his bone marrow is failing to manufacture red blood cells at an appropriate rate. His haptoglobin is unmeasurable, so there is some free heme circulating. Hence, I infer that hemolysis and ineffective erythropoiesis are both occurring within the bone marrow, which also explains the slight elevation in bilirubin.

Intramedullary hemolysis with a markedly elevated LDH can be seen in severe vitamin B₁₂ deficiency, which has many causes, but one cause in particular warrants consideration in this case: pernicious anemia. Pernicious anemia has an overall prevalence of about 0.1%, but is more common in older adults, and is estimated to be present in 2% to 3% of adults aged > 65 years.² Prevalence is also increased in patients with other autoimmune diseases such as vitiligo and hypothyroidism, which our patient has.³ The pathophysiology of pernicious anemia relates to either autoimmune gastric parietal cell destruction and/or the development of antibodies against intrinsic factor, which is required for absorption of vitamin B₁₂. Early disease may present with macrocytosis and a normal hemoglobin initially, but anemia develops over time if left untreated. When the primary cause of pernicious anemia is gastric parietal cell destruction, there is also an associated lack of stomach acid production (achlorhydria) with resulting poor micronutrient absorption; specifically, vitamin D, vitamin C, and iron. Hence, 30% of patients diagnosed with pernicious anemia have concurrent iron deficiency, which may counteract macrocytosis and result in a normal mean corpuscular volume. 4 Some medications are also poorly absorbed in achlorhydric states, such as levothyroxine, and treatment doses need to be increased, which could explain his markedly elevated TSH despite presumed medication adherence.

Vitamin B₁₂ is essential for both the peripheral and central nervous systems. Longstanding severe B₁₂ deficiency can explain all of his neurological and neurocognitive changes. The most common neurologic findings in B₁₂ deficiency are symmetric paresthesias or numbness and gait problems. The sensory neuropathy affects the lower extremities more commonly than the upper. Untreated, patients can develop progressive weakness, ataxia, and orthostatic hypotension with syncope, as well as neuropsychiatric changes including depression or mood impairment, cognitive slowing, forgetfulness, and dementia.

Dr. Ulin:

Dr. Orlander, which pieces of objective data are most important in forming your differential diagnosis, and what tests would you obtain next?

Dr. Orlander:

The 3 most salient laboratory tests to me are a complete blood count, with all cell lines impacted but the hemoglobin and hematocrit most dramatically impacted, reticulocyte count of 0.8%, which is inappropriately low and hence suggests a hypoproliferative anemia, and the elevated LDH > 5000 IU/L.

Since my suspected diagnosis is pernicious anemia, I would obtain a blood smear looking for hypersegmented neutrophils, > 1 white blood cells with 5 lobes, or 1 with 6 lobes, which should clinch the diagnosis. Methylmalonic acid (MMA) levels are the most sensitive test for B₁₂ deficiency, so I would also obtain that. Finally, I would check a B₁₂ level, since in a patient with pernicious anemia, I would expect the level to be < 200 pg/mL.

Dr. Ulin:

Before we reveal the results of the patient’s additional workup, how do you approach interpreting B₁₂ levels?

Dr. Orlander:

Measuring B12 can sometimes be problematic: the normal range is considered 200 to 900 pg/mL, but patients with measured low-normal levels in the range of 200 to 400 pg/mL can actually be physiologically deficient. There are also several common causes of falsely low and falsely high B₁₂ levels in the absence of B₁₂ deficiency. Hence, for patients with mild symptoms that could be due to B₁₂ deficiency, many clinicians choose to just treat with B₁₂ supplementation, deeming it safer to treat than miss an early diagnosis. B₁₂ is involved in hydrogen transfer to convert MMA into succinyl-CoA and hence true vitamin B₁₂ deficiency causes an increase in MMA.

Decreased production of vitamin B12 binding proteins, like haptocorrin, has been proposed as the mechanism for spurious low values.⁵ Certain conditions or medications can also cause spurious low serum vitamin B₁₂ levels and thus might cause the appearance of vitamin B₁₂ deficiency when the patient is not deficient. Examples include multiple myeloma, HIV infection, pregnancy, oral contraceptives, and phenytoin use. An example of spuriously low vitamin B₁₂ level in pregnancy was demonstrated in a series of 50 pregnant individuals with low vitamin B₁₂ levels (45-199 pg/mL), in whom metabolite testing for MMA and homocysteine showed no correlation with vitamin B₁₂ level.⁶

Further complicating things, some conditions can cause spuriously increased vitamin B₁₂ levels and thus might cause the appearance of normal vitamin B₁₂ levels when the patient is actually deficient.⁷ Examples include occult malignancy, myeloproliferative neoplasms, alcoholic liver disease, kidney disease, and nitrous oxide exposure (the latter of which is unique in that it can also cause true vitamin B₁₂ deficiency, as evidenced by clinical symptoms and high MMA levels).^8,9

Lastly, autoantibodies to intrinsic factor in individuals with pernicious anemia may compete with intrinsic factor in the chemiluminescence assay and result in spuriously normal vitamin B₁₂ levels in the presence of true deficiency.^10-12 If the vitamin B₁₂ level is very high (eg, 800 pg/mL), we do not worry about this effect in the absence of clinical features suggesting vitamin B₁₂ deficiency; however, if the vitamin B₁₂ level is borderline or low-normal and/or other clinical features suggest vitamin B₁₂ deficiency, it is prudent to obtain other testing such as an MMA level.

Dr. Ulin:

We are also joined by Dr. Rahul Ganatra, who cared for the patient at the time the diagnosis was made. Dr. Ganatra, can you share the final diagnosis and provide an update on the patient?

Rahul Ganatra, MD, MPH, Director of Continuing Medical Education, VABHS:

The patient’s hemoglobin rose to 6.9 g/dL after transfusion of 2 units of packed red blood cells, and his dyspnea on exertion and fatigue improved. Iron studies, serum thiamine, serum folate, ADAMTS13 activity levels, and AM cortisol level were normal. Upon closer examination of the peripheral blood smear, rare hypersegmented neutrophils were noted. Serum B₁₂ level returned below assay (< 146 pg/mL), and serum MMA was 50,800 nmol/L, confirming the diagnosis of severe vitamin B₁₂ deficiency. Antibodies against intrinsic factor were detected, confirming the diagnosis of pernicious anemia. Treatment was initiated with intramuscular cyanocobalamin every other day and was transitioned to weekly dosing at the time of hospital discharge. After excluding adrenal insufficiency, his levothyroxine dose was increased. Finally, a liver mass biopsy confirmed a concomitant diagnosis of HCC. The patient was discharged home. Five weeks after discharge, his serum B₁₂ level rose to > 1000 pg/mL, and 10 months after discharge, his TSH fell to 0.97 uIU/mL. Several months later, he underwent stereotactic body radiotherapy for the HCC. One year after his initial presentation, he has not resumed work as a barber.

The COVID-19 pandemic established a new normal for health care delivery, with leaders rethinking core practices to survive and thrive in a changing environment and improve the health and well-being of patients. The Veterans Health Administration (VHA) is embracing a shift in focus from “what is the matter” to “what really matters” to address pre- and postpandemic challenges through a whole health approach.¹ Initially conceptualized by the VHA in 2011, whole health “is an approach to health care that empowers and equips people to take charge of their health and well-being so that they can live their life to the fullest.”¹ Whole health integrates evidence-based complementary and integrative health (CIH) therapies to manage pain; this includes acupuncture, meditation, tai chi, yoga, massage therapy, guided imagery, biofeedback, and clinical hypnosis.¹ The VHA now recognizes well-being as a core value, helping clinicians respond to emerging challenges related to the social determinants of health (eg, access to health care, physical activity, and healthy foods) and guiding health care decision making.^1,2

Well-being through empowerment—elements of whole health and Age-Friendly Health Systems (AFHS)—encourages health care institutions to work with employees, patients, and other stakeholders to address global challenges, clinician burnout, and social issues faced by their communities. This approach focuses on life’s purpose and meaning for individuals and inspires leaders to engage with patients, staff, and communities in new, impactful ways by focusing on wellbeing and wholeness rather than illness and disease. Having a higher sense of purpose is associated with lower all-cause mortality, reduced risk of specific diseases, better health behaviors, greater use of preventive services, and fewer hospital days of care.³

This article describes how AFHS supports the well-being of older adults and aligns with the whole health model of care. It also outlines the VHA investment to transform health care to be more person-centered by documenting what matters in the electronic health record (EHR).

AGE-FRIENDLY CARE

Given that nearly half of veterans enrolled in the VHA are aged ≥ 65 years, there is an increased need to identify models of care to support this aging population.⁴ This is especially critical because older veterans often have multiple chronic conditions and complex care needs that benefit from a whole person approach. The AFHS movement aims to provide evidence-based care aligned with what matters to older adults and provides a mechanism for transforming care to meet the needs of older veterans. This includes addressing age-related health concerns while promoting optimal health outcomes and quality of life. AFHS follows the 4Ms framework: what matters, medication, mentation, and mobility.⁵ The 4Ms serve as a guide for the health care of older adults in any setting, where each “M” is assessed and acted on to support what matters.⁵ Since 2020, > 390 teams have developed a plan to implement the 4Ms at 156 VHA facilities, demonstrating the VHA commitment to transforming health care for veterans.⁶

When VHA teams join the AFHS movement, they may also engage older veterans in a whole health system (WHS) (Figure). While AFHS is designed to improve care for patients aged ≥ 65 years, it also complements whole health, a person-centered approach available to all veterans enrolled in the VHA. Through the WHS and AFHS, veterans are empowered and equipped to take charge of their health and well-being through conversations about their unique goals, preferences, and health priorities.⁴ Clinicians are challenged to assess what matters by asking questions like, “What brings you joy?” and, “How can we help you meet your health goals?”^1,5 These questions shift the conversation from disease-based treatment and enable clinicians to better understand the veteran as a person.^1,5

For whole health and AFHS, conversations about what matters are anchored in the veteran’s goals and preferences, especially those facing a significant health change (ie, a new diagnosis or treatment decision).^5,7 Together, the veteran’s goals and priorities serve as the foundation for developing person-centered care plans that often go beyond conventional medical treatments to address the physical, mental, emotional, and social aspects of health.

SYSTEM-WIDE DIRECTIVE

The WHS enhances AFHS discussions about what matters to veterans by adding a system-level lens for conceptualizing health care delivery by leveraging the 3 components of WHS: the “pathway,” well-being programs, and whole health clinical care.

The Pathway

Discovering what matters, or the veteran’s “mission, aspiration, and purpose,” begins with the WHS pathway. When stepping into the pathway, veterans begin completing a personal health inventory, or “walking the circle of health,” which encourages self-reflection that focuses on components of their life that can influence health and well-being.^1,8 The circle of health offers a visual representation of the 4 most important aspects of health and well-being: First, “Me” at the center as an individual who is the expert on their life, values, goals, and priorities. Only the individual can know what really matters through mindful awareness and what works for their life. Second, self-care consists of 8 areas that impact health and wellbeing: working your body; surroundings; personal development; food and drink; recharge; family, friends, and coworkers; spirit and soul; and power of the mind. Third, professional care consists of prevention, conventional care, and complementary care. Finally, the community that supports the individual.

Well-Being Programs

VHA provides WHS programs that support veterans in building self-care skills and improving their quality of life, often through integrative care clinics that offer coaching and CIH therapies. For example, a veteran who prioritizes mobility when seeking care at an integrative care clinic will not only receive conventional medical treatment for their physical symptoms but may also be offered CIH therapies depending on their goals. The veteran may set a daily mobility goal with their care team that supports what matters, incorporating CIH approaches, such as yoga and tai chi into the care plan.⁵ These holistic approaches for moving the body can help alleviate physical symptoms, reduce stress, improve mindful awareness, and provide opportunities for self-discovery and growth, thus promote overall well-being

Whole Health Clinical Care

AFHS and the 4Ms embody the clinical care component of the WHS. Because what matters is the driver of the 4Ms, every action taken by the care team supports wellbeing and quality of life by promoting independence, connection, and support, and addressing external factors, such as social determinants of health. At a minimum, well-being includes “functioning well: the experience of positive emotions such as happiness and contentment as well as the development of one’s potential, having some control over one’s life, having a sense of purpose, and experiencing positive relationships.”⁹ From a system perspective, the VHA has begun to normalize focusing on what matters to veterans, using an interprofessional approach, one of the first steps to implementing AFHS.

As the programs expand, AFHS teams can learn from whole health well-being programs and increase the capacity for self-care in older veterans. Learning about the key elements included in the circle of health helps clinicians understand each veteran’s perceived strengths and weaknesses to support their self-care. From there, teams can act on the 4Ms and connect older veterans with the most appropriate programs and services at their facility, ensuring continuum of care.

DOCUMENTATION

The VHA leverages several tools and evidence-based practices to assess and act on what matters for veterans of all ages (Table).^5,10-16 The VHA EHR and associated dashboards contain a wealth of information about whole health and AFHS implementation, scale up, and spread. A national AFHS 4Ms note template contains standardized data elements called health factors, which provide a mechanism for monitoring 4Ms care via its related dashboard. This template was developed by an interprofessional workgroup of VHA staff and underwent a thorough human factors engineering review and testing process prior to its release. Although teams continue to personalize care based on what matters to the veteran, data from the standardized 4Ms note template and dashboard provide a way to establish consistent, equitable care across multiple care settings.¹⁷

Between January 2022 and December 2023, > 612,000 participants aged ≥ 65 years identified what matters to them through 1.35 million assessments. During that period, > 36,000 veterans aged ≥ 65 years participated in AFHS and had what matters conversations documented. A personalized health plan was completed by 585,270 veterans for a total of 1.1 million assessments.11 Whole health coaching has been documented for > 57,000 veterans with > 200,000 assessments completed.¹³ In fiscal year 2023, a total of 1,802,131 veterans participated in whole health.

When teams share information about what matters to the veteran in a clinicianfacing format in the EHR, this helps ensure that the VHA honors veteran preferences throughout transitions of care and across all phases of health care. Although the EHR captures data on what matters, measurement of the overall impact on veteran and health system outcomes is essential. Further evaluation and ongoing education are needed to ensure clinicians are accurately and efficiently capturing the care provided by completing the appropriate EHR. Additional challenges include identifying ways to balance the documentation burden, while ensuring notes include valuable patient-centered information to guide care. EHR tools and templates have helped to unlock important insights on health care delivery in the VHA; however, health systems must consider how these clinical practices support the overall well-being of patients. How leaders empower frontline clinicians in any care setting to use these data to drive meaningful change is also important.

TRANSFORMING VHA CARE DELIVERY

In Achieving Whole Health: A New Approach for Veterans and the Nation, the National Academy of Science proposes a framework for the transformation of health care institutions to provide better whole health to veterans.³ Transformation requires change in entire systems and leaders who mobilize people “for participation in the process of change, encouraging a sense of collective identity and collective efficacy, which in turn brings stronger feelings of self-worth and self-efficacy,” and an enhanced sense of meaningfulness in their work and lives.¹⁸

Shifting health care approaches to equipping and empowering veterans and employees with whole health and AFHS resources is transformational and requires radically different assumptions and approaches that cannot be realized through traditional approaches. This change requires robust and multifaceted cultural transformation spanning all levels of the organization. Whole health and AFHS are facilitating this transformation by supporting documentation and data needs, tracking outcomes across settings, and accelerating spread to new facilities and care settings nationwide to support older veterans in improving their health and well-being.

Whole health and AFHS are complementary approaches to care that can work to empower veterans (as well as caregivers and clinicians) to align services with what matters most to veterans. Lessons such as standardizing person-centered assessments of what matters, creating supportive structures to better align care with veterans’ priorities, and identifying meaningful veteran and system-level outcomes to help sustain transformational change can be applied from whole health to AFHS. Together these programs have the potential to enhance overall health outcomes and quality of life for veterans.

The COVID-19 pandemic established a new normal for health care delivery, with leaders rethinking core practices to survive and thrive in a changing environment and improve the health and well-being of patients. The Veterans Health Administration (VHA) is embracing a shift in focus from “what is the matter” to “what really matters” to address pre- and postpandemic challenges through a whole health approach.¹ Initially conceptualized by the VHA in 2011, whole health “is an approach to health care that empowers and equips people to take charge of their health and well-being so that they can live their life to the fullest.”¹ Whole health integrates evidence-based complementary and integrative health (CIH) therapies to manage pain; this includes acupuncture, meditation, tai chi, yoga, massage therapy, guided imagery, biofeedback, and clinical hypnosis.¹ The VHA now recognizes well-being as a core value, helping clinicians respond to emerging challenges related to the social determinants of health (eg, access to health care, physical activity, and healthy foods) and guiding health care decision making.^1,2

Well-being through empowerment—elements of whole health and Age-Friendly Health Systems (AFHS)—encourages health care institutions to work with employees, patients, and other stakeholders to address global challenges, clinician burnout, and social issues faced by their communities. This approach focuses on life’s purpose and meaning for individuals and inspires leaders to engage with patients, staff, and communities in new, impactful ways by focusing on wellbeing and wholeness rather than illness and disease. Having a higher sense of purpose is associated with lower all-cause mortality, reduced risk of specific diseases, better health behaviors, greater use of preventive services, and fewer hospital days of care.³

This article describes how AFHS supports the well-being of older adults and aligns with the whole health model of care. It also outlines the VHA investment to transform health care to be more person-centered by documenting what matters in the electronic health record (EHR).

AGE-FRIENDLY CARE

Given that nearly half of veterans enrolled in the VHA are aged ≥ 65 years, there is an increased need to identify models of care to support this aging population.⁴ This is especially critical because older veterans often have multiple chronic conditions and complex care needs that benefit from a whole person approach. The AFHS movement aims to provide evidence-based care aligned with what matters to older adults and provides a mechanism for transforming care to meet the needs of older veterans. This includes addressing age-related health concerns while promoting optimal health outcomes and quality of life. AFHS follows the 4Ms framework: what matters, medication, mentation, and mobility.⁵ The 4Ms serve as a guide for the health care of older adults in any setting, where each “M” is assessed and acted on to support what matters.⁵ Since 2020, > 390 teams have developed a plan to implement the 4Ms at 156 VHA facilities, demonstrating the VHA commitment to transforming health care for veterans.⁶

When VHA teams join the AFHS movement, they may also engage older veterans in a whole health system (WHS) (Figure). While AFHS is designed to improve care for patients aged ≥ 65 years, it also complements whole health, a person-centered approach available to all veterans enrolled in the VHA. Through the WHS and AFHS, veterans are empowered and equipped to take charge of their health and well-being through conversations about their unique goals, preferences, and health priorities.⁴ Clinicians are challenged to assess what matters by asking questions like, “What brings you joy?” and, “How can we help you meet your health goals?”^1,5 These questions shift the conversation from disease-based treatment and enable clinicians to better understand the veteran as a person.^1,5

For whole health and AFHS, conversations about what matters are anchored in the veteran’s goals and preferences, especially those facing a significant health change (ie, a new diagnosis or treatment decision).^5,7 Together, the veteran’s goals and priorities serve as the foundation for developing person-centered care plans that often go beyond conventional medical treatments to address the physical, mental, emotional, and social aspects of health.

