Mixed Topics

Hypergammaglobulinemic purpura of Waldenström (HGPW) is a rare chronic skin condition characterized by recurrent petechiae and purpura on the lower legs, elevated erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia, and elevated titers of IgG and IgA rheumatoid factor (RF).^1,2 This condition can be a primary (idiopathic) syndrome or secondary to an autoimmune connective tissue disease. We report 2 cases of patients with episodic skin eruptions that were consistent with HGPW.

Patient 1

A 41-year-old woman presented to our clinic with a rash on the legs of 20 years’ duration. She had first been evaluated at an outside dermatology clinic 5 years prior, and a biopsy performed at the time led to a diagnosis of leukocytoclastic vasculitis (LCV). The rash affected her ability to work, as her job involved standing for prolonged periods of time. If she stood for more than 2 hours, she experienced leg pain and worsening of the rash. The rash also was exacerbated by nonsteroidal anti-inflammatory drugs but improved with multiple days of rest. She had been on dapsone 75 mg daily, but the dose was reduced to 50 mg daily after elevated liver enzymes were noted. This regimen had improved her rash for 4 years until she experienced breakthrough symptoms, leading to her re-evaluation. Prior outside therapies included systemic steroids with limited response, then oral dapsone.

Upon our initial evaluation, laboratory tests were notable for an elevated ESR of 43 mm/h. Results of antinuclear antibody (ANA), anti–double-stranded DNA, extractable nuclear antigen, RF, HIV, cryoglobulin, hepatitis panel, serum protein electrophoresis, complete blood count, basic metabolic panel, urinalysis, and thyroid-stimulating hormone testing were within reference range. Physical examination revealed scattered pinpoint violaceous papules on the lower extremities. Photographs on the patient’s phone from 2 months prior showed a more robust manifestation with diffuse palpable purpura on the lower extremities.

At 3-year follow-up, laboratory evaluation including ESR, IgA, IgG, IgM, serum protein electrophoresis with reflex immunofixation, and Mycoplasma pneumoniae IgM/IgG showed elevated ESR (29 mm/h) and IgG (1654 mg), with otherwise unremarkable results. Because of the extended period of time since the previous biopsy, a repeat biopsy with hematoxylin and eosin staining and direct immunofluorescence was performed. Biopsy from the left calf demonstrated a perivascular and interstitial infiltrate with lymphocytes and neutrophils with nuclear debris and hemorrhage (Figure 1). Direct immunofluorescence was positive for IgA, C3, and fibrin within vessel walls (Figure 2).

Overall the features of recurrent dependent palpable purpura and the pathology findings were consistent with evolving LCV. Given the chronic nature of her symptoms; flares with prolonged standing; presence of polyclonol hypergammaglobulinemia; and negative evaluation for underling autoimmune disease, infection, and malignancy, the clinicopathologic correlation was most consistent with primary HGPW. The patient was treated with colchicine 0.6 mg twice daily and continued on dapsone 50 mg daily. The colchicine was reduced to once daily due to diarrhea. Nonetheless, the patient had less frequent and less intense flares. On follow-up examination 4 months later, she was satisfied with her current level of control and did not wish to escalate her treatment.

Patient 2

A 53-year-old woman with a 1-year history of sicca symptoms presented for evaluation of a transient rash on the legs and feet of 2 months’ duration. At that time, the heels began to feel swollen. The rash was painful on the feet and caused calf myalgias. She did not endorse pruritus or pain elsewhere. The rash was not associated with prolonged standing, walking, or wearing tight socks. She had no fevers, chills, or joint pain. Flares would come and go within a week.

Laboratory evaluation was notable for an ANA of 1:1280 (reference range, 1:80) with positive anti-Ro/SS-A and anti-La/SS-B. Rheumatology evaluation confirmed the diagnosis of Sjögren syndrome. Physical examination revealed minimal petechiae on the heel of the left foot. Photographs from the previous month provided by the patient revealed linear petechiae of the lower extremities with postinflammatory hyperpigmentation (Figure 3). An additional photograph from the prior week revealed more diffuse erythematous plaques without secondary changes on the feet up to the ankles (Figure 4).

The patient experienced a recurrence of the rash within a month and had an expedited visit for biopsies, which demonstrated mixed inflammation with neutrophils, nuclear debris, hemorrhage, and C3 and fibrin immunoreactants within vessel walls. As with patient 1, the features were consistent with LCV.

In the context of Sjögren syndrome and elevated IgG and RF, the patient’s symptoms were consistent with secondary HGPW. Rheumatology prescribed hydroxychloroquine 400 mg daily alternating every other day with 300 mg and 0.6 mg of colchicine. The rash cleared within approximately 1 month.

Comment

Also known as benign hypergammaglobulinemic purpura, HGPW is a rare purpuric eruption that is exacerbated with prolonged standing and increased hydrostatic pressure.³ First described in 1943, HGPW is characterized by recurrent petechiae, purpuric macules, or palpable purpura, depending on the degree of inflammation.^1,4,5 It typically is distributed on the bilateral lower extremities or trunk. Chronic postinflammatory hyperpigmentation with hemosiderin deposition also can be observed. The lesions last for up to 1 week at a time and are frequently asymmetrically distributed.²