SYSTEM-WIDE DIRECTIVE

The WHS enhances AFHS discussions about what matters to veterans by adding a system-level lens for conceptualizing health care delivery by leveraging the 3 components of WHS: the “pathway,” well-being programs, and whole health clinical care.

The Pathway

Discovering what matters, or the veteran’s “mission, aspiration, and purpose,” begins with the WHS pathway. When stepping into the pathway, veterans begin completing a personal health inventory, or “walking the circle of health,” which encourages self-reflection that focuses on components of their life that can influence health and well-being.^1,8 The circle of health offers a visual representation of the 4 most important aspects of health and well-being: First, “Me” at the center as an individual who is the expert on their life, values, goals, and priorities. Only the individual can know what really matters through mindful awareness and what works for their life. Second, self-care consists of 8 areas that impact health and wellbeing: working your body; surroundings; personal development; food and drink; recharge; family, friends, and coworkers; spirit and soul; and power of the mind. Third, professional care consists of prevention, conventional care, and complementary care. Finally, the community that supports the individual.

Well-Being Programs

VHA provides WHS programs that support veterans in building self-care skills and improving their quality of life, often through integrative care clinics that offer coaching and CIH therapies. For example, a veteran who prioritizes mobility when seeking care at an integrative care clinic will not only receive conventional medical treatment for their physical symptoms but may also be offered CIH therapies depending on their goals. The veteran may set a daily mobility goal with their care team that supports what matters, incorporating CIH approaches, such as yoga and tai chi into the care plan.⁵ These holistic approaches for moving the body can help alleviate physical symptoms, reduce stress, improve mindful awareness, and provide opportunities for self-discovery and growth, thus promote overall well-being

Whole Health Clinical Care

AFHS and the 4Ms embody the clinical care component of the WHS. Because what matters is the driver of the 4Ms, every action taken by the care team supports wellbeing and quality of life by promoting independence, connection, and support, and addressing external factors, such as social determinants of health. At a minimum, well-being includes “functioning well: the experience of positive emotions such as happiness and contentment as well as the development of one’s potential, having some control over one’s life, having a sense of purpose, and experiencing positive relationships.”⁹ From a system perspective, the VHA has begun to normalize focusing on what matters to veterans, using an interprofessional approach, one of the first steps to implementing AFHS.

As the programs expand, AFHS teams can learn from whole health well-being programs and increase the capacity for self-care in older veterans. Learning about the key elements included in the circle of health helps clinicians understand each veteran’s perceived strengths and weaknesses to support their self-care. From there, teams can act on the 4Ms and connect older veterans with the most appropriate programs and services at their facility, ensuring continuum of care.

DOCUMENTATION

The VHA leverages several tools and evidence-based practices to assess and act on what matters for veterans of all ages (Table).^5,10-16 The VHA EHR and associated dashboards contain a wealth of information about whole health and AFHS implementation, scale up, and spread. A national AFHS 4Ms note template contains standardized data elements called health factors, which provide a mechanism for monitoring 4Ms care via its related dashboard. This template was developed by an interprofessional workgroup of VHA staff and underwent a thorough human factors engineering review and testing process prior to its release. Although teams continue to personalize care based on what matters to the veteran, data from the standardized 4Ms note template and dashboard provide a way to establish consistent, equitable care across multiple care settings.¹⁷

Between January 2022 and December 2023, > 612,000 participants aged ≥ 65 years identified what matters to them through 1.35 million assessments. During that period, > 36,000 veterans aged ≥ 65 years participated in AFHS and had what matters conversations documented. A personalized health plan was completed by 585,270 veterans for a total of 1.1 million assessments.11 Whole health coaching has been documented for > 57,000 veterans with > 200,000 assessments completed.¹³ In fiscal year 2023, a total of 1,802,131 veterans participated in whole health.

When teams share information about what matters to the veteran in a clinicianfacing format in the EHR, this helps ensure that the VHA honors veteran preferences throughout transitions of care and across all phases of health care. Although the EHR captures data on what matters, measurement of the overall impact on veteran and health system outcomes is essential. Further evaluation and ongoing education are needed to ensure clinicians are accurately and efficiently capturing the care provided by completing the appropriate EHR. Additional challenges include identifying ways to balance the documentation burden, while ensuring notes include valuable patient-centered information to guide care. EHR tools and templates have helped to unlock important insights on health care delivery in the VHA; however, health systems must consider how these clinical practices support the overall well-being of patients. How leaders empower frontline clinicians in any care setting to use these data to drive meaningful change is also important.

TRANSFORMING VHA CARE DELIVERY

In Achieving Whole Health: A New Approach for Veterans and the Nation, the National Academy of Science proposes a framework for the transformation of health care institutions to provide better whole health to veterans.³ Transformation requires change in entire systems and leaders who mobilize people “for participation in the process of change, encouraging a sense of collective identity and collective efficacy, which in turn brings stronger feelings of self-worth and self-efficacy,” and an enhanced sense of meaningfulness in their work and lives.¹⁸

Shifting health care approaches to equipping and empowering veterans and employees with whole health and AFHS resources is transformational and requires radically different assumptions and approaches that cannot be realized through traditional approaches. This change requires robust and multifaceted cultural transformation spanning all levels of the organization. Whole health and AFHS are facilitating this transformation by supporting documentation and data needs, tracking outcomes across settings, and accelerating spread to new facilities and care settings nationwide to support older veterans in improving their health and well-being.

Whole health and AFHS are complementary approaches to care that can work to empower veterans (as well as caregivers and clinicians) to align services with what matters most to veterans. Lessons such as standardizing person-centered assessments of what matters, creating supportive structures to better align care with veterans’ priorities, and identifying meaningful veteran and system-level outcomes to help sustain transformational change can be applied from whole health to AFHS. Together these programs have the potential to enhance overall health outcomes and quality of life for veterans.

The COVID-19 pandemic established a new normal for health care delivery, with leaders rethinking core practices to survive and thrive in a changing environment and improve the health and well-being of patients. The Veterans Health Administration (VHA) is embracing a shift in focus from “what is the matter” to “what really matters” to address pre- and postpandemic challenges through a whole health approach.¹ Initially conceptualized by the VHA in 2011, whole health “is an approach to health care that empowers and equips people to take charge of their health and well-being so that they can live their life to the fullest.”¹ Whole health integrates evidence-based complementary and integrative health (CIH) therapies to manage pain; this includes acupuncture, meditation, tai chi, yoga, massage therapy, guided imagery, biofeedback, and clinical hypnosis.¹ The VHA now recognizes well-being as a core value, helping clinicians respond to emerging challenges related to the social determinants of health (eg, access to health care, physical activity, and healthy foods) and guiding health care decision making.^1,2

Well-being through empowerment—elements of whole health and Age-Friendly Health Systems (AFHS)—encourages health care institutions to work with employees, patients, and other stakeholders to address global challenges, clinician burnout, and social issues faced by their communities. This approach focuses on life’s purpose and meaning for individuals and inspires leaders to engage with patients, staff, and communities in new, impactful ways by focusing on wellbeing and wholeness rather than illness and disease. Having a higher sense of purpose is associated with lower all-cause mortality, reduced risk of specific diseases, better health behaviors, greater use of preventive services, and fewer hospital days of care.³

This article describes how AFHS supports the well-being of older adults and aligns with the whole health model of care. It also outlines the VHA investment to transform health care to be more person-centered by documenting what matters in the electronic health record (EHR).

AGE-FRIENDLY CARE

Given that nearly half of veterans enrolled in the VHA are aged ≥ 65 years, there is an increased need to identify models of care to support this aging population.⁴ This is especially critical because older veterans often have multiple chronic conditions and complex care needs that benefit from a whole person approach. The AFHS movement aims to provide evidence-based care aligned with what matters to older adults and provides a mechanism for transforming care to meet the needs of older veterans. This includes addressing age-related health concerns while promoting optimal health outcomes and quality of life. AFHS follows the 4Ms framework: what matters, medication, mentation, and mobility.⁵ The 4Ms serve as a guide for the health care of older adults in any setting, where each “M” is assessed and acted on to support what matters.⁵ Since 2020, > 390 teams have developed a plan to implement the 4Ms at 156 VHA facilities, demonstrating the VHA commitment to transforming health care for veterans.⁶

When VHA teams join the AFHS movement, they may also engage older veterans in a whole health system (WHS) (Figure). While AFHS is designed to improve care for patients aged ≥ 65 years, it also complements whole health, a person-centered approach available to all veterans enrolled in the VHA. Through the WHS and AFHS, veterans are empowered and equipped to take charge of their health and well-being through conversations about their unique goals, preferences, and health priorities.⁴ Clinicians are challenged to assess what matters by asking questions like, “What brings you joy?” and, “How can we help you meet your health goals?”^1,5 These questions shift the conversation from disease-based treatment and enable clinicians to better understand the veteran as a person.^1,5

For whole health and AFHS, conversations about what matters are anchored in the veteran’s goals and preferences, especially those facing a significant health change (ie, a new diagnosis or treatment decision).^5,7 Together, the veteran’s goals and priorities serve as the foundation for developing person-centered care plans that often go beyond conventional medical treatments to address the physical, mental, emotional, and social aspects of health.

SYSTEM-WIDE DIRECTIVE

The WHS enhances AFHS discussions about what matters to veterans by adding a system-level lens for conceptualizing health care delivery by leveraging the 3 components of WHS: the “pathway,” well-being programs, and whole health clinical care.

The Pathway

Discovering what matters, or the veteran’s “mission, aspiration, and purpose,” begins with the WHS pathway. When stepping into the pathway, veterans begin completing a personal health inventory, or “walking the circle of health,” which encourages self-reflection that focuses on components of their life that can influence health and well-being.^1,8 The circle of health offers a visual representation of the 4 most important aspects of health and well-being: First, “Me” at the center as an individual who is the expert on their life, values, goals, and priorities. Only the individual can know what really matters through mindful awareness and what works for their life. Second, self-care consists of 8 areas that impact health and wellbeing: working your body; surroundings; personal development; food and drink; recharge; family, friends, and coworkers; spirit and soul; and power of the mind. Third, professional care consists of prevention, conventional care, and complementary care. Finally, the community that supports the individual.

Well-Being Programs

VHA provides WHS programs that support veterans in building self-care skills and improving their quality of life, often through integrative care clinics that offer coaching and CIH therapies. For example, a veteran who prioritizes mobility when seeking care at an integrative care clinic will not only receive conventional medical treatment for their physical symptoms but may also be offered CIH therapies depending on their goals. The veteran may set a daily mobility goal with their care team that supports what matters, incorporating CIH approaches, such as yoga and tai chi into the care plan.⁵ These holistic approaches for moving the body can help alleviate physical symptoms, reduce stress, improve mindful awareness, and provide opportunities for self-discovery and growth, thus promote overall well-being

Whole Health Clinical Care

AFHS and the 4Ms embody the clinical care component of the WHS. Because what matters is the driver of the 4Ms, every action taken by the care team supports wellbeing and quality of life by promoting independence, connection, and support, and addressing external factors, such as social determinants of health. At a minimum, well-being includes “functioning well: the experience of positive emotions such as happiness and contentment as well as the development of one’s potential, having some control over one’s life, having a sense of purpose, and experiencing positive relationships.”⁹ From a system perspective, the VHA has begun to normalize focusing on what matters to veterans, using an interprofessional approach, one of the first steps to implementing AFHS.

As the programs expand, AFHS teams can learn from whole health well-being programs and increase the capacity for self-care in older veterans. Learning about the key elements included in the circle of health helps clinicians understand each veteran’s perceived strengths and weaknesses to support their self-care. From there, teams can act on the 4Ms and connect older veterans with the most appropriate programs and services at their facility, ensuring continuum of care.

DOCUMENTATION

The VHA leverages several tools and evidence-based practices to assess and act on what matters for veterans of all ages (Table).^5,10-16 The VHA EHR and associated dashboards contain a wealth of information about whole health and AFHS implementation, scale up, and spread. A national AFHS 4Ms note template contains standardized data elements called health factors, which provide a mechanism for monitoring 4Ms care via its related dashboard. This template was developed by an interprofessional workgroup of VHA staff and underwent a thorough human factors engineering review and testing process prior to its release. Although teams continue to personalize care based on what matters to the veteran, data from the standardized 4Ms note template and dashboard provide a way to establish consistent, equitable care across multiple care settings.¹⁷

Between January 2022 and December 2023, > 612,000 participants aged ≥ 65 years identified what matters to them through 1.35 million assessments. During that period, > 36,000 veterans aged ≥ 65 years participated in AFHS and had what matters conversations documented. A personalized health plan was completed by 585,270 veterans for a total of 1.1 million assessments.11 Whole health coaching has been documented for > 57,000 veterans with > 200,000 assessments completed.¹³ In fiscal year 2023, a total of 1,802,131 veterans participated in whole health.

When teams share information about what matters to the veteran in a clinicianfacing format in the EHR, this helps ensure that the VHA honors veteran preferences throughout transitions of care and across all phases of health care. Although the EHR captures data on what matters, measurement of the overall impact on veteran and health system outcomes is essential. Further evaluation and ongoing education are needed to ensure clinicians are accurately and efficiently capturing the care provided by completing the appropriate EHR. Additional challenges include identifying ways to balance the documentation burden, while ensuring notes include valuable patient-centered information to guide care. EHR tools and templates have helped to unlock important insights on health care delivery in the VHA; however, health systems must consider how these clinical practices support the overall well-being of patients. How leaders empower frontline clinicians in any care setting to use these data to drive meaningful change is also important.

TRANSFORMING VHA CARE DELIVERY

In Achieving Whole Health: A New Approach for Veterans and the Nation, the National Academy of Science proposes a framework for the transformation of health care institutions to provide better whole health to veterans.³ Transformation requires change in entire systems and leaders who mobilize people “for participation in the process of change, encouraging a sense of collective identity and collective efficacy, which in turn brings stronger feelings of self-worth and self-efficacy,” and an enhanced sense of meaningfulness in their work and lives.¹⁸

Shifting health care approaches to equipping and empowering veterans and employees with whole health and AFHS resources is transformational and requires radically different assumptions and approaches that cannot be realized through traditional approaches. This change requires robust and multifaceted cultural transformation spanning all levels of the organization. Whole health and AFHS are facilitating this transformation by supporting documentation and data needs, tracking outcomes across settings, and accelerating spread to new facilities and care settings nationwide to support older veterans in improving their health and well-being.

Whole health and AFHS are complementary approaches to care that can work to empower veterans (as well as caregivers and clinicians) to align services with what matters most to veterans. Lessons such as standardizing person-centered assessments of what matters, creating supportive structures to better align care with veterans’ priorities, and identifying meaningful veteran and system-level outcomes to help sustain transformational change can be applied from whole health to AFHS. Together these programs have the potential to enhance overall health outcomes and quality of life for veterans.

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

Biologics have revolutionized dermatologic treatment, offering substantial relief from chronic and ­debilitating skin conditions such as psoriasis, hidradenitis suppurativa, atopic dermatitis (AD), chronic urticaria, and immunobullous diseases (eg, pemphigus vulgaris, bullous pemphigoid). By drastically decreasing symptom burden, biologics have the potential to transform patients’ lives by improving their overall quality of life (QOL). However, the use of biologics during ­pregnancy raises critical considerations, especially ­regarding safety.

Biologics for Cutaneous Conditions

Biologics—tumor necrosis factor (TNF) α inhibitors; IL-17, IL-23, IL-12, and IL-36 inhibitors; and agents such as omalizumab and dupilumab—have shown remarkable efficacy in controlling severe or recalcitrant dermatologic conditions and typically are more effective than traditional systemic therapies.¹ For instance, randomized clinical trials (RCTs) and real-world data have shown that patients with psoriasis can achieve considerable skin clearance with biologics, greatly enhancing QOL.² Adalimumab and secukinumab, which have been approved for use in moderate to severe cases of hidradenitis suppurativa, reduce the frequency of painful nodules and abscesses, thereby decreasing pain and improving QOL. Dupilumab, an IL-4/13 receptor antagonist, has revolutionized the treatment of AD by drastically reducing itch and skin lesions and improving QOL.³ For chronic urticaria, the anti-IgE antibody omalizumab has effectively reduced the incidence of hives and itching, providing pronounced symptom relief when traditional antihistamines fail.⁴ Use of rituximab, an anti-CD20 monoclonal antibody, has led to remission in severe cases of pemphigus vulgaris and bullous pemphigoid.⁵

Impact of Untreated Cutaneous Conditions in Pregnancy

When treating patients who are pregnant, dermatologists must consider the health of both the expectant mother and the developing fetus. This dual focus complicates decision-making, particularly with the use of biologics. Untreated cutaneous conditions can profoundly impact a pregnant patient’s health and QOL as well as lead to pregnancy complications affecting the fetus, such as preterm birth or low birth weight. In some studies, moderate to severe psoriasis has been associated with increased risk for complications during pregnancy, including preeclampsia and intrauterine growth restriction.⁶ Although specific data on hidradenitis suppurativa are lacking, the highly inflammatory nature of the condition suggests similar adverse effects on pregnancy.⁷ Atopic dermatitis can be exacerbated during pregnancy due to a shift in the immune system to become more allergic dominant.⁸ Generalized pustular psoriasis manifests with widespread pustules, fever, and systemic inflammation, posing serious risks to both the mother and the fetus if left untreated⁹; in such a life-threatening scenario, the use of potent treatments such as spesolimab, an IL-36 receptor antagonist, may be warranted. Therefore, managing these conditions effectively is crucial not only for the mother’s health but also for fetal well-being.

Which Biologics Can Dermatologists Safely Prescribe?

Despite the benefits, many dermatologists are hesitant to prescribe biologics to pregnant patients due to the lack of understanding and definitive safety data.^10,11 Although there are no RCTs that involve pregnant patients, current evidence suggests that several biologics are not teratogenic and do not cause fetal malformations. Extensive postexposure data support the safety of TNF-α inhibitors during pregnancy.¹² Research has shown that children exposed to these agents in utero have normal development, infection rates, and vaccination outcomes comparable to nonexposed children. For example, a systematic review and meta-analysis found no significant increase in the risk for major congenital malformations, spontaneous abortions, or preterm births among patients exposed to anti–TNF-α agents during pregnancy.² The Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project has provided valuable real-world data indicating that the use of TNF-α inhibitors in pregnancy, particularly during the first trimester, does not substantially elevate the risk for adverse outcomes.¹³ These findings have been corroborated by several other registry studies and RCTs, providing a robust safety profile for these agents during pregnancy.¹⁴

Similarly, postexposure data on IL-17 and IL-12/23 inhibitors indicate a favorable safety profile, though the sample sizes are smaller than those for anti–TNF-α agents.^12,14 Studies of drugs such as secukinumab (IL-17 inhibitor), guselkumab (IL-23 inhibitor), or ustekinumab (IL-12/23 inhibitor) have shown no association with teratogenic effects or increased risk for miscarriage.¹⁴ However, agents such as spesolimab (IL-36 inhibitor) are relatively new, and ongoing studies are expected to provide more comprehensive safety data.¹⁵ Similarly, omalizumab and dupilumab have not been associated with increased risk for fetal malformations or adverse pregnancy outcomes. Omalizumab, indicated for chronic urticaria, has a good safety profile in pregnancy, with no significant increase in adverse outcomes reported in studies and registries.¹⁶ Dupilumab, used for AD, has demonstrated safety in pregnancy, with ongoing studies continuing to monitor outcomes.¹⁷

Conversely, rituximab (an anti-CD20 antibody for autoimmune bullous diseases) has shown evidence of adverse pregnancy outcomes, including fetal harm.¹⁸ Its use generally is discouraged unless deemed absolutely necessary, and no safer alternatives are available. Rituximab can cross the placenta, especially in the second and third trimesters, and has been associated with B-cell depletion in the fetus, leading to potential immunosuppression and increased risk for infections.⁵

Although the data on the safety of biologics in pregnancy are largely reassuring, it is essential to recognize that potential risks have not been ruled out entirely. There are extensive safety data for anti–TNF-α inhibitors, which provides a level of confidence; although newer agents such as IL-17 and IL-23 inhibitors have shown promising early results, further research is required to solidify their safety profiles during pregnancy.

Dermatologists must balance the risks and benefits of using biologics in pregnant patients. This decision-­making process involves careful consideration of the severity of the mother’s condition, the potential risks to the fetus, and the availability of alternative treatments. For many severe dermatologic conditions, the benefits of biologics in controlling disease activity and improving QOL may outweigh the potential risks, especially when other treatments have failed or are not suitable.

Final Thoughts

The increasing use of biologics in dermatology has undoubtedly improved the management of severe skin conditions, substantially enhancing patients’ QOL. As more data become available and clinical guidelines evolve, health care providers will be better equipped to make informed decisions about the use of biologics, particularly in pregnant patients. Collaborative efforts between dermatologists, obstetricians, and researchers will help refine treatment guidelines and ensure that pregnant patients with severe dermatologic conditions receive the best possible care.

For now, although the current evidence supports the safety of many biologics during pregnancy,^10,11 individualized care and informed decision-making remain paramount. Careful management and adherence to current guidelines make it possible to navigate the complexities of treating severe dermatologic conditions in pregnant patients, ensuring the best outcomes for both mother and child.

Biologics have revolutionized dermatologic treatment, offering substantial relief from chronic and ­debilitating skin conditions such as psoriasis, hidradenitis suppurativa, atopic dermatitis (AD), chronic urticaria, and immunobullous diseases (eg, pemphigus vulgaris, bullous pemphigoid). By drastically decreasing symptom burden, biologics have the potential to transform patients’ lives by improving their overall quality of life (QOL). However, the use of biologics during ­pregnancy raises critical considerations, especially ­regarding safety.

Biologics for Cutaneous Conditions

Biologics—tumor necrosis factor (TNF) α inhibitors; IL-17, IL-23, IL-12, and IL-36 inhibitors; and agents such as omalizumab and dupilumab—have shown remarkable efficacy in controlling severe or recalcitrant dermatologic conditions and typically are more effective than traditional systemic therapies.¹ For instance, randomized clinical trials (RCTs) and real-world data have shown that patients with psoriasis can achieve considerable skin clearance with biologics, greatly enhancing QOL.² Adalimumab and secukinumab, which have been approved for use in moderate to severe cases of hidradenitis suppurativa, reduce the frequency of painful nodules and abscesses, thereby decreasing pain and improving QOL. Dupilumab, an IL-4/13 receptor antagonist, has revolutionized the treatment of AD by drastically reducing itch and skin lesions and improving QOL.³ For chronic urticaria, the anti-IgE antibody omalizumab has effectively reduced the incidence of hives and itching, providing pronounced symptom relief when traditional antihistamines fail.⁴ Use of rituximab, an anti-CD20 monoclonal antibody, has led to remission in severe cases of pemphigus vulgaris and bullous pemphigoid.⁵

Impact of Untreated Cutaneous Conditions in Pregnancy

When treating patients who are pregnant, dermatologists must consider the health of both the expectant mother and the developing fetus. This dual focus complicates decision-making, particularly with the use of biologics. Untreated cutaneous conditions can profoundly impact a pregnant patient’s health and QOL as well as lead to pregnancy complications affecting the fetus, such as preterm birth or low birth weight. In some studies, moderate to severe psoriasis has been associated with increased risk for complications during pregnancy, including preeclampsia and intrauterine growth restriction.⁶ Although specific data on hidradenitis suppurativa are lacking, the highly inflammatory nature of the condition suggests similar adverse effects on pregnancy.⁷ Atopic dermatitis can be exacerbated during pregnancy due to a shift in the immune system to become more allergic dominant.⁸ Generalized pustular psoriasis manifests with widespread pustules, fever, and systemic inflammation, posing serious risks to both the mother and the fetus if left untreated⁹; in such a life-threatening scenario, the use of potent treatments such as spesolimab, an IL-36 receptor antagonist, may be warranted. Therefore, managing these conditions effectively is crucial not only for the mother’s health but also for fetal well-being.

Which Biologics Can Dermatologists Safely Prescribe?

Despite the benefits, many dermatologists are hesitant to prescribe biologics to pregnant patients due to the lack of understanding and definitive safety data.^10,11 Although there are no RCTs that involve pregnant patients, current evidence suggests that several biologics are not teratogenic and do not cause fetal malformations. Extensive postexposure data support the safety of TNF-α inhibitors during pregnancy.¹² Research has shown that children exposed to these agents in utero have normal development, infection rates, and vaccination outcomes comparable to nonexposed children. For example, a systematic review and meta-analysis found no significant increase in the risk for major congenital malformations, spontaneous abortions, or preterm births among patients exposed to anti–TNF-α agents during pregnancy.² The Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project has provided valuable real-world data indicating that the use of TNF-α inhibitors in pregnancy, particularly during the first trimester, does not substantially elevate the risk for adverse outcomes.¹³ These findings have been corroborated by several other registry studies and RCTs, providing a robust safety profile for these agents during pregnancy.¹⁴

Similarly, postexposure data on IL-17 and IL-12/23 inhibitors indicate a favorable safety profile, though the sample sizes are smaller than those for anti–TNF-α agents.^12,14 Studies of drugs such as secukinumab (IL-17 inhibitor), guselkumab (IL-23 inhibitor), or ustekinumab (IL-12/23 inhibitor) have shown no association with teratogenic effects or increased risk for miscarriage.¹⁴ However, agents such as spesolimab (IL-36 inhibitor) are relatively new, and ongoing studies are expected to provide more comprehensive safety data.¹⁵ Similarly, omalizumab and dupilumab have not been associated with increased risk for fetal malformations or adverse pregnancy outcomes. Omalizumab, indicated for chronic urticaria, has a good safety profile in pregnancy, with no significant increase in adverse outcomes reported in studies and registries.¹⁶ Dupilumab, used for AD, has demonstrated safety in pregnancy, with ongoing studies continuing to monitor outcomes.¹⁷

Conversely, rituximab (an anti-CD20 antibody for autoimmune bullous diseases) has shown evidence of adverse pregnancy outcomes, including fetal harm.¹⁸ Its use generally is discouraged unless deemed absolutely necessary, and no safer alternatives are available. Rituximab can cross the placenta, especially in the second and third trimesters, and has been associated with B-cell depletion in the fetus, leading to potential immunosuppression and increased risk for infections.⁵

Although the data on the safety of biologics in pregnancy are largely reassuring, it is essential to recognize that potential risks have not been ruled out entirely. There are extensive safety data for anti–TNF-α inhibitors, which provides a level of confidence; although newer agents such as IL-17 and IL-23 inhibitors have shown promising early results, further research is required to solidify their safety profiles during pregnancy.

Dermatologists must balance the risks and benefits of using biologics in pregnant patients. This decision-­making process involves careful consideration of the severity of the mother’s condition, the potential risks to the fetus, and the availability of alternative treatments. For many severe dermatologic conditions, the benefits of biologics in controlling disease activity and improving QOL may outweigh the potential risks, especially when other treatments have failed or are not suitable.

Final Thoughts

The increasing use of biologics in dermatology has undoubtedly improved the management of severe skin conditions, substantially enhancing patients’ QOL. As more data become available and clinical guidelines evolve, health care providers will be better equipped to make informed decisions about the use of biologics, particularly in pregnant patients. Collaborative efforts between dermatologists, obstetricians, and researchers will help refine treatment guidelines and ensure that pregnant patients with severe dermatologic conditions receive the best possible care.

For now, although the current evidence supports the safety of many biologics during pregnancy,^10,11 individualized care and informed decision-making remain paramount. Careful management and adherence to current guidelines make it possible to navigate the complexities of treating severe dermatologic conditions in pregnant patients, ensuring the best outcomes for both mother and child.

Biologics have revolutionized dermatologic treatment, offering substantial relief from chronic and ­debilitating skin conditions such as psoriasis, hidradenitis suppurativa, atopic dermatitis (AD), chronic urticaria, and immunobullous diseases (eg, pemphigus vulgaris, bullous pemphigoid). By drastically decreasing symptom burden, biologics have the potential to transform patients’ lives by improving their overall quality of life (QOL). However, the use of biologics during ­pregnancy raises critical considerations, especially ­regarding safety.

Biologics for Cutaneous Conditions

Biologics—tumor necrosis factor (TNF) α inhibitors; IL-17, IL-23, IL-12, and IL-36 inhibitors; and agents such as omalizumab and dupilumab—have shown remarkable efficacy in controlling severe or recalcitrant dermatologic conditions and typically are more effective than traditional systemic therapies.¹ For instance, randomized clinical trials (RCTs) and real-world data have shown that patients with psoriasis can achieve considerable skin clearance with biologics, greatly enhancing QOL.² Adalimumab and secukinumab, which have been approved for use in moderate to severe cases of hidradenitis suppurativa, reduce the frequency of painful nodules and abscesses, thereby decreasing pain and improving QOL. Dupilumab, an IL-4/13 receptor antagonist, has revolutionized the treatment of AD by drastically reducing itch and skin lesions and improving QOL.³ For chronic urticaria, the anti-IgE antibody omalizumab has effectively reduced the incidence of hives and itching, providing pronounced symptom relief when traditional antihistamines fail.⁴ Use of rituximab, an anti-CD20 monoclonal antibody, has led to remission in severe cases of pemphigus vulgaris and bullous pemphigoid.⁵

Impact of Untreated Cutaneous Conditions in Pregnancy

When treating patients who are pregnant, dermatologists must consider the health of both the expectant mother and the developing fetus. This dual focus complicates decision-making, particularly with the use of biologics. Untreated cutaneous conditions can profoundly impact a pregnant patient’s health and QOL as well as lead to pregnancy complications affecting the fetus, such as preterm birth or low birth weight. In some studies, moderate to severe psoriasis has been associated with increased risk for complications during pregnancy, including preeclampsia and intrauterine growth restriction.⁶ Although specific data on hidradenitis suppurativa are lacking, the highly inflammatory nature of the condition suggests similar adverse effects on pregnancy.⁷ Atopic dermatitis can be exacerbated during pregnancy due to a shift in the immune system to become more allergic dominant.⁸ Generalized pustular psoriasis manifests with widespread pustules, fever, and systemic inflammation, posing serious risks to both the mother and the fetus if left untreated⁹; in such a life-threatening scenario, the use of potent treatments such as spesolimab, an IL-36 receptor antagonist, may be warranted. Therefore, managing these conditions effectively is crucial not only for the mother’s health but also for fetal well-being.

Which Biologics Can Dermatologists Safely Prescribe?

Despite the benefits, many dermatologists are hesitant to prescribe biologics to pregnant patients due to the lack of understanding and definitive safety data.^10,11 Although there are no RCTs that involve pregnant patients, current evidence suggests that several biologics are not teratogenic and do not cause fetal malformations. Extensive postexposure data support the safety of TNF-α inhibitors during pregnancy.¹² Research has shown that children exposed to these agents in utero have normal development, infection rates, and vaccination outcomes comparable to nonexposed children. For example, a systematic review and meta-analysis found no significant increase in the risk for major congenital malformations, spontaneous abortions, or preterm births among patients exposed to anti–TNF-α agents during pregnancy.² The Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project has provided valuable real-world data indicating that the use of TNF-α inhibitors in pregnancy, particularly during the first trimester, does not substantially elevate the risk for adverse outcomes.¹³ These findings have been corroborated by several other registry studies and RCTs, providing a robust safety profile for these agents during pregnancy.¹⁴

Similarly, postexposure data on IL-17 and IL-12/23 inhibitors indicate a favorable safety profile, though the sample sizes are smaller than those for anti–TNF-α agents.^12,14 Studies of drugs such as secukinumab (IL-17 inhibitor), guselkumab (IL-23 inhibitor), or ustekinumab (IL-12/23 inhibitor) have shown no association with teratogenic effects or increased risk for miscarriage.¹⁴ However, agents such as spesolimab (IL-36 inhibitor) are relatively new, and ongoing studies are expected to provide more comprehensive safety data.¹⁵ Similarly, omalizumab and dupilumab have not been associated with increased risk for fetal malformations or adverse pregnancy outcomes. Omalizumab, indicated for chronic urticaria, has a good safety profile in pregnancy, with no significant increase in adverse outcomes reported in studies and registries.¹⁶ Dupilumab, used for AD, has demonstrated safety in pregnancy, with ongoing studies continuing to monitor outcomes.¹⁷

Conversely, rituximab (an anti-CD20 antibody for autoimmune bullous diseases) has shown evidence of adverse pregnancy outcomes, including fetal harm.¹⁸ Its use generally is discouraged unless deemed absolutely necessary, and no safer alternatives are available. Rituximab can cross the placenta, especially in the second and third trimesters, and has been associated with B-cell depletion in the fetus, leading to potential immunosuppression and increased risk for infections.⁵

Although the data on the safety of biologics in pregnancy are largely reassuring, it is essential to recognize that potential risks have not been ruled out entirely. There are extensive safety data for anti–TNF-α inhibitors, which provides a level of confidence; although newer agents such as IL-17 and IL-23 inhibitors have shown promising early results, further research is required to solidify their safety profiles during pregnancy.

Dermatologists must balance the risks and benefits of using biologics in pregnant patients. This decision-­making process involves careful consideration of the severity of the mother’s condition, the potential risks to the fetus, and the availability of alternative treatments. For many severe dermatologic conditions, the benefits of biologics in controlling disease activity and improving QOL may outweigh the potential risks, especially when other treatments have failed or are not suitable.

Final Thoughts

The increasing use of biologics in dermatology has undoubtedly improved the management of severe skin conditions, substantially enhancing patients’ QOL. As more data become available and clinical guidelines evolve, health care providers will be better equipped to make informed decisions about the use of biologics, particularly in pregnant patients. Collaborative efforts between dermatologists, obstetricians, and researchers will help refine treatment guidelines and ensure that pregnant patients with severe dermatologic conditions receive the best possible care.

For now, although the current evidence supports the safety of many biologics during pregnancy,^10,11 individualized care and informed decision-making remain paramount. Careful management and adherence to current guidelines make it possible to navigate the complexities of treating severe dermatologic conditions in pregnant patients, ensuring the best outcomes for both mother and child.

Practice Gap

The term nail biopsy (NB) may refer to a punch, excisional, shave, or longitudinal biopsy of the nail matrix and/or nail bed.¹ Nail surgeries, including NBs, are performed relatively infrequently. In a study using data from the Medicare Provider Utilization and Payment Database 2012-2017, only 1.01% of Mohs surgeons and 0.28% of general dermatologists in the United States performed NBs. Thirty-one states had no dermatologist-performed NBs, while 3 states had no nail biopsies performed by any physician, podiatrist, nurse practitioner, or physician assistant, indicating that there is a shortage of dermatology clinicians performing nail surgeries.²

Dermatologists may not be performing NBs due to unfamiliarity with nail unit anatomy and lack of formal NB training during residency.³ In a survey of 240 dermatology residents in the United States, 58% reported performing fewer than 10 nail procedures during residency, with 25% observing only.⁴ Of those surveyed, 1% had no exposure to nail procedures during 3 years of residency. Furthermore, when asked to assess their competency in nail surgery on a scale of not competent, competent, and very competent, approximately 30% responded that they were not competent.⁴ Without sufficient education on procedures involving the nail unit, residents may be reluctant to incorporate nail surgery into their clinical practice.

Due to their complexity, NBs require the use of several specialized surgical instruments that are not used for other dermatologic procedures, and residents and attending physicians who have limited nail training may be unfamiliar with these tools. To address this educational gap, we sought to create a guide that details the surgical instruments used for the nail matrix tangential excision (shave) biopsy technique—the most common technique used in our nail specialty clinic. This guide is intended for educational use by dermatologists who wish to incorporate NB as part of their practice.

Tools and Technique

As a major referral center, our New York City–based nail specialty clinic performs a large volume of NBs, many of them performed for clinically concerning longitudinal melanonychias for which a nail matrix shave biopsy most often is performed. We utilize a standardized tray consisting of 12 surgical instruments that are needed to successfully perform a NB from start to finish (Figure). In addition to standard surgical tray items, such as sutures and tissue scissors, additional specialized instruments are necessary for NB procedures, including a nail elevator, an English nail splitter, and skin hook.

After the initial incisions are made at 45° angles to the proximal nail fold surrounding the longitudinal band, the nail elevator is used to separate the proximal nail plate from the underlying nail bed. The English nail splitter is used to create a transverse split separating the proximal from the distal nail plate, and the proximal nail plate then is retracted using a clamp. The skin hook is used to retract the proximal nail fold to expose the pigment in the nail matrix, which is biopsied using the #15 blade and sent for histopathology. The proximal nail fold and retracted nail plate then are put back in place, and absorbable sutures are used to repair the defect. In certain cases, a 3-mm punch biopsy may be used to sample the nail plate and/or the surrounding soft tissue.

Practice Implications

A guide to surgical tools used during NB procedures, including less commonly encountered tools such as a nail elevator and English nail splitter, helps to close the educational gap of NB procedures among dermatology trainees and attending physicians. In conjunction with practical training with cadavers and models, a guide to surgical tools can be reviewed by trainees before hands-on exposure to nail surgery in a clinical setting. By increasing awareness of the tools needed to complete the procedure from start to finish, dermatologists may feel more prepared and confident in their ability to perform NBs, ultimately allowing for more rapid diagnosis of nail malignancies.

Practice Gap

The term nail biopsy (NB) may refer to a punch, excisional, shave, or longitudinal biopsy of the nail matrix and/or nail bed.¹ Nail surgeries, including NBs, are performed relatively infrequently. In a study using data from the Medicare Provider Utilization and Payment Database 2012-2017, only 1.01% of Mohs surgeons and 0.28% of general dermatologists in the United States performed NBs. Thirty-one states had no dermatologist-performed NBs, while 3 states had no nail biopsies performed by any physician, podiatrist, nurse practitioner, or physician assistant, indicating that there is a shortage of dermatology clinicians performing nail surgeries.²

Dermatologists may not be performing NBs due to unfamiliarity with nail unit anatomy and lack of formal NB training during residency.³ In a survey of 240 dermatology residents in the United States, 58% reported performing fewer than 10 nail procedures during residency, with 25% observing only.⁴ Of those surveyed, 1% had no exposure to nail procedures during 3 years of residency. Furthermore, when asked to assess their competency in nail surgery on a scale of not competent, competent, and very competent, approximately 30% responded that they were not competent.⁴ Without sufficient education on procedures involving the nail unit, residents may be reluctant to incorporate nail surgery into their clinical practice.

Due to their complexity, NBs require the use of several specialized surgical instruments that are not used for other dermatologic procedures, and residents and attending physicians who have limited nail training may be unfamiliar with these tools. To address this educational gap, we sought to create a guide that details the surgical instruments used for the nail matrix tangential excision (shave) biopsy technique—the most common technique used in our nail specialty clinic. This guide is intended for educational use by dermatologists who wish to incorporate NB as part of their practice.

Tools and Technique

As a major referral center, our New York City–based nail specialty clinic performs a large volume of NBs, many of them performed for clinically concerning longitudinal melanonychias for which a nail matrix shave biopsy most often is performed. We utilize a standardized tray consisting of 12 surgical instruments that are needed to successfully perform a NB from start to finish (Figure). In addition to standard surgical tray items, such as sutures and tissue scissors, additional specialized instruments are necessary for NB procedures, including a nail elevator, an English nail splitter, and skin hook.

After the initial incisions are made at 45° angles to the proximal nail fold surrounding the longitudinal band, the nail elevator is used to separate the proximal nail plate from the underlying nail bed. The English nail splitter is used to create a transverse split separating the proximal from the distal nail plate, and the proximal nail plate then is retracted using a clamp. The skin hook is used to retract the proximal nail fold to expose the pigment in the nail matrix, which is biopsied using the #15 blade and sent for histopathology. The proximal nail fold and retracted nail plate then are put back in place, and absorbable sutures are used to repair the defect. In certain cases, a 3-mm punch biopsy may be used to sample the nail plate and/or the surrounding soft tissue.

Practice Implications

A guide to surgical tools used during NB procedures, including less commonly encountered tools such as a nail elevator and English nail splitter, helps to close the educational gap of NB procedures among dermatology trainees and attending physicians. In conjunction with practical training with cadavers and models, a guide to surgical tools can be reviewed by trainees before hands-on exposure to nail surgery in a clinical setting. By increasing awareness of the tools needed to complete the procedure from start to finish, dermatologists may feel more prepared and confident in their ability to perform NBs, ultimately allowing for more rapid diagnosis of nail malignancies.

Practice Gap

The term nail biopsy (NB) may refer to a punch, excisional, shave, or longitudinal biopsy of the nail matrix and/or nail bed.¹ Nail surgeries, including NBs, are performed relatively infrequently. In a study using data from the Medicare Provider Utilization and Payment Database 2012-2017, only 1.01% of Mohs surgeons and 0.28% of general dermatologists in the United States performed NBs. Thirty-one states had no dermatologist-performed NBs, while 3 states had no nail biopsies performed by any physician, podiatrist, nurse practitioner, or physician assistant, indicating that there is a shortage of dermatology clinicians performing nail surgeries.²

Dermatologists may not be performing NBs due to unfamiliarity with nail unit anatomy and lack of formal NB training during residency.³ In a survey of 240 dermatology residents in the United States, 58% reported performing fewer than 10 nail procedures during residency, with 25% observing only.⁴ Of those surveyed, 1% had no exposure to nail procedures during 3 years of residency. Furthermore, when asked to assess their competency in nail surgery on a scale of not competent, competent, and very competent, approximately 30% responded that they were not competent.⁴ Without sufficient education on procedures involving the nail unit, residents may be reluctant to incorporate nail surgery into their clinical practice.

Due to their complexity, NBs require the use of several specialized surgical instruments that are not used for other dermatologic procedures, and residents and attending physicians who have limited nail training may be unfamiliar with these tools. To address this educational gap, we sought to create a guide that details the surgical instruments used for the nail matrix tangential excision (shave) biopsy technique—the most common technique used in our nail specialty clinic. This guide is intended for educational use by dermatologists who wish to incorporate NB as part of their practice.

Tools and Technique

As a major referral center, our New York City–based nail specialty clinic performs a large volume of NBs, many of them performed for clinically concerning longitudinal melanonychias for which a nail matrix shave biopsy most often is performed. We utilize a standardized tray consisting of 12 surgical instruments that are needed to successfully perform a NB from start to finish (Figure). In addition to standard surgical tray items, such as sutures and tissue scissors, additional specialized instruments are necessary for NB procedures, including a nail elevator, an English nail splitter, and skin hook.

After the initial incisions are made at 45° angles to the proximal nail fold surrounding the longitudinal band, the nail elevator is used to separate the proximal nail plate from the underlying nail bed. The English nail splitter is used to create a transverse split separating the proximal from the distal nail plate, and the proximal nail plate then is retracted using a clamp. The skin hook is used to retract the proximal nail fold to expose the pigment in the nail matrix, which is biopsied using the #15 blade and sent for histopathology. The proximal nail fold and retracted nail plate then are put back in place, and absorbable sutures are used to repair the defect. In certain cases, a 3-mm punch biopsy may be used to sample the nail plate and/or the surrounding soft tissue.

Practice Implications

A guide to surgical tools used during NB procedures, including less commonly encountered tools such as a nail elevator and English nail splitter, helps to close the educational gap of NB procedures among dermatology trainees and attending physicians. In conjunction with practical training with cadavers and models, a guide to surgical tools can be reviewed by trainees before hands-on exposure to nail surgery in a clinical setting. By increasing awareness of the tools needed to complete the procedure from start to finish, dermatologists may feel more prepared and confident in their ability to perform NBs, ultimately allowing for more rapid diagnosis of nail malignancies.

Psoriasis is a chronic inflammatory disease affecting approximately 8 million adults in the United States and 2% of the global population.^1,2 Psoriasis causes pain, itching, and disfigurement and is associated with a physical, psychological, and economic burden that substantially affects health-related quality of life.^3-5

Setting treatment goals and treating to target are evidence-based approaches that have been successfully applied to several chronic diseases to improve patient outcomes, including diabetes, hypertension, and rheumatoid arthritis.^6-9 Treat-to-target strategies generally set low disease activity (or remission) as an overall goal and seek to achieve this using available therapeutic options as necessary. Introduced following the availability of biologics and targeted systemic therapies, treat-to-target strategies generally provide guidance on expectations of treatment but not specific treatments, as personalized treatment decisions depend on an assessment of individual patients and consider clinical and demographic features as well as preferences for available therapeutic options. If targets are not achieved in the assigned time span, adjustments can be made to the treatment approach in close consultation with the patient. If the target is reached, follow-up visits can be scheduled to ensure improvement is maintained or to establish if more aggressive goals could be selected.

Treat-to-target strategies for the management of psoriasis developed by the National Psoriasis Foundation (NPF) Medical Board include reducing the extent of psoriasis to 1% or lower total body surface area (BSA) after 3 months of treatment.¹⁰ Treatment targets endorsed by the European Academy of Dermatology and Venereology (EADV) in guidelines on the use of systemic therapies in psoriasis include achieving a 75% or greater reduction in Psoriasis Area and Severity Index (PASI) score within 3 to 4 months of treatment.¹¹

In clinical practice, many patients do not achieve these treatment targets, and topical treatments alone generally are insufficient in achieving treatment goals for psoriasis.^12,13 Moreover, conventional topical treatments (eg, topical corticosteroids) used by most patients with psoriasis regardless of disease severity are associated with adverse events that can limit their use. Most topical corticosteroids have US Food and Drug Administration label restrictions relating to sites of application, duration and extent of use, and frequency of administration.^14,15

Tapinarof cream 1% (VTAMA [Dermavant Sciences, Inc]) is a first-in-class topical nonsteroidal aryl hydrocarbon receptor agonist that was approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults¹⁶ and is being studied for the treatment of plaque psoriasis in children 2 years and older as well as for atopic dermatitis in adults and children 2 years and older. In PSOARING 1 (ClinicalTrials .gov identifier NCT03956355) and PSOARING 2 (NCT03983980)—identical 12-week pivotal phase 3 trials—monotherapy with tapinarof cream 1% once daily (QD) demonstrated statistically significant efficacy vs vehicle cream and was well tolerated in adults with mild to severe plaque psoriasis (Supplementary Figure S1).¹⁷ Lebwohl et al¹⁷ reported that significantly higher PASI75 responses were observed at week 12 with tapinarof cream vs vehicle in PSOARING 1 and PSOARING 2 (36% and 48% vs 10% and 7%, respectively; both P<.0001). A significantly higher PASI90 response of 19% and 21% at week 12 also was observed with tapinarof cream vs 2% and 3% with vehicle in PSOARING 1 and PSOARING 2, respectively (P=.0005 and P<.0001).¹⁷

In PSOARING 3 (NCT04053387)—the long-term extension trial (Supplementary Figure S1)—efficacy continued to improve or was maintained beyond the two 12-week trials, with improvements in total BSA affected and PASI scores for up to 52 weeks.¹⁸ Tapinarof cream 1% QD demonstrated positive, rapid, and durable outcomes in PSOARING 3, including high rates of complete disease clearance (Physician Global Assessment [PGA] score=0 [clear])(40.9% [312/763]), durability of response on treatment with no evidence of tachyphylaxis, and a remittive effect of approximately 4 months when off therapy (defined as maintenance of a PGA score of 0 [clear] or 1 [almost clear] after first achieving a PGA score of 0).¹⁸

Herein, we report absolute treatment targets for patients with plaque psoriasis who received tapinarof cream 1% QD in the PSOARING trials that are at least as stringent as the corresponding NPF and EADV targets of achieving a total BSA affected of 1% or lower or a PASI75 response within 3 to 4 months, respectively.

METHODS

Study Design

The pooled efficacy analyses included all patients with a baseline PGA score of 2 or higher (mild or worse) before treatment with tapinarof cream 1% QD in the PSOARING trials. This included patients who received tapinarof cream 1% in PSOARING 1 and PSOARING 2 who may or may not have continued into PSOARING 3, as well as those who received the vehicle in PSOARING 1 and PSOARING 2 who enrolled in PSOARING 3 and had a PGA score of 2 or higher before receiving tapinarof cream 1%.

Trial Participants

Full methods, including inclusion and exclusion criteria, for the PSOARING trials have been previously reported.^17,18 Patients were aged 18 to 75 years and had chronic plaque psoriasis that was stable for at least 6 months before randomization; 3% to 20% total BSA affected (excluding the scalp, palms, fingernails, toenails, and soles); and a PGA score of 2 (mild), 3 (moderate), or 4 (severe) at baseline.

The clinical trials were conducted in compliance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Approval was obtained from local ethics committees or institutional review boards at each center. All patients provided written informed consent.

Trial Treatment

In PSOARING 1 and PSOARING 2, patients were randomized (2:1) to receive tapinarof cream 1% or vehicle QD for 12 weeks. In PSOARING 3 (the long-term extension trial), patients received up to 40 weeks of open-label tapinarof, followed by 4 weeks of follow-up off treatment. Patients received intermittent or continuous treatment with tapinarof cream 1% in PSOARING 3 based on PGA score: those entering the trial with a PGA score of 1 or higher received tapinarof cream 1% until complete disease clearance was achieved (defined as a PGA score of 0 [clear]). Those entering PSOARING 3 with or achieving a PGA score of 0 (clear) discontinued treatment and were observed for the duration of maintenance of a PGA score of 0 (clear) or 1 (almost clear) while off therapy (the protocol-defined “duration of remittive effect”). If disease worsening (defined as a PGA score 2 or higher) occurred, tapinarof cream 1% was restarted and continued until a PGA score of 0 (clear) was achieved. This pattern of treatment, discontinuation on achieving a PGA score of 0 (clear), and retreatment on disease worsening continued until the end of the trial. As a result, patients in PSOARING 3 could receive tapinarof cream 1% continuously or intermittently for 40 weeks.

Outcome Measures and Statistical Analyses

The assessment of total BSA affected by plaque psoriasis is an estimate of the total extent of disease as a percentage of total skin area. In the PSOARING trials, the skin surface of one hand (palm and digits) was assumed to be approximately equivalent to 1% BSA. The total BSA affected by psoriasis was evaluated from 0% to 100%, with greater total BSA affected being an indication of more extensive disease. The BSA efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved a 1% or lower or 0.5% or lower total BSA affected. The smallest BSA affected increment that investigators were trained to measure and could record was 0.1%.

Psoriasis Area and Severity Index scores assess both the severity and extent of psoriasis. A PASI score lower than 5 often is considered indicative of mild psoriasis, a score of 5 to 10 indicates moderate disease, and a score higher than 10 indicates severe disease.¹⁹ The maximum PASI score is 72. The PASI efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved an absolute total PASI score of 3 or lower, 2 or lower, and 1 or lower.

Efficacy analyses were based on pooled data for all patients in the PSOARING trials who had a PGA score of 2 to 4 (mild to severe) before treatment with tapinarof cream 1% in the intention-to-treat population using observed cases. Time-to-target analyses were based on Kaplan-Meier (KM) estimates using observed cases.

Safety analyses included the incidence and frequency of adverse events and were based on all patients who received tapinarof cream 1% in the PSOARING trials.

RESULTS

Baseline Patient Demographics and Disease Characteristics

The pooled efficacy analyses included 915 eligible patients (Table). At baseline, the mean (SD) age was 50.2 (13.25) years, 58.7% were male, the mean (SD) weight was 92.2 (23.67) kg, and the mean (SD) body mass index was 31.6 (7.53) kg/m². The percentage of patients with a PGA score of 2 (mild), 3 (moderate), or 4 (severe) was 13.9%, 78.1%, and 8.0%, respectively. The mean (SD) PASI score was 8.7 (4.23) and mean (SD) total BSA affected was 7.8% (4.98).

Efficacy

Achievement of BSA-Affected Targets—The NPF-recommended target of 1% or lower total BSA affected within 3 months was achieved by 40% of patients (KM estimate [95% CI, 37%-43%])(Figure 1). Across the total trial period of up to 52 weeks, a total BSA affected of 1% or lower was achieved by 61% of patients (561/915), with the median time to target of approximately 4 months (KM estimate: 120 days [95% CI, 113-141])(Supplementary Figure S2a). Approximately 50% of patients (455/915) achieved a total BSA affected of 0.5% or lower, with a median time to target of 199 days (KM estimate [95% CI, 172-228)(Figure 1; Supplementary Figure S2b).

Achievement of Absolute PASI Targets—Across the total trial period (up to 52 weeks), an absolute total PASI score of 3 or lower was achieved by 75% of patients (686/915), with a median time to achieve this of 2 months (KM estimate: 58 days [95% CI, 57-63]); approximately 67% of patients (612/915) achieved a total PASI score of 2 or lower, with a median time to achieve of 3 months (KM estimate: 87 days [95% CI, 85-110])(Figure 2; Supplementary Figures S3a and S3b). A PASI score of 1 or lower was achieved by approximately 50% of patients (460/915), with a median time to achieve of approximately 6 months (KM estimate: 185 days [95% CI, 169-218])(Figure 2, Supplementary Figure S3c).

Illustrative Case—Case photography showing the clinical response in a 63-year-old man with moderate plaque psoriasis in PSOARING 2 is shown in Figure 3. After 12 weeks of treatment with tapinarof cream 1% QD, the patient achieved all primary and secondary efficacy end points. In addition to achieving the regulatory end point of a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points, achievement of 0% total BSA affected and a total PASI score of 0 at week 12 exceeded the NPF and EADV consensus treatment targets.^10,11 Targets were achieved as early as week 4, with a total BSA affected of 0.5% or lower and a total PASI score of 1 or lower, illustrated by marked skin clearing and only faint residual erythema that completely resolved at week 12, with the absence of postinflammatory hyperpigmentation.

Safety

Safety data for the PSOARING trials have been previously reported.^17,18 The most common treatment-emergent adverse events were folliculitis, contact dermatitis, upper respiratory tract infection, and nasopharyngitis. Treatment-emergent adverse events generally were mild or moderate in severity and did not lead to trial discontinuation.^17,18

COMMENT

Treat-to-target management approaches aim to improve patient outcomes by striving to achieve optimal goals. The treat-to-target approach supports shared decision-making between clinicians and patients based on common expectations of what constitutes treatment success.

The findings of this analysis based on pooled data from a large cohort of patients demonstrate that a high proportion of patients can achieve or exceed recommended treatment targets with tapinarof cream 1% QD and maintain improvements long-term. The NPF-recommended treatment target of 1% or lower BSA affected within approximately 3 months (90 days) of treatment was achieved by 40% of tapinarof-treated patients. In addition, 1% or lower BSA affected at any time during the trials was achieved by 61% of patients (median, approximately 4 months). The analyses also indicated that PASI total scores of 3 or lower and 2 or lower were achieved by 75% and 67% of tapinarof-treated patients, respectively, within 2 to 3 months.

These findings support the previously reported efficacy of tapinarof cream, including high rates of complete disease clearance (40.9% [312/763]), durable response following treatment interruption, an off-therapy remittive effect of approximately 4 months, and good disease control on therapy with no evidence of tachyphylaxis.^17,18

CONCLUSION

Taken together with previously reported tapinarof efficacy and safety results, our findings demonstrate that a high proportion of patients treated with tapinarof cream as monotherapy can achieve aggressive treatment targets set by both US and European guidelines developed for systemic and biologic therapies. Tapinarof cream 1% QD is an effective topical treatment option for patients with plaque psoriasis that has been approved without restrictions relating to severity or extent of disease treated, duration of use, or application sites, including application to sensitive and intertriginous skin.

Acknowledgments—Editorial and medical writing support under the guidance of the authors was provided by Melanie Govender, MSc (Med), ApotheCom (United Kingdom), and was funded by Dermavant Sciences, Inc, in accordance with Good Publication Practice (GPP) guidelines.

Psoriasis is a chronic inflammatory disease affecting approximately 8 million adults in the United States and 2% of the global population.^1,2 Psoriasis causes pain, itching, and disfigurement and is associated with a physical, psychological, and economic burden that substantially affects health-related quality of life.^3-5

Setting treatment goals and treating to target are evidence-based approaches that have been successfully applied to several chronic diseases to improve patient outcomes, including diabetes, hypertension, and rheumatoid arthritis.^6-9 Treat-to-target strategies generally set low disease activity (or remission) as an overall goal and seek to achieve this using available therapeutic options as necessary. Introduced following the availability of biologics and targeted systemic therapies, treat-to-target strategies generally provide guidance on expectations of treatment but not specific treatments, as personalized treatment decisions depend on an assessment of individual patients and consider clinical and demographic features as well as preferences for available therapeutic options. If targets are not achieved in the assigned time span, adjustments can be made to the treatment approach in close consultation with the patient. If the target is reached, follow-up visits can be scheduled to ensure improvement is maintained or to establish if more aggressive goals could be selected.

Treat-to-target strategies for the management of psoriasis developed by the National Psoriasis Foundation (NPF) Medical Board include reducing the extent of psoriasis to 1% or lower total body surface area (BSA) after 3 months of treatment.¹⁰ Treatment targets endorsed by the European Academy of Dermatology and Venereology (EADV) in guidelines on the use of systemic therapies in psoriasis include achieving a 75% or greater reduction in Psoriasis Area and Severity Index (PASI) score within 3 to 4 months of treatment.¹¹

In clinical practice, many patients do not achieve these treatment targets, and topical treatments alone generally are insufficient in achieving treatment goals for psoriasis.^12,13 Moreover, conventional topical treatments (eg, topical corticosteroids) used by most patients with psoriasis regardless of disease severity are associated with adverse events that can limit their use. Most topical corticosteroids have US Food and Drug Administration label restrictions relating to sites of application, duration and extent of use, and frequency of administration.^14,15

Tapinarof cream 1% (VTAMA [Dermavant Sciences, Inc]) is a first-in-class topical nonsteroidal aryl hydrocarbon receptor agonist that was approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults¹⁶ and is being studied for the treatment of plaque psoriasis in children 2 years and older as well as for atopic dermatitis in adults and children 2 years and older. In PSOARING 1 (ClinicalTrials .gov identifier NCT03956355) and PSOARING 2 (NCT03983980)—identical 12-week pivotal phase 3 trials—monotherapy with tapinarof cream 1% once daily (QD) demonstrated statistically significant efficacy vs vehicle cream and was well tolerated in adults with mild to severe plaque psoriasis (Supplementary Figure S1).¹⁷ Lebwohl et al¹⁷ reported that significantly higher PASI75 responses were observed at week 12 with tapinarof cream vs vehicle in PSOARING 1 and PSOARING 2 (36% and 48% vs 10% and 7%, respectively; both P<.0001). A significantly higher PASI90 response of 19% and 21% at week 12 also was observed with tapinarof cream vs 2% and 3% with vehicle in PSOARING 1 and PSOARING 2, respectively (P=.0005 and P<.0001).¹⁷

In PSOARING 3 (NCT04053387)—the long-term extension trial (Supplementary Figure S1)—efficacy continued to improve or was maintained beyond the two 12-week trials, with improvements in total BSA affected and PASI scores for up to 52 weeks.¹⁸ Tapinarof cream 1% QD demonstrated positive, rapid, and durable outcomes in PSOARING 3, including high rates of complete disease clearance (Physician Global Assessment [PGA] score=0 [clear])(40.9% [312/763]), durability of response on treatment with no evidence of tachyphylaxis, and a remittive effect of approximately 4 months when off therapy (defined as maintenance of a PGA score of 0 [clear] or 1 [almost clear] after first achieving a PGA score of 0).¹⁸

Herein, we report absolute treatment targets for patients with plaque psoriasis who received tapinarof cream 1% QD in the PSOARING trials that are at least as stringent as the corresponding NPF and EADV targets of achieving a total BSA affected of 1% or lower or a PASI75 response within 3 to 4 months, respectively.

METHODS

Study Design

The pooled efficacy analyses included all patients with a baseline PGA score of 2 or higher (mild or worse) before treatment with tapinarof cream 1% QD in the PSOARING trials. This included patients who received tapinarof cream 1% in PSOARING 1 and PSOARING 2 who may or may not have continued into PSOARING 3, as well as those who received the vehicle in PSOARING 1 and PSOARING 2 who enrolled in PSOARING 3 and had a PGA score of 2 or higher before receiving tapinarof cream 1%.

Trial Participants

Full methods, including inclusion and exclusion criteria, for the PSOARING trials have been previously reported.^17,18 Patients were aged 18 to 75 years and had chronic plaque psoriasis that was stable for at least 6 months before randomization; 3% to 20% total BSA affected (excluding the scalp, palms, fingernails, toenails, and soles); and a PGA score of 2 (mild), 3 (moderate), or 4 (severe) at baseline.

The clinical trials were conducted in compliance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Approval was obtained from local ethics committees or institutional review boards at each center. All patients provided written informed consent.

Trial Treatment

In PSOARING 1 and PSOARING 2, patients were randomized (2:1) to receive tapinarof cream 1% or vehicle QD for 12 weeks. In PSOARING 3 (the long-term extension trial), patients received up to 40 weeks of open-label tapinarof, followed by 4 weeks of follow-up off treatment. Patients received intermittent or continuous treatment with tapinarof cream 1% in PSOARING 3 based on PGA score: those entering the trial with a PGA score of 1 or higher received tapinarof cream 1% until complete disease clearance was achieved (defined as a PGA score of 0 [clear]). Those entering PSOARING 3 with or achieving a PGA score of 0 (clear) discontinued treatment and were observed for the duration of maintenance of a PGA score of 0 (clear) or 1 (almost clear) while off therapy (the protocol-defined “duration of remittive effect”). If disease worsening (defined as a PGA score 2 or higher) occurred, tapinarof cream 1% was restarted and continued until a PGA score of 0 (clear) was achieved. This pattern of treatment, discontinuation on achieving a PGA score of 0 (clear), and retreatment on disease worsening continued until the end of the trial. As a result, patients in PSOARING 3 could receive tapinarof cream 1% continuously or intermittently for 40 weeks.

Outcome Measures and Statistical Analyses

The assessment of total BSA affected by plaque psoriasis is an estimate of the total extent of disease as a percentage of total skin area. In the PSOARING trials, the skin surface of one hand (palm and digits) was assumed to be approximately equivalent to 1% BSA. The total BSA affected by psoriasis was evaluated from 0% to 100%, with greater total BSA affected being an indication of more extensive disease. The BSA efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved a 1% or lower or 0.5% or lower total BSA affected. The smallest BSA affected increment that investigators were trained to measure and could record was 0.1%.

Psoriasis Area and Severity Index scores assess both the severity and extent of psoriasis. A PASI score lower than 5 often is considered indicative of mild psoriasis, a score of 5 to 10 indicates moderate disease, and a score higher than 10 indicates severe disease.¹⁹ The maximum PASI score is 72. The PASI efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved an absolute total PASI score of 3 or lower, 2 or lower, and 1 or lower.

Efficacy analyses were based on pooled data for all patients in the PSOARING trials who had a PGA score of 2 to 4 (mild to severe) before treatment with tapinarof cream 1% in the intention-to-treat population using observed cases. Time-to-target analyses were based on Kaplan-Meier (KM) estimates using observed cases.

Safety analyses included the incidence and frequency of adverse events and were based on all patients who received tapinarof cream 1% in the PSOARING trials.

RESULTS

Baseline Patient Demographics and Disease Characteristics

The pooled efficacy analyses included 915 eligible patients (Table). At baseline, the mean (SD) age was 50.2 (13.25) years, 58.7% were male, the mean (SD) weight was 92.2 (23.67) kg, and the mean (SD) body mass index was 31.6 (7.53) kg/m². The percentage of patients with a PGA score of 2 (mild), 3 (moderate), or 4 (severe) was 13.9%, 78.1%, and 8.0%, respectively. The mean (SD) PASI score was 8.7 (4.23) and mean (SD) total BSA affected was 7.8% (4.98).

Efficacy

Achievement of BSA-Affected Targets—The NPF-recommended target of 1% or lower total BSA affected within 3 months was achieved by 40% of patients (KM estimate [95% CI, 37%-43%])(Figure 1). Across the total trial period of up to 52 weeks, a total BSA affected of 1% or lower was achieved by 61% of patients (561/915), with the median time to target of approximately 4 months (KM estimate: 120 days [95% CI, 113-141])(Supplementary Figure S2a). Approximately 50% of patients (455/915) achieved a total BSA affected of 0.5% or lower, with a median time to target of 199 days (KM estimate [95% CI, 172-228)(Figure 1; Supplementary Figure S2b).

Achievement of Absolute PASI Targets—Across the total trial period (up to 52 weeks), an absolute total PASI score of 3 or lower was achieved by 75% of patients (686/915), with a median time to achieve this of 2 months (KM estimate: 58 days [95% CI, 57-63]); approximately 67% of patients (612/915) achieved a total PASI score of 2 or lower, with a median time to achieve of 3 months (KM estimate: 87 days [95% CI, 85-110])(Figure 2; Supplementary Figures S3a and S3b). A PASI score of 1 or lower was achieved by approximately 50% of patients (460/915), with a median time to achieve of approximately 6 months (KM estimate: 185 days [95% CI, 169-218])(Figure 2, Supplementary Figure S3c).

Illustrative Case—Case photography showing the clinical response in a 63-year-old man with moderate plaque psoriasis in PSOARING 2 is shown in Figure 3. After 12 weeks of treatment with tapinarof cream 1% QD, the patient achieved all primary and secondary efficacy end points. In addition to achieving the regulatory end point of a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points, achievement of 0% total BSA affected and a total PASI score of 0 at week 12 exceeded the NPF and EADV consensus treatment targets.^10,11 Targets were achieved as early as week 4, with a total BSA affected of 0.5% or lower and a total PASI score of 1 or lower, illustrated by marked skin clearing and only faint residual erythema that completely resolved at week 12, with the absence of postinflammatory hyperpigmentation.

Safety

Safety data for the PSOARING trials have been previously reported.^17,18 The most common treatment-emergent adverse events were folliculitis, contact dermatitis, upper respiratory tract infection, and nasopharyngitis. Treatment-emergent adverse events generally were mild or moderate in severity and did not lead to trial discontinuation.^17,18

COMMENT

Treat-to-target management approaches aim to improve patient outcomes by striving to achieve optimal goals. The treat-to-target approach supports shared decision-making between clinicians and patients based on common expectations of what constitutes treatment success.

The findings of this analysis based on pooled data from a large cohort of patients demonstrate that a high proportion of patients can achieve or exceed recommended treatment targets with tapinarof cream 1% QD and maintain improvements long-term. The NPF-recommended treatment target of 1% or lower BSA affected within approximately 3 months (90 days) of treatment was achieved by 40% of tapinarof-treated patients. In addition, 1% or lower BSA affected at any time during the trials was achieved by 61% of patients (median, approximately 4 months). The analyses also indicated that PASI total scores of 3 or lower and 2 or lower were achieved by 75% and 67% of tapinarof-treated patients, respectively, within 2 to 3 months.

These findings support the previously reported efficacy of tapinarof cream, including high rates of complete disease clearance (40.9% [312/763]), durable response following treatment interruption, an off-therapy remittive effect of approximately 4 months, and good disease control on therapy with no evidence of tachyphylaxis.^17,18

CONCLUSION

Taken together with previously reported tapinarof efficacy and safety results, our findings demonstrate that a high proportion of patients treated with tapinarof cream as monotherapy can achieve aggressive treatment targets set by both US and European guidelines developed for systemic and biologic therapies. Tapinarof cream 1% QD is an effective topical treatment option for patients with plaque psoriasis that has been approved without restrictions relating to severity or extent of disease treated, duration of use, or application sites, including application to sensitive and intertriginous skin.

Acknowledgments—Editorial and medical writing support under the guidance of the authors was provided by Melanie Govender, MSc (Med), ApotheCom (United Kingdom), and was funded by Dermavant Sciences, Inc, in accordance with Good Publication Practice (GPP) guidelines.

Psoriasis is a chronic inflammatory disease affecting approximately 8 million adults in the United States and 2% of the global population.^1,2 Psoriasis causes pain, itching, and disfigurement and is associated with a physical, psychological, and economic burden that substantially affects health-related quality of life.^3-5

Setting treatment goals and treating to target are evidence-based approaches that have been successfully applied to several chronic diseases to improve patient outcomes, including diabetes, hypertension, and rheumatoid arthritis.^6-9 Treat-to-target strategies generally set low disease activity (or remission) as an overall goal and seek to achieve this using available therapeutic options as necessary. Introduced following the availability of biologics and targeted systemic therapies, treat-to-target strategies generally provide guidance on expectations of treatment but not specific treatments, as personalized treatment decisions depend on an assessment of individual patients and consider clinical and demographic features as well as preferences for available therapeutic options. If targets are not achieved in the assigned time span, adjustments can be made to the treatment approach in close consultation with the patient. If the target is reached, follow-up visits can be scheduled to ensure improvement is maintained or to establish if more aggressive goals could be selected.

Treat-to-target strategies for the management of psoriasis developed by the National Psoriasis Foundation (NPF) Medical Board include reducing the extent of psoriasis to 1% or lower total body surface area (BSA) after 3 months of treatment.¹⁰ Treatment targets endorsed by the European Academy of Dermatology and Venereology (EADV) in guidelines on the use of systemic therapies in psoriasis include achieving a 75% or greater reduction in Psoriasis Area and Severity Index (PASI) score within 3 to 4 months of treatment.¹¹

In clinical practice, many patients do not achieve these treatment targets, and topical treatments alone generally are insufficient in achieving treatment goals for psoriasis.^12,13 Moreover, conventional topical treatments (eg, topical corticosteroids) used by most patients with psoriasis regardless of disease severity are associated with adverse events that can limit their use. Most topical corticosteroids have US Food and Drug Administration label restrictions relating to sites of application, duration and extent of use, and frequency of administration.^14,15

Tapinarof cream 1% (VTAMA [Dermavant Sciences, Inc]) is a first-in-class topical nonsteroidal aryl hydrocarbon receptor agonist that was approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults¹⁶ and is being studied for the treatment of plaque psoriasis in children 2 years and older as well as for atopic dermatitis in adults and children 2 years and older. In PSOARING 1 (ClinicalTrials .gov identifier NCT03956355) and PSOARING 2 (NCT03983980)—identical 12-week pivotal phase 3 trials—monotherapy with tapinarof cream 1% once daily (QD) demonstrated statistically significant efficacy vs vehicle cream and was well tolerated in adults with mild to severe plaque psoriasis (Supplementary Figure S1).¹⁷ Lebwohl et al¹⁷ reported that significantly higher PASI75 responses were observed at week 12 with tapinarof cream vs vehicle in PSOARING 1 and PSOARING 2 (36% and 48% vs 10% and 7%, respectively; both P<.0001). A significantly higher PASI90 response of 19% and 21% at week 12 also was observed with tapinarof cream vs 2% and 3% with vehicle in PSOARING 1 and PSOARING 2, respectively (P=.0005 and P<.0001).¹⁷

In PSOARING 3 (NCT04053387)—the long-term extension trial (Supplementary Figure S1)—efficacy continued to improve or was maintained beyond the two 12-week trials, with improvements in total BSA affected and PASI scores for up to 52 weeks.¹⁸ Tapinarof cream 1% QD demonstrated positive, rapid, and durable outcomes in PSOARING 3, including high rates of complete disease clearance (Physician Global Assessment [PGA] score=0 [clear])(40.9% [312/763]), durability of response on treatment with no evidence of tachyphylaxis, and a remittive effect of approximately 4 months when off therapy (defined as maintenance of a PGA score of 0 [clear] or 1 [almost clear] after first achieving a PGA score of 0).¹⁸

Herein, we report absolute treatment targets for patients with plaque psoriasis who received tapinarof cream 1% QD in the PSOARING trials that are at least as stringent as the corresponding NPF and EADV targets of achieving a total BSA affected of 1% or lower or a PASI75 response within 3 to 4 months, respectively.

METHODS

Study Design

The pooled efficacy analyses included all patients with a baseline PGA score of 2 or higher (mild or worse) before treatment with tapinarof cream 1% QD in the PSOARING trials. This included patients who received tapinarof cream 1% in PSOARING 1 and PSOARING 2 who may or may not have continued into PSOARING 3, as well as those who received the vehicle in PSOARING 1 and PSOARING 2 who enrolled in PSOARING 3 and had a PGA score of 2 or higher before receiving tapinarof cream 1%.

Trial Participants

Full methods, including inclusion and exclusion criteria, for the PSOARING trials have been previously reported.^17,18 Patients were aged 18 to 75 years and had chronic plaque psoriasis that was stable for at least 6 months before randomization; 3% to 20% total BSA affected (excluding the scalp, palms, fingernails, toenails, and soles); and a PGA score of 2 (mild), 3 (moderate), or 4 (severe) at baseline.

The clinical trials were conducted in compliance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Approval was obtained from local ethics committees or institutional review boards at each center. All patients provided written informed consent.

Trial Treatment

In PSOARING 1 and PSOARING 2, patients were randomized (2:1) to receive tapinarof cream 1% or vehicle QD for 12 weeks. In PSOARING 3 (the long-term extension trial), patients received up to 40 weeks of open-label tapinarof, followed by 4 weeks of follow-up off treatment. Patients received intermittent or continuous treatment with tapinarof cream 1% in PSOARING 3 based on PGA score: those entering the trial with a PGA score of 1 or higher received tapinarof cream 1% until complete disease clearance was achieved (defined as a PGA score of 0 [clear]). Those entering PSOARING 3 with or achieving a PGA score of 0 (clear) discontinued treatment and were observed for the duration of maintenance of a PGA score of 0 (clear) or 1 (almost clear) while off therapy (the protocol-defined “duration of remittive effect”). If disease worsening (defined as a PGA score 2 or higher) occurred, tapinarof cream 1% was restarted and continued until a PGA score of 0 (clear) was achieved. This pattern of treatment, discontinuation on achieving a PGA score of 0 (clear), and retreatment on disease worsening continued until the end of the trial. As a result, patients in PSOARING 3 could receive tapinarof cream 1% continuously or intermittently for 40 weeks.

Outcome Measures and Statistical Analyses

The assessment of total BSA affected by plaque psoriasis is an estimate of the total extent of disease as a percentage of total skin area. In the PSOARING trials, the skin surface of one hand (palm and digits) was assumed to be approximately equivalent to 1% BSA. The total BSA affected by psoriasis was evaluated from 0% to 100%, with greater total BSA affected being an indication of more extensive disease. The BSA efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved a 1% or lower or 0.5% or lower total BSA affected. The smallest BSA affected increment that investigators were trained to measure and could record was 0.1%.

Psoriasis Area and Severity Index scores assess both the severity and extent of psoriasis. A PASI score lower than 5 often is considered indicative of mild psoriasis, a score of 5 to 10 indicates moderate disease, and a score higher than 10 indicates severe disease.¹⁹ The maximum PASI score is 72. The PASI efficacy outcomes used in these analyses were based post hoc on the proportion of patients who achieved an absolute total PASI score of 3 or lower, 2 or lower, and 1 or lower.

Efficacy analyses were based on pooled data for all patients in the PSOARING trials who had a PGA score of 2 to 4 (mild to severe) before treatment with tapinarof cream 1% in the intention-to-treat population using observed cases. Time-to-target analyses were based on Kaplan-Meier (KM) estimates using observed cases.

Safety analyses included the incidence and frequency of adverse events and were based on all patients who received tapinarof cream 1% in the PSOARING trials.

RESULTS

Baseline Patient Demographics and Disease Characteristics

The pooled efficacy analyses included 915 eligible patients (Table). At baseline, the mean (SD) age was 50.2 (13.25) years, 58.7% were male, the mean (SD) weight was 92.2 (23.67) kg, and the mean (SD) body mass index was 31.6 (7.53) kg/m². The percentage of patients with a PGA score of 2 (mild), 3 (moderate), or 4 (severe) was 13.9%, 78.1%, and 8.0%, respectively. The mean (SD) PASI score was 8.7 (4.23) and mean (SD) total BSA affected was 7.8% (4.98).

Efficacy

Achievement of BSA-Affected Targets—The NPF-recommended target of 1% or lower total BSA affected within 3 months was achieved by 40% of patients (KM estimate [95% CI, 37%-43%])(Figure 1). Across the total trial period of up to 52 weeks, a total BSA affected of 1% or lower was achieved by 61% of patients (561/915), with the median time to target of approximately 4 months (KM estimate: 120 days [95% CI, 113-141])(Supplementary Figure S2a). Approximately 50% of patients (455/915) achieved a total BSA affected of 0.5% or lower, with a median time to target of 199 days (KM estimate [95% CI, 172-228)(Figure 1; Supplementary Figure S2b).

Achievement of Absolute PASI Targets—Across the total trial period (up to 52 weeks), an absolute total PASI score of 3 or lower was achieved by 75% of patients (686/915), with a median time to achieve this of 2 months (KM estimate: 58 days [95% CI, 57-63]); approximately 67% of patients (612/915) achieved a total PASI score of 2 or lower, with a median time to achieve of 3 months (KM estimate: 87 days [95% CI, 85-110])(Figure 2; Supplementary Figures S3a and S3b). A PASI score of 1 or lower was achieved by approximately 50% of patients (460/915), with a median time to achieve of approximately 6 months (KM estimate: 185 days [95% CI, 169-218])(Figure 2, Supplementary Figure S3c).

Illustrative Case—Case photography showing the clinical response in a 63-year-old man with moderate plaque psoriasis in PSOARING 2 is shown in Figure 3. After 12 weeks of treatment with tapinarof cream 1% QD, the patient achieved all primary and secondary efficacy end points. In addition to achieving the regulatory end point of a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points, achievement of 0% total BSA affected and a total PASI score of 0 at week 12 exceeded the NPF and EADV consensus treatment targets.^10,11 Targets were achieved as early as week 4, with a total BSA affected of 0.5% or lower and a total PASI score of 1 or lower, illustrated by marked skin clearing and only faint residual erythema that completely resolved at week 12, with the absence of postinflammatory hyperpigmentation.

Safety

Safety data for the PSOARING trials have been previously reported.^17,18 The most common treatment-emergent adverse events were folliculitis, contact dermatitis, upper respiratory tract infection, and nasopharyngitis. Treatment-emergent adverse events generally were mild or moderate in severity and did not lead to trial discontinuation.^17,18

COMMENT

Treat-to-target management approaches aim to improve patient outcomes by striving to achieve optimal goals. The treat-to-target approach supports shared decision-making between clinicians and patients based on common expectations of what constitutes treatment success.

The findings of this analysis based on pooled data from a large cohort of patients demonstrate that a high proportion of patients can achieve or exceed recommended treatment targets with tapinarof cream 1% QD and maintain improvements long-term. The NPF-recommended treatment target of 1% or lower BSA affected within approximately 3 months (90 days) of treatment was achieved by 40% of tapinarof-treated patients. In addition, 1% or lower BSA affected at any time during the trials was achieved by 61% of patients (median, approximately 4 months). The analyses also indicated that PASI total scores of 3 or lower and 2 or lower were achieved by 75% and 67% of tapinarof-treated patients, respectively, within 2 to 3 months.

These findings support the previously reported efficacy of tapinarof cream, including high rates of complete disease clearance (40.9% [312/763]), durable response following treatment interruption, an off-therapy remittive effect of approximately 4 months, and good disease control on therapy with no evidence of tachyphylaxis.^17,18

CONCLUSION

Taken together with previously reported tapinarof efficacy and safety results, our findings demonstrate that a high proportion of patients treated with tapinarof cream as monotherapy can achieve aggressive treatment targets set by both US and European guidelines developed for systemic and biologic therapies. Tapinarof cream 1% QD is an effective topical treatment option for patients with plaque psoriasis that has been approved without restrictions relating to severity or extent of disease treated, duration of use, or application sites, including application to sensitive and intertriginous skin.

Acknowledgments—Editorial and medical writing support under the guidance of the authors was provided by Melanie Govender, MSc (Med), ApotheCom (United Kingdom), and was funded by Dermavant Sciences, Inc, in accordance with Good Publication Practice (GPP) guidelines.

The Diagnosis: Nevus Sebaceus of Jadassohn

The diagnosis of nevus sebaceus of Jadassohn was made clinically based on the lesion’s appearance and presence since birth as well as the absence of systemic symptoms. Clinically, nevus sebaceus of Jadassohn typically manifests as a well-demarcated, yellow- brown plaque often located on the scalp, as was seen in our patient. The lack of pruritus and pain further supported the diagnosis in our patient. No biopsy was performed, as the presentation was considered classic for this condition. Our patient opted to forgo surgery and will be routinely monitored for any changes, as nevus sebaceus has a potential risk, albeit low, for malignant transformation later in life. No changes have been observed since the initial presentation, and regular follow-ups are planned to monitor for future developments.

Nevus sebaceus of Jadassohn is a hamartomatous lesion involving the pilosebaceous follicle and adjacent adnexal structures.^1-3 It most commonly forms on the scalp (59.3%) and is accompanied by partial or total alopecia. ^3,4 It is seen less often on the face, periauricular area, or neck^1,4; thorax or limbs⁵; and oral or genital mucosae.⁶ Nevus sebaceus of Jadassohn affects approximately 0.3% of newborns,¹ usually as a solitary lesion that can form an extensive plaque. The male-to-female occurrence ratio has been reported as equal to slightly more predominant in females; all races and ethnicities are affected.^1,5

Nevus sebaceus of Jadassohn follows 3 stages of clinical development: infantile, adolescent, and adulthood. It manifests at birth or shortly afterward as a smooth hairless patch or plaque that is yellowish and can be hyperpigmented in Black patients.⁵ It may have an oval or linear configuration, typically is asymptomatic, and often arises along the Blaschko lines when it occurs as multiple lesions (a rare manifestation).¹ During puberty, hormonal changes cause accelerated growth, sebaceous gland maturation, and epidermal hyperplasia. ⁷ Nevus sebaceus of Jadassohn often is not identified until this stage, when its classic wartlike appearance has fully developed.¹

Patients with nevus sebaceus of Jadassohn have a 10% to 20% risk for tumor development in adulthood.^2,7 Trichoblastoma and syringocystadenoma papilliferum are the most frequently described neoplasms.⁸ Basal cell carcinoma is the most common malignant secondary neoplasm with an occurrence rate of 0.8%.^6,9 However, basal cell carcinoma and trichoblastoma may share histopathologic features, which may lead to misdiagnosis and a higher reported incidence of basal cell carcinoma in adults than is accurate.²

Early prophylactic surgical removal of nevus sebaceus of Jadassohn has been recommended; however, surgical management is controversial because the risk for a benign secondary neoplasm remains relatively high while the risk for malignancy is much lower.^2,7 Surgical excision remains an acceptable option once the patient is mature enough to tolerate the procedure.¹ However, patient education regarding watchful waiting vs a surgical approach— and the risks of each—is critical to ensure shared decision-making and a management plan tailored to the individual.

The differential diagnosis includes hypertrophic lichen planus, Langerhans cell histiocytosis (Letterer-Siwe disease type), epidermal nevus, and seborrheic keratosis. Hypertrophic lichen planus often occurs symmetrically on the dorsal feet and shins with thick, scaly, and extremely pruritic plaques. The lesions often persist for an average of 6 years and may lead to multiple keratoacanthomas or follicular base squamous cell carcinomas. Langerhans cell histiocytosis (Letterer-Siwe disease type) manifests with acute, disseminated, visceral, and cutaneous lesions before 2 years of age. These lesions appear as 1- to 2-mm, pink, seborrheic papules, pustules, or vesicles on the scalp, flexural neck, axilla, perineum, and trunk; they often are associated with petechiae, purpura, scale, crust, erosion, impetiginization, and tender fissures. Epidermal nevus occurs within the first year of life and is a hamartoma of the epidermis and papillary dermis. It manifests as papillomatous pigmented linear lines along the Blaschko lines. Seborrheic keratosis manifests as well-demarcated, waxy/verrucous, brown papules with a “stuck on” appearance on hair-bearing skin sparing the mucosae. They are common benign lesions associated with sun exposure and often manifest in the fourth decade of life.¹⁰

The Diagnosis: Nevus Sebaceus of Jadassohn

The diagnosis of nevus sebaceus of Jadassohn was made clinically based on the lesion’s appearance and presence since birth as well as the absence of systemic symptoms. Clinically, nevus sebaceus of Jadassohn typically manifests as a well-demarcated, yellow- brown plaque often located on the scalp, as was seen in our patient. The lack of pruritus and pain further supported the diagnosis in our patient. No biopsy was performed, as the presentation was considered classic for this condition. Our patient opted to forgo surgery and will be routinely monitored for any changes, as nevus sebaceus has a potential risk, albeit low, for malignant transformation later in life. No changes have been observed since the initial presentation, and regular follow-ups are planned to monitor for future developments.

Nevus sebaceus of Jadassohn is a hamartomatous lesion involving the pilosebaceous follicle and adjacent adnexal structures.^1-3 It most commonly forms on the scalp (59.3%) and is accompanied by partial or total alopecia. ^3,4 It is seen less often on the face, periauricular area, or neck^1,4; thorax or limbs⁵; and oral or genital mucosae.⁶ Nevus sebaceus of Jadassohn affects approximately 0.3% of newborns,¹ usually as a solitary lesion that can form an extensive plaque. The male-to-female occurrence ratio has been reported as equal to slightly more predominant in females; all races and ethnicities are affected.^1,5

Nevus sebaceus of Jadassohn follows 3 stages of clinical development: infantile, adolescent, and adulthood. It manifests at birth or shortly afterward as a smooth hairless patch or plaque that is yellowish and can be hyperpigmented in Black patients.⁵ It may have an oval or linear configuration, typically is asymptomatic, and often arises along the Blaschko lines when it occurs as multiple lesions (a rare manifestation).¹ During puberty, hormonal changes cause accelerated growth, sebaceous gland maturation, and epidermal hyperplasia. ⁷ Nevus sebaceus of Jadassohn often is not identified until this stage, when its classic wartlike appearance has fully developed.¹

Patients with nevus sebaceus of Jadassohn have a 10% to 20% risk for tumor development in adulthood.^2,7 Trichoblastoma and syringocystadenoma papilliferum are the most frequently described neoplasms.⁸ Basal cell carcinoma is the most common malignant secondary neoplasm with an occurrence rate of 0.8%.^6,9 However, basal cell carcinoma and trichoblastoma may share histopathologic features, which may lead to misdiagnosis and a higher reported incidence of basal cell carcinoma in adults than is accurate.²

Early prophylactic surgical removal of nevus sebaceus of Jadassohn has been recommended; however, surgical management is controversial because the risk for a benign secondary neoplasm remains relatively high while the risk for malignancy is much lower.^2,7 Surgical excision remains an acceptable option once the patient is mature enough to tolerate the procedure.¹ However, patient education regarding watchful waiting vs a surgical approach— and the risks of each—is critical to ensure shared decision-making and a management plan tailored to the individual.

The differential diagnosis includes hypertrophic lichen planus, Langerhans cell histiocytosis (Letterer-Siwe disease type), epidermal nevus, and seborrheic keratosis. Hypertrophic lichen planus often occurs symmetrically on the dorsal feet and shins with thick, scaly, and extremely pruritic plaques. The lesions often persist for an average of 6 years and may lead to multiple keratoacanthomas or follicular base squamous cell carcinomas. Langerhans cell histiocytosis (Letterer-Siwe disease type) manifests with acute, disseminated, visceral, and cutaneous lesions before 2 years of age. These lesions appear as 1- to 2-mm, pink, seborrheic papules, pustules, or vesicles on the scalp, flexural neck, axilla, perineum, and trunk; they often are associated with petechiae, purpura, scale, crust, erosion, impetiginization, and tender fissures. Epidermal nevus occurs within the first year of life and is a hamartoma of the epidermis and papillary dermis. It manifests as papillomatous pigmented linear lines along the Blaschko lines. Seborrheic keratosis manifests as well-demarcated, waxy/verrucous, brown papules with a “stuck on” appearance on hair-bearing skin sparing the mucosae. They are common benign lesions associated with sun exposure and often manifest in the fourth decade of life.¹⁰

The Diagnosis: Nevus Sebaceus of Jadassohn

The diagnosis of nevus sebaceus of Jadassohn was made clinically based on the lesion’s appearance and presence since birth as well as the absence of systemic symptoms. Clinically, nevus sebaceus of Jadassohn typically manifests as a well-demarcated, yellow- brown plaque often located on the scalp, as was seen in our patient. The lack of pruritus and pain further supported the diagnosis in our patient. No biopsy was performed, as the presentation was considered classic for this condition. Our patient opted to forgo surgery and will be routinely monitored for any changes, as nevus sebaceus has a potential risk, albeit low, for malignant transformation later in life. No changes have been observed since the initial presentation, and regular follow-ups are planned to monitor for future developments.

Nevus sebaceus of Jadassohn is a hamartomatous lesion involving the pilosebaceous follicle and adjacent adnexal structures.^1-3 It most commonly forms on the scalp (59.3%) and is accompanied by partial or total alopecia. ^3,4 It is seen less often on the face, periauricular area, or neck^1,4; thorax or limbs⁵; and oral or genital mucosae.⁶ Nevus sebaceus of Jadassohn affects approximately 0.3% of newborns,¹ usually as a solitary lesion that can form an extensive plaque. The male-to-female occurrence ratio has been reported as equal to slightly more predominant in females; all races and ethnicities are affected.^1,5

Nevus sebaceus of Jadassohn follows 3 stages of clinical development: infantile, adolescent, and adulthood. It manifests at birth or shortly afterward as a smooth hairless patch or plaque that is yellowish and can be hyperpigmented in Black patients.⁵ It may have an oval or linear configuration, typically is asymptomatic, and often arises along the Blaschko lines when it occurs as multiple lesions (a rare manifestation).¹ During puberty, hormonal changes cause accelerated growth, sebaceous gland maturation, and epidermal hyperplasia. ⁷ Nevus sebaceus of Jadassohn often is not identified until this stage, when its classic wartlike appearance has fully developed.¹

Patients with nevus sebaceus of Jadassohn have a 10% to 20% risk for tumor development in adulthood.^2,7 Trichoblastoma and syringocystadenoma papilliferum are the most frequently described neoplasms.⁸ Basal cell carcinoma is the most common malignant secondary neoplasm with an occurrence rate of 0.8%.^6,9 However, basal cell carcinoma and trichoblastoma may share histopathologic features, which may lead to misdiagnosis and a higher reported incidence of basal cell carcinoma in adults than is accurate.²

Early prophylactic surgical removal of nevus sebaceus of Jadassohn has been recommended; however, surgical management is controversial because the risk for a benign secondary neoplasm remains relatively high while the risk for malignancy is much lower.^2,7 Surgical excision remains an acceptable option once the patient is mature enough to tolerate the procedure.¹ However, patient education regarding watchful waiting vs a surgical approach— and the risks of each—is critical to ensure shared decision-making and a management plan tailored to the individual.

The differential diagnosis includes hypertrophic lichen planus, Langerhans cell histiocytosis (Letterer-Siwe disease type), epidermal nevus, and seborrheic keratosis. Hypertrophic lichen planus often occurs symmetrically on the dorsal feet and shins with thick, scaly, and extremely pruritic plaques. The lesions often persist for an average of 6 years and may lead to multiple keratoacanthomas or follicular base squamous cell carcinomas. Langerhans cell histiocytosis (Letterer-Siwe disease type) manifests with acute, disseminated, visceral, and cutaneous lesions before 2 years of age. These lesions appear as 1- to 2-mm, pink, seborrheic papules, pustules, or vesicles on the scalp, flexural neck, axilla, perineum, and trunk; they often are associated with petechiae, purpura, scale, crust, erosion, impetiginization, and tender fissures. Epidermal nevus occurs within the first year of life and is a hamartoma of the epidermis and papillary dermis. It manifests as papillomatous pigmented linear lines along the Blaschko lines. Seborrheic keratosis manifests as well-demarcated, waxy/verrucous, brown papules with a “stuck on” appearance on hair-bearing skin sparing the mucosae. They are common benign lesions associated with sun exposure and often manifest in the fourth decade of life.¹⁰

There are 375 species of poisonous snakes, with approximately 20,000 deaths worldwide each year due to snakebites, mostly in Asia and Africa.¹ The death rate in the United States is 14 to 20 cases per year. In the United States, a variety of rattlesnakes are poisonous. There are 2 genera of rattlesnakes: Sistrurus (3 species) and Crotalus (23 species). The pygmy rattlesnake belongs to the Sistrurus miliarius species that is divided into 3 subspecies: the Carolina pigmy rattlesnake (S miliarius miliarius), the western pygmy rattlesnake (S miliarius streckeri), and the dusky pygmy rattlesnake (S miliarius barbouri).²

The western pygmy rattlesnake belongs to the Crotalidae family. The rattlesnakes in this family also are known as pit vipers. All pit vipers have common characteristics for identification: triangular head, fangs, elliptical pupils, and a heat-sensing pit between the eyes. The western pygmy rattlesnake is found in Missouri, Arkansas, Oklahoma, Kentucky, and Tennessee.¹ It is small bodied (15–20 inches)³ and grayish-brown, with a brown dorsal stripe with black blotches on its back. It is found in glades, second-growth forests near rock ledges, and areas where powerlines cut through dense forest.³ Its venom is hemorrhagic, causing tissue damage, but does not contain neurotoxins.⁴ Bites from the western pygmy rattlesnake often do not lead to death, but the venom, which contains numerous proteins and enzymes, does cause necrotic hemorrhagic ulceration at the site of envenomation and possible loss of digit.^5,6

We present a case of a man who was bitten on the right third digit by a western pygmy rattlesnake. We describe the clinical course and treatment.

Case Report

A 56-year-old right-handed man presented to the emergency department with a rapidly swelling, painful hand following a snakebite to the dorsal aspect of the right third digit (Figure 1). He was able to capture a photograph of the snake at the time of injury, which helped identify it as a western pygmy rattlesnake (Figure 2). He also photographed the hand immediately after the bite occurred (Figure 3). Vitals on presentation included an elevated blood pressure of 161/100 mm Hg; no fever (temperature, 36.4 °C); and normal pulse oximetry of 98%, pulse of 86 beats per minute, and respiratory rate of 16 breaths per minute.

After the snakebite, the patient’s family called the Missouri Poison Center immediately. The family identified the snake species and shared this information with the poison center. Poison control recommended calling the nearest hospitals to determine if antivenom was available and make notification of arrival. 

The patient’s tetanus toxoid immunization was updated immediately upon arrival. The hand was marked to monitor swelling. Initial laboratory test results revealed the following values: sodium, 133 mmol/L (reference range, 136–145 mmol/L); potassium, 3.4 mmol/L (3.6–5.2 mmol/L); lactic acid, 2.4 mmol/L (0.5–2.2 mmol/L); creatine kinase, 425 U/L (55–170 U/L); platelet count, 68/µL (150,000–450,000/µL); fibrinogen, 169 mg/dL (185–410 mg/dL); and glucose, 121 mg/dL (74–106 mg/dL). The remainder of the complete blood cell count and metabolic panel was unremarkable. Radiographs of the hand did not show any fractures, dislocations, or foreign bodies. Missouri Poison Center was consulted. Given the patient’s severe pain, edema beyond 40 cm, and developing ecchymosis on the inner arm, the bite was graded as a 3 on the traditional snakebite severity scale. Poison control recommended 4 to 6 vials of antivenom over 60 minutes. Six vials of Crotalidae polyvalent immune fab antivenom were given.

The patient’s complete blood cell count remained unremarkable throughout his admission. His metabolic panel returned to normal at 6 hours postadmission: sodium, 139 mmol/L; potassium, 4.0 mmol/L. His lactate and creatinine kinase were not rechecked. His fibrinogen was trending upward. Serial laboratory test results revealed fibrinogen levels of 153, 158, 161, 159, 173, and 216 mg/dL at 6, 12, 18, 24, 30, and 36 hours, respectively. Other laboratory test results including prothrombin time (11.0 s) and international normalized ratio (0.98) remained within reference range (11–13 s and 0.80–1.39, respectively) during serial monitoring.

The patient was hospitalized for 40 hours while waiting for his fibrinogen level to normalize. The local skin necrosis worsened acutely in this 40-hour window (Figure 4). Intravenous antibiotics were not administered during the hospital stay. Before discharge, the patient was evaluated by the surgery service, who did not recommend debridement.

Surgical Management of Snakebites

The surgeon’s role in managing snakebites is controversial. Snakebites were once perceived as a surgical emergency due to symptoms mimicking compartment syndrome; however, snakebites rarely cause a true compartment syndrome.⁷ Prophylactic bite excision and fasciotomies are not recommended. Incision and suction of the fang marks may be beneficial if performed within 15 to 30 minutes from the time of the bite.⁸ With access to a surgeon in this short time period being nearly impossible, incision and suctioning of fang marks generally is not recommended.⁹ Retained snake fangs are a possibility, and the infection could spread to a nearby joint, causing septic arthritis,¹⁰ which would be an indication for surgical intervention. Bites to the finger often cause major swelling, and the benefits of dermotomy are documented.¹¹ Generally, early administration of antivenom will decrease local tissue reaction and prevent additional tissue loss.¹² In our patient, the decision to perform dermotomy was made when the area of necrosis had declared itself and the skin reached its elastic limit. Bozkurt et al¹³ described the neurovascular bundles within the digit as functioning as small compartments. When the skin of the digit reaches its elastic limit, pressure within the compartment may exceed the capillary closing pressure, and the integrity of small vessels and nerves may be compromised. Our case highlights the benefit of dermotomy as well as the functional and cosmetic results that can be achieved.

Wound Care for Snakebites

There is little published on the treatment of snakebites after patients are stabilized medically for hospital discharge. Venomous snakes inject toxins that predominantly consist of enzymes (eg, phospholipase A2, phosphodiesterase, hyaluronidase, peptidase, metalloproteinase) that cause tissue destruction through diverse mechanisms.¹⁴ The venom of western pygmy rattlesnakes is hemotoxic and can cause necrotic hemorrhagic ulceration,⁴ as was the case in our patient.

Silver sulfadiazine commonly is used to prevent infection in burn patients. Given the large surface area of exposed dermis after debridement and concern for infection, silver sulfadiazine was chosen in our patient for local wound care treatment. Silver sulfadiazine is a widely available and low-cost drug.¹⁵ Its antibacterial effects are due to the silver ions, which only act superficially and therefore limit systemic absorption.¹⁶ Application should be performed in a clean manner with minimal trauma to the tissue. This technique is best achieved by using sterile gloves and applying the medication manually. A 0.0625-inch layer should be applied to entirely cover the cleaned debrided area.¹⁷ When performing application with tongue blades or cotton swabs, it is important to never “double dip.” Patient education on proper administration is imperative to a successful outcome.

Final Thoughts

Our case demonstrates the safe use of Crotalidae polyvalent immune fab antivenom for the treatment of western pygmy rattlesnake (S miliarius streckeri) envenomation. Early administration of antivenom following pit viper rattlesnake envenomations is important to mitigate systemic effects and the extent of soft tissue damage. There are few studies on local wound care treatment after rattlesnake envenomation. This case highlights the role of dermotomy and wound care with silver sulfadiazine cream 1%.

There are 375 species of poisonous snakes, with approximately 20,000 deaths worldwide each year due to snakebites, mostly in Asia and Africa.¹ The death rate in the United States is 14 to 20 cases per year. In the United States, a variety of rattlesnakes are poisonous. There are 2 genera of rattlesnakes: Sistrurus (3 species) and Crotalus (23 species). The pygmy rattlesnake belongs to the Sistrurus miliarius species that is divided into 3 subspecies: the Carolina pigmy rattlesnake (S miliarius miliarius), the western pygmy rattlesnake (S miliarius streckeri), and the dusky pygmy rattlesnake (S miliarius barbouri).²

The western pygmy rattlesnake belongs to the Crotalidae family. The rattlesnakes in this family also are known as pit vipers. All pit vipers have common characteristics for identification: triangular head, fangs, elliptical pupils, and a heat-sensing pit between the eyes. The western pygmy rattlesnake is found in Missouri, Arkansas, Oklahoma, Kentucky, and Tennessee.¹ It is small bodied (15–20 inches)³ and grayish-brown, with a brown dorsal stripe with black blotches on its back. It is found in glades, second-growth forests near rock ledges, and areas where powerlines cut through dense forest.³ Its venom is hemorrhagic, causing tissue damage, but does not contain neurotoxins.⁴ Bites from the western pygmy rattlesnake often do not lead to death, but the venom, which contains numerous proteins and enzymes, does cause necrotic hemorrhagic ulceration at the site of envenomation and possible loss of digit.^5,6

We present a case of a man who was bitten on the right third digit by a western pygmy rattlesnake. We describe the clinical course and treatment.

Case Report

A 56-year-old right-handed man presented to the emergency department with a rapidly swelling, painful hand following a snakebite to the dorsal aspect of the right third digit (Figure 1). He was able to capture a photograph of the snake at the time of injury, which helped identify it as a western pygmy rattlesnake (Figure 2). He also photographed the hand immediately after the bite occurred (Figure 3). Vitals on presentation included an elevated blood pressure of 161/100 mm Hg; no fever (temperature, 36.4 °C); and normal pulse oximetry of 98%, pulse of 86 beats per minute, and respiratory rate of 16 breaths per minute.

After the snakebite, the patient’s family called the Missouri Poison Center immediately. The family identified the snake species and shared this information with the poison center. Poison control recommended calling the nearest hospitals to determine if antivenom was available and make notification of arrival. 

The patient’s tetanus toxoid immunization was updated immediately upon arrival. The hand was marked to monitor swelling. Initial laboratory test results revealed the following values: sodium, 133 mmol/L (reference range, 136–145 mmol/L); potassium, 3.4 mmol/L (3.6–5.2 mmol/L); lactic acid, 2.4 mmol/L (0.5–2.2 mmol/L); creatine kinase, 425 U/L (55–170 U/L); platelet count, 68/µL (150,000–450,000/µL); fibrinogen, 169 mg/dL (185–410 mg/dL); and glucose, 121 mg/dL (74–106 mg/dL). The remainder of the complete blood cell count and metabolic panel was unremarkable. Radiographs of the hand did not show any fractures, dislocations, or foreign bodies. Missouri Poison Center was consulted. Given the patient’s severe pain, edema beyond 40 cm, and developing ecchymosis on the inner arm, the bite was graded as a 3 on the traditional snakebite severity scale. Poison control recommended 4 to 6 vials of antivenom over 60 minutes. Six vials of Crotalidae polyvalent immune fab antivenom were given.

The patient’s complete blood cell count remained unremarkable throughout his admission. His metabolic panel returned to normal at 6 hours postadmission: sodium, 139 mmol/L; potassium, 4.0 mmol/L. His lactate and creatinine kinase were not rechecked. His fibrinogen was trending upward. Serial laboratory test results revealed fibrinogen levels of 153, 158, 161, 159, 173, and 216 mg/dL at 6, 12, 18, 24, 30, and 36 hours, respectively. Other laboratory test results including prothrombin time (11.0 s) and international normalized ratio (0.98) remained within reference range (11–13 s and 0.80–1.39, respectively) during serial monitoring.

The patient was hospitalized for 40 hours while waiting for his fibrinogen level to normalize. The local skin necrosis worsened acutely in this 40-hour window (Figure 4). Intravenous antibiotics were not administered during the hospital stay. Before discharge, the patient was evaluated by the surgery service, who did not recommend debridement.

Surgical Management of Snakebites

The surgeon’s role in managing snakebites is controversial. Snakebites were once perceived as a surgical emergency due to symptoms mimicking compartment syndrome; however, snakebites rarely cause a true compartment syndrome.⁷ Prophylactic bite excision and fasciotomies are not recommended. Incision and suction of the fang marks may be beneficial if performed within 15 to 30 minutes from the time of the bite.⁸ With access to a surgeon in this short time period being nearly impossible, incision and suctioning of fang marks generally is not recommended.⁹ Retained snake fangs are a possibility, and the infection could spread to a nearby joint, causing septic arthritis,¹⁰ which would be an indication for surgical intervention. Bites to the finger often cause major swelling, and the benefits of dermotomy are documented.¹¹ Generally, early administration of antivenom will decrease local tissue reaction and prevent additional tissue loss.¹² In our patient, the decision to perform dermotomy was made when the area of necrosis had declared itself and the skin reached its elastic limit. Bozkurt et al¹³ described the neurovascular bundles within the digit as functioning as small compartments. When the skin of the digit reaches its elastic limit, pressure within the compartment may exceed the capillary closing pressure, and the integrity of small vessels and nerves may be compromised. Our case highlights the benefit of dermotomy as well as the functional and cosmetic results that can be achieved.

Wound Care for Snakebites

There is little published on the treatment of snakebites after patients are stabilized medically for hospital discharge. Venomous snakes inject toxins that predominantly consist of enzymes (eg, phospholipase A2, phosphodiesterase, hyaluronidase, peptidase, metalloproteinase) that cause tissue destruction through diverse mechanisms.¹⁴ The venom of western pygmy rattlesnakes is hemotoxic and can cause necrotic hemorrhagic ulceration,⁴ as was the case in our patient.

Silver sulfadiazine commonly is used to prevent infection in burn patients. Given the large surface area of exposed dermis after debridement and concern for infection, silver sulfadiazine was chosen in our patient for local wound care treatment. Silver sulfadiazine is a widely available and low-cost drug.¹⁵ Its antibacterial effects are due to the silver ions, which only act superficially and therefore limit systemic absorption.¹⁶ Application should be performed in a clean manner with minimal trauma to the tissue. This technique is best achieved by using sterile gloves and applying the medication manually. A 0.0625-inch layer should be applied to entirely cover the cleaned debrided area.¹⁷ When performing application with tongue blades or cotton swabs, it is important to never “double dip.” Patient education on proper administration is imperative to a successful outcome.

Final Thoughts

Our case demonstrates the safe use of Crotalidae polyvalent immune fab antivenom for the treatment of western pygmy rattlesnake (S miliarius streckeri) envenomation. Early administration of antivenom following pit viper rattlesnake envenomations is important to mitigate systemic effects and the extent of soft tissue damage. There are few studies on local wound care treatment after rattlesnake envenomation. This case highlights the role of dermotomy and wound care with silver sulfadiazine cream 1%.

There are 375 species of poisonous snakes, with approximately 20,000 deaths worldwide each year due to snakebites, mostly in Asia and Africa.¹ The death rate in the United States is 14 to 20 cases per year. In the United States, a variety of rattlesnakes are poisonous. There are 2 genera of rattlesnakes: Sistrurus (3 species) and Crotalus (23 species). The pygmy rattlesnake belongs to the Sistrurus miliarius species that is divided into 3 subspecies: the Carolina pigmy rattlesnake (S miliarius miliarius), the western pygmy rattlesnake (S miliarius streckeri), and the dusky pygmy rattlesnake (S miliarius barbouri).²

The western pygmy rattlesnake belongs to the Crotalidae family. The rattlesnakes in this family also are known as pit vipers. All pit vipers have common characteristics for identification: triangular head, fangs, elliptical pupils, and a heat-sensing pit between the eyes. The western pygmy rattlesnake is found in Missouri, Arkansas, Oklahoma, Kentucky, and Tennessee.¹ It is small bodied (15–20 inches)³ and grayish-brown, with a brown dorsal stripe with black blotches on its back. It is found in glades, second-growth forests near rock ledges, and areas where powerlines cut through dense forest.³ Its venom is hemorrhagic, causing tissue damage, but does not contain neurotoxins.⁴ Bites from the western pygmy rattlesnake often do not lead to death, but the venom, which contains numerous proteins and enzymes, does cause necrotic hemorrhagic ulceration at the site of envenomation and possible loss of digit.^5,6

We present a case of a man who was bitten on the right third digit by a western pygmy rattlesnake. We describe the clinical course and treatment.

Case Report

A 56-year-old right-handed man presented to the emergency department with a rapidly swelling, painful hand following a snakebite to the dorsal aspect of the right third digit (Figure 1). He was able to capture a photograph of the snake at the time of injury, which helped identify it as a western pygmy rattlesnake (Figure 2). He also photographed the hand immediately after the bite occurred (Figure 3). Vitals on presentation included an elevated blood pressure of 161/100 mm Hg; no fever (temperature, 36.4 °C); and normal pulse oximetry of 98%, pulse of 86 beats per minute, and respiratory rate of 16 breaths per minute.

After the snakebite, the patient’s family called the Missouri Poison Center immediately. The family identified the snake species and shared this information with the poison center. Poison control recommended calling the nearest hospitals to determine if antivenom was available and make notification of arrival. 

The patient’s tetanus toxoid immunization was updated immediately upon arrival. The hand was marked to monitor swelling. Initial laboratory test results revealed the following values: sodium, 133 mmol/L (reference range, 136–145 mmol/L); potassium, 3.4 mmol/L (3.6–5.2 mmol/L); lactic acid, 2.4 mmol/L (0.5–2.2 mmol/L); creatine kinase, 425 U/L (55–170 U/L); platelet count, 68/µL (150,000–450,000/µL); fibrinogen, 169 mg/dL (185–410 mg/dL); and glucose, 121 mg/dL (74–106 mg/dL). The remainder of the complete blood cell count and metabolic panel was unremarkable. Radiographs of the hand did not show any fractures, dislocations, or foreign bodies. Missouri Poison Center was consulted. Given the patient’s severe pain, edema beyond 40 cm, and developing ecchymosis on the inner arm, the bite was graded as a 3 on the traditional snakebite severity scale. Poison control recommended 4 to 6 vials of antivenom over 60 minutes. Six vials of Crotalidae polyvalent immune fab antivenom were given.

The patient’s complete blood cell count remained unremarkable throughout his admission. His metabolic panel returned to normal at 6 hours postadmission: sodium, 139 mmol/L; potassium, 4.0 mmol/L. His lactate and creatinine kinase were not rechecked. His fibrinogen was trending upward. Serial laboratory test results revealed fibrinogen levels of 153, 158, 161, 159, 173, and 216 mg/dL at 6, 12, 18, 24, 30, and 36 hours, respectively. Other laboratory test results including prothrombin time (11.0 s) and international normalized ratio (0.98) remained within reference range (11–13 s and 0.80–1.39, respectively) during serial monitoring.

The patient was hospitalized for 40 hours while waiting for his fibrinogen level to normalize. The local skin necrosis worsened acutely in this 40-hour window (Figure 4). Intravenous antibiotics were not administered during the hospital stay. Before discharge, the patient was evaluated by the surgery service, who did not recommend debridement.

Surgical Management of Snakebites

The surgeon’s role in managing snakebites is controversial. Snakebites were once perceived as a surgical emergency due to symptoms mimicking compartment syndrome; however, snakebites rarely cause a true compartment syndrome.⁷ Prophylactic bite excision and fasciotomies are not recommended. Incision and suction of the fang marks may be beneficial if performed within 15 to 30 minutes from the time of the bite.⁸ With access to a surgeon in this short time period being nearly impossible, incision and suctioning of fang marks generally is not recommended.⁹ Retained snake fangs are a possibility, and the infection could spread to a nearby joint, causing septic arthritis,¹⁰ which would be an indication for surgical intervention. Bites to the finger often cause major swelling, and the benefits of dermotomy are documented.¹¹ Generally, early administration of antivenom will decrease local tissue reaction and prevent additional tissue loss.¹² In our patient, the decision to perform dermotomy was made when the area of necrosis had declared itself and the skin reached its elastic limit. Bozkurt et al¹³ described the neurovascular bundles within the digit as functioning as small compartments. When the skin of the digit reaches its elastic limit, pressure within the compartment may exceed the capillary closing pressure, and the integrity of small vessels and nerves may be compromised. Our case highlights the benefit of dermotomy as well as the functional and cosmetic results that can be achieved.

Wound Care for Snakebites

There is little published on the treatment of snakebites after patients are stabilized medically for hospital discharge. Venomous snakes inject toxins that predominantly consist of enzymes (eg, phospholipase A2, phosphodiesterase, hyaluronidase, peptidase, metalloproteinase) that cause tissue destruction through diverse mechanisms.¹⁴ The venom of western pygmy rattlesnakes is hemotoxic and can cause necrotic hemorrhagic ulceration,⁴ as was the case in our patient.

Silver sulfadiazine commonly is used to prevent infection in burn patients. Given the large surface area of exposed dermis after debridement and concern for infection, silver sulfadiazine was chosen in our patient for local wound care treatment. Silver sulfadiazine is a widely available and low-cost drug.¹⁵ Its antibacterial effects are due to the silver ions, which only act superficially and therefore limit systemic absorption.¹⁶ Application should be performed in a clean manner with minimal trauma to the tissue. This technique is best achieved by using sterile gloves and applying the medication manually. A 0.0625-inch layer should be applied to entirely cover the cleaned debrided area.¹⁷ When performing application with tongue blades or cotton swabs, it is important to never “double dip.” Patient education on proper administration is imperative to a successful outcome.

Final Thoughts

Our case demonstrates the safe use of Crotalidae polyvalent immune fab antivenom for the treatment of western pygmy rattlesnake (S miliarius streckeri) envenomation. Early administration of antivenom following pit viper rattlesnake envenomations is important to mitigate systemic effects and the extent of soft tissue damage. There are few studies on local wound care treatment after rattlesnake envenomation. This case highlights the role of dermotomy and wound care with silver sulfadiazine cream 1%.

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

To the Editor:

Skin cancers are extremely common worldwide. Malignant melanomas comprise approximately 1 in 5 of these cancers. Exposure to UV radiation is postulated to be responsible for a global rise in melanoma cases over the past 50 years.¹ Pediatric melanoma is a particularly rare condition that affects approximately 6 in every 1 million children.² Melanoma incidence in children ranges by age, increasing by approximately 10-fold from age 1 to 4 years to age 15 to 19 years. Tumor ulceration is a feature more commonly seen among children younger than 10 years and is associated with worse outcomes. Tumor thickness and ulceration strongly predict sentinel lymph node metastases among children, which also is associated with a poor prognosis.³

A recent study evaluating stage IV melanoma survival rates in adolescents and young adults (AYAs) vs older adults found that survival is much worse among AYAs. Thicker tumors and public health insurance also were associated with worse survival rates for AYAs, while early detection was associated with better survival rates.⁴

Health disparities and their role in the prognosis of pediatric melanoma is another important factor. One study analyzed this relationship at the state level using Texas Cancer Registry data (1995-2009).⁵ Patients’ socioeconomic status (SES) and driving distance to the nearest pediatric cancer care center were included in the analysis. Hispanic children were found to be 3 times more likely to present with advanced disease than non-Hispanic White children. Although SES and distance to the nearest treatment center were not found to affect the melanoma stage at presentation, Hispanic ethnicity or being in the lowest SES quartile were correlated with a higher mortality risk.⁵

When considering specific subtypes of melanoma, acral lentiginous melanoma (ALM) is known to develop in patients with skin of color. A 2023 study by Holman et al⁶ reported that the percentage of melanomas that were ALMs ranged from 0.8% in non-Hispanic White individuals to 19.1% in Hispanic Black, American Indian/Alaska Native, and Asian/Pacific Islander individuals. However, ALM is rare in children. In a pooled cohort study with patient information retrieved from the nationwide Dutch Pathology Registry, only 1 child and 1 adolescent were found to have ALM across a total of 514 patients.⁷ We sought to analyze pediatric melanoma outcomes based on race and other barriers to appropriate care.

We conducted a search of the Surveillance, Epidemiology, and End Results (SEER) database from January 1995 to December 2016 for patients aged 21 years and younger with a primary melanoma diagnosis. The primary outcome was the 5-year survival rate. County-level SES variables were used to calculate a prosperity index. Kaplan-Meier analysis and Cox proportional hazards model were used to compare 5-year survival rates among the different racial/ethnic groups.

A sample of 2742 patients was identified during the study period and followed for 5 years. Eighty-two percent were White, 6% Hispanic, 2% Asian, 1% Black, and 5% classified as other/unknown race (data were missing for 4%). The cohort was predominantly female (61%). White patients were more likely to present with localized disease than any other race/ethnicity (83% vs 65% in Hispanic, 60% in Asian/Pacific Islander, and 45% in Black patients [P<.05]).

Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis. On multivariate analysis, this finding remained significant for Hispanic patients when compared with White patients (hazard ratio, 2.37 [P<.05]). Increasing age, male sex, advanced stage at diagnosis, and failure to receive surgery were associated with increased odds of mortality.

Patients with regionalized and disseminated disease had increased odds of mortality (6.16 and 64.45, respectively; P<.05) compared with patients with localized disease. Socioeconomic status and urbanization were not found to influence 5-year survival rates.

Pediatric melanoma often presents a clinical challenge with special considerations. Pediatric-specific predisposing risk factors for melanoma and an atypical clinical presentation are some of the major concerns that necessitate a tailored approach to this malignancy, especially among different age groups, skin types, and racial and socioeconomic groups.⁵

Standard ABCDE criteria often are inadequate for accurate detection of pediatric melanomas. Initial lesions often manifest as raised, red, amelanotic lesions mimicking pyogenic granulomas. Lesions tend to be very small (<6 mm in diameter) and can be uniform in color, thereby making the melanoma more difficult to detect compared to the characteristic findings in adults.⁵ Bleeding or ulceration often can be a warning sign during physical examination.

With regard to incidence, pediatric melanoma is relatively rare. Since the 1970s, the incidence of pediatric melanoma has been increasing; however, a recent analysis of the SEER database showed a decreasing trend from 2000 to 2010.⁴

Our analysis of the SEER data showed an increased risk for pediatric melanoma in older adolescents. In addition, the incidence of pediatric melanoma was higher in females of all racial groups except Asian/Pacific Islander individuals. However, SES was not found to significantly influence the 5-year survival rate in pediatric melanoma.

White pediatric patients were more likely to present with localized disease compared with other races. Pediatric melanoma patients with regional disease had a 6-fold increase in mortality rate vs those with localized disease; those with disseminated disease had a 65-fold higher risk. Consistent with this, Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis.

These findings suggest a relationship between race, melanoma spread, and disease severity. Patient education programs need to be directed specifically to minority groups to improve their knowledge on evolving skin lesions and sun protection practices. Physicians also need to have heightened suspicion and better knowledge of the unique traits of pediatric melanoma.⁵

Given the considerable influence these disparities can have on melanoma outcomes, further research is needed to characterize outcomes based on race and determine obstacles to appropriate care. Improved public outreach initiatives that accommodate specific cultural barriers (eg, language, traditional patterns of behavior) also are required to improve current circumstances.

To the Editor:

Skin cancers are extremely common worldwide. Malignant melanomas comprise approximately 1 in 5 of these cancers. Exposure to UV radiation is postulated to be responsible for a global rise in melanoma cases over the past 50 years.¹ Pediatric melanoma is a particularly rare condition that affects approximately 6 in every 1 million children.² Melanoma incidence in children ranges by age, increasing by approximately 10-fold from age 1 to 4 years to age 15 to 19 years. Tumor ulceration is a feature more commonly seen among children younger than 10 years and is associated with worse outcomes. Tumor thickness and ulceration strongly predict sentinel lymph node metastases among children, which also is associated with a poor prognosis.³

A recent study evaluating stage IV melanoma survival rates in adolescents and young adults (AYAs) vs older adults found that survival is much worse among AYAs. Thicker tumors and public health insurance also were associated with worse survival rates for AYAs, while early detection was associated with better survival rates.⁴

Health disparities and their role in the prognosis of pediatric melanoma is another important factor. One study analyzed this relationship at the state level using Texas Cancer Registry data (1995-2009).⁵ Patients’ socioeconomic status (SES) and driving distance to the nearest pediatric cancer care center were included in the analysis. Hispanic children were found to be 3 times more likely to present with advanced disease than non-Hispanic White children. Although SES and distance to the nearest treatment center were not found to affect the melanoma stage at presentation, Hispanic ethnicity or being in the lowest SES quartile were correlated with a higher mortality risk.⁵

When considering specific subtypes of melanoma, acral lentiginous melanoma (ALM) is known to develop in patients with skin of color. A 2023 study by Holman et al⁶ reported that the percentage of melanomas that were ALMs ranged from 0.8% in non-Hispanic White individuals to 19.1% in Hispanic Black, American Indian/Alaska Native, and Asian/Pacific Islander individuals. However, ALM is rare in children. In a pooled cohort study with patient information retrieved from the nationwide Dutch Pathology Registry, only 1 child and 1 adolescent were found to have ALM across a total of 514 patients.⁷ We sought to analyze pediatric melanoma outcomes based on race and other barriers to appropriate care.

We conducted a search of the Surveillance, Epidemiology, and End Results (SEER) database from January 1995 to December 2016 for patients aged 21 years and younger with a primary melanoma diagnosis. The primary outcome was the 5-year survival rate. County-level SES variables were used to calculate a prosperity index. Kaplan-Meier analysis and Cox proportional hazards model were used to compare 5-year survival rates among the different racial/ethnic groups.

A sample of 2742 patients was identified during the study period and followed for 5 years. Eighty-two percent were White, 6% Hispanic, 2% Asian, 1% Black, and 5% classified as other/unknown race (data were missing for 4%). The cohort was predominantly female (61%). White patients were more likely to present with localized disease than any other race/ethnicity (83% vs 65% in Hispanic, 60% in Asian/Pacific Islander, and 45% in Black patients [P<.05]).

Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis. On multivariate analysis, this finding remained significant for Hispanic patients when compared with White patients (hazard ratio, 2.37 [P<.05]). Increasing age, male sex, advanced stage at diagnosis, and failure to receive surgery were associated with increased odds of mortality.

Patients with regionalized and disseminated disease had increased odds of mortality (6.16 and 64.45, respectively; P<.05) compared with patients with localized disease. Socioeconomic status and urbanization were not found to influence 5-year survival rates.

Pediatric melanoma often presents a clinical challenge with special considerations. Pediatric-specific predisposing risk factors for melanoma and an atypical clinical presentation are some of the major concerns that necessitate a tailored approach to this malignancy, especially among different age groups, skin types, and racial and socioeconomic groups.⁵

Standard ABCDE criteria often are inadequate for accurate detection of pediatric melanomas. Initial lesions often manifest as raised, red, amelanotic lesions mimicking pyogenic granulomas. Lesions tend to be very small (<6 mm in diameter) and can be uniform in color, thereby making the melanoma more difficult to detect compared to the characteristic findings in adults.⁵ Bleeding or ulceration often can be a warning sign during physical examination.

With regard to incidence, pediatric melanoma is relatively rare. Since the 1970s, the incidence of pediatric melanoma has been increasing; however, a recent analysis of the SEER database showed a decreasing trend from 2000 to 2010.⁴

Our analysis of the SEER data showed an increased risk for pediatric melanoma in older adolescents. In addition, the incidence of pediatric melanoma was higher in females of all racial groups except Asian/Pacific Islander individuals. However, SES was not found to significantly influence the 5-year survival rate in pediatric melanoma.

White pediatric patients were more likely to present with localized disease compared with other races. Pediatric melanoma patients with regional disease had a 6-fold increase in mortality rate vs those with localized disease; those with disseminated disease had a 65-fold higher risk. Consistent with this, Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis.

These findings suggest a relationship between race, melanoma spread, and disease severity. Patient education programs need to be directed specifically to minority groups to improve their knowledge on evolving skin lesions and sun protection practices. Physicians also need to have heightened suspicion and better knowledge of the unique traits of pediatric melanoma.⁵

Given the considerable influence these disparities can have on melanoma outcomes, further research is needed to characterize outcomes based on race and determine obstacles to appropriate care. Improved public outreach initiatives that accommodate specific cultural barriers (eg, language, traditional patterns of behavior) also are required to improve current circumstances.

To the Editor:

Skin cancers are extremely common worldwide. Malignant melanomas comprise approximately 1 in 5 of these cancers. Exposure to UV radiation is postulated to be responsible for a global rise in melanoma cases over the past 50 years.¹ Pediatric melanoma is a particularly rare condition that affects approximately 6 in every 1 million children.² Melanoma incidence in children ranges by age, increasing by approximately 10-fold from age 1 to 4 years to age 15 to 19 years. Tumor ulceration is a feature more commonly seen among children younger than 10 years and is associated with worse outcomes. Tumor thickness and ulceration strongly predict sentinel lymph node metastases among children, which also is associated with a poor prognosis.³

A recent study evaluating stage IV melanoma survival rates in adolescents and young adults (AYAs) vs older adults found that survival is much worse among AYAs. Thicker tumors and public health insurance also were associated with worse survival rates for AYAs, while early detection was associated with better survival rates.⁴

Health disparities and their role in the prognosis of pediatric melanoma is another important factor. One study analyzed this relationship at the state level using Texas Cancer Registry data (1995-2009).⁵ Patients’ socioeconomic status (SES) and driving distance to the nearest pediatric cancer care center were included in the analysis. Hispanic children were found to be 3 times more likely to present with advanced disease than non-Hispanic White children. Although SES and distance to the nearest treatment center were not found to affect the melanoma stage at presentation, Hispanic ethnicity or being in the lowest SES quartile were correlated with a higher mortality risk.⁵

When considering specific subtypes of melanoma, acral lentiginous melanoma (ALM) is known to develop in patients with skin of color. A 2023 study by Holman et al⁶ reported that the percentage of melanomas that were ALMs ranged from 0.8% in non-Hispanic White individuals to 19.1% in Hispanic Black, American Indian/Alaska Native, and Asian/Pacific Islander individuals. However, ALM is rare in children. In a pooled cohort study with patient information retrieved from the nationwide Dutch Pathology Registry, only 1 child and 1 adolescent were found to have ALM across a total of 514 patients.⁷ We sought to analyze pediatric melanoma outcomes based on race and other barriers to appropriate care.

We conducted a search of the Surveillance, Epidemiology, and End Results (SEER) database from January 1995 to December 2016 for patients aged 21 years and younger with a primary melanoma diagnosis. The primary outcome was the 5-year survival rate. County-level SES variables were used to calculate a prosperity index. Kaplan-Meier analysis and Cox proportional hazards model were used to compare 5-year survival rates among the different racial/ethnic groups.

A sample of 2742 patients was identified during the study period and followed for 5 years. Eighty-two percent were White, 6% Hispanic, 2% Asian, 1% Black, and 5% classified as other/unknown race (data were missing for 4%). The cohort was predominantly female (61%). White patients were more likely to present with localized disease than any other race/ethnicity (83% vs 65% in Hispanic, 60% in Asian/Pacific Islander, and 45% in Black patients [P<.05]).

Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis. On multivariate analysis, this finding remained significant for Hispanic patients when compared with White patients (hazard ratio, 2.37 [P<.05]). Increasing age, male sex, advanced stage at diagnosis, and failure to receive surgery were associated with increased odds of mortality.

Patients with regionalized and disseminated disease had increased odds of mortality (6.16 and 64.45, respectively; P<.05) compared with patients with localized disease. Socioeconomic status and urbanization were not found to influence 5-year survival rates.

Pediatric melanoma often presents a clinical challenge with special considerations. Pediatric-specific predisposing risk factors for melanoma and an atypical clinical presentation are some of the major concerns that necessitate a tailored approach to this malignancy, especially among different age groups, skin types, and racial and socioeconomic groups.⁵

Standard ABCDE criteria often are inadequate for accurate detection of pediatric melanomas. Initial lesions often manifest as raised, red, amelanotic lesions mimicking pyogenic granulomas. Lesions tend to be very small (<6 mm in diameter) and can be uniform in color, thereby making the melanoma more difficult to detect compared to the characteristic findings in adults.⁵ Bleeding or ulceration often can be a warning sign during physical examination.

With regard to incidence, pediatric melanoma is relatively rare. Since the 1970s, the incidence of pediatric melanoma has been increasing; however, a recent analysis of the SEER database showed a decreasing trend from 2000 to 2010.⁴

Our analysis of the SEER data showed an increased risk for pediatric melanoma in older adolescents. In addition, the incidence of pediatric melanoma was higher in females of all racial groups except Asian/Pacific Islander individuals. However, SES was not found to significantly influence the 5-year survival rate in pediatric melanoma.

White pediatric patients were more likely to present with localized disease compared with other races. Pediatric melanoma patients with regional disease had a 6-fold increase in mortality rate vs those with localized disease; those with disseminated disease had a 65-fold higher risk. Consistent with this, Black and Hispanic patients had the worst 5-year survival rates on bivariate analysis.

These findings suggest a relationship between race, melanoma spread, and disease severity. Patient education programs need to be directed specifically to minority groups to improve their knowledge on evolving skin lesions and sun protection practices. Physicians also need to have heightened suspicion and better knowledge of the unique traits of pediatric melanoma.⁵

Given the considerable influence these disparities can have on melanoma outcomes, further research is needed to characterize outcomes based on race and determine obstacles to appropriate care. Improved public outreach initiatives that accommodate specific cultural barriers (eg, language, traditional patterns of behavior) also are required to improve current circumstances.