Patient 1 demonstrated the typical clinical manifestations and laboratory findings of HGPW. The eruption often is asymptomatic, and patients report that the skin worsens with prolonged immobilization, walking, and wearing of tight clothing.^2,6-8 Increased hydrostatic pressure is thought to cause the erythrocyte extravasation, resulting in the purpuric lesions. However, patient 2 was less typical, presenting with prominent skin pain and myalgias. Some patients experience discomfort, burning dysesthesia, pruritus, and swelling of the affected area.¹ Hypergammaglobulinemic purpura of Waldenström is a chronic condition. Recurrent episodes can occur yearly or as frequently as multiple times per week.⁸

Women are most commonly diagnosed with HGPW, but many cases have been reported in children.^9,10 In spite of the “condition being considered largely benign,” women with a diagnosis of HGPW require preconception counseling due to risks for congenital heart block, neonatal lupus, intrauterine growth restriction, intrauterine demise, and preterm birth.^7,9,11,12

The etiology of the rash remains undefined. It is hypothesized that it develops due to underlying immune dysregulation with associated immune complex formation and deposition in the blood vessel wall.¹ Small circulating immune complexes containing IgG or IgA RF are a specific finding in patients with HGPW. These highly soluble autoantibodies are hypothesized to influence the rapid appearance and disappearance of lesions.¹

The role of hypergammaglobulinemia in the pathogenesis of HGPW is unknown.¹³ Serum IgG levels do not correlate with the appearance and regression of lesions.¹³ Additionally, hypergammaglobulinemia can be found in autoimmune connective tissue diseases such as Sjögren syndrome without resulting cutaneous vasculitis.¹³

Characteristic laboratory abnormalities include polyclonal hypergammaglobulinemia, elevated ESR, and elevated IgA and IgG RF. Positive ANA and anti-Ro/SS-A and anti-La/SS-B indicate a potential to develop autoimmune connective tissue diseases, including Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis.^1,14 Additional recommended workup includes complete blood counts, metabolic panel, complement levels, urinalysis, and urine protein/creatinine ratio.⁹ Repeat monitoring for antibodies, inflammatory markers, immunoglobulins, and RF should be completed 3 months after initial evaluation. Patients with symptoms of systemic disease should have laboratory evaluation repeated.

Erythrocyte sedimentation rate abnormalities are a defining feature of HGPW. Erythrocyte sedimentation rate is an inexpensive and commonly ordered inflammatory marker that measures settling of erythrocytes within 1 hour and can be elevated by plasma proteins such as gamma globulins. Erythrocyte sedimentation rate is nonspecific and is not sensitive as a general screening test. It can be elevated by autoimmune connective tissue disease, infection, and malignancy.¹⁵ Notably, ESR is not specific to inflammation. Confounding factors include red blood cell abnormalities, physiologic factors, and the quantity of plasma proteins such as fibrinogen.¹⁶ These positively charged plasma proteins neutralize the negative surface charge of erythrocytes, resulting in erythrocytes that are prone to rouleaux formation.¹⁷

The utility of the ESR is to expedite the diagnostic process and indicate the need for further workup.¹⁶ Patients with mild to moderate elevation in ESR without an identified etiology should have repeat testing to confirm the validity of the laboratory value. Patients with an ESR higher than 100 mm/h are more likely have an infectious cause, collagen vascular disease, or underlying malignancy.¹⁵ Elevation of ESR in HGPW is likely a result of increased immunoglobulins and acute phase proteins.¹⁷

The histopathology of HGPW is nonspecific and may show LCV or erythrocyte extravasation with mild perivascular lymphocytic infiltrates.^1,9 Direct immunofluorescence testing may show immune-complex deposition.⁵ For patients with evidence of LCV, the biopsy of a fresh but well-developed lesion is important in confirming the presence of vasculitis.¹ Incorrect sampling may lead to underreporting of LCV with HGPW.³

Associated underlying conditions include Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, hepatitis C, and hematologic malignancies.^1,3 Our patients demonstrated primary and secondary causes of HGPW. Patient 1’s case was not associated with any autoimmune disease but demonstrated chronic recurrence. Patient 2’s case was secondary to Sjögren syndrome.

In patients with suspected HGPW, differential diagnoses to consider include IgA vasculitis, cutaneous small vessel vasculitis, pigmented purpuric dermatoses, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and scurvy.^1,4

For patients with primary disease, treatment is focused on symptom management with compression stockings and avoidance of triggers. Compression stockings may exacerbate purpura but can provide symptom relief in some individuals.¹⁴ Patients with frequent or painful episodes can benefit from systemic treatment. In patients with an underlying disease, systemic therapies include prednisone, hydroxychloroquine, indomethacin, colchicine, chlorambucil, mycophenolate mofetil, rituximab, and plasmapheresis. Dapsone, a treatment for LCV, has been reported to be beneficial in patients with a neutrophilic infiltrate.¹⁸

Hypergammaglobulinemic purpura of Waldenström requires a thorough evaluation due to its association with underlying systemic disease. Patients without evidence of systemic disease should receive long-term monitoring and coordination of care with rheumatology, as systemic manifestations can develop years after the initial cutaneous manifestation. Dermatologists should consider HGPW in the differential diagnosis for cutaneous vasculitides.

Hypergammaglobulinemic purpura of Waldenström (HGPW) is a rare chronic skin condition characterized by recurrent petechiae and purpura on the lower legs, elevated erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia, and elevated titers of IgG and IgA rheumatoid factor (RF).^1,2 This condition can be a primary (idiopathic) syndrome or secondary to an autoimmune connective tissue disease. We report 2 cases of patients with episodic skin eruptions that were consistent with HGPW.

Patient 1

A 41-year-old woman presented to our clinic with a rash on the legs of 20 years’ duration. She had first been evaluated at an outside dermatology clinic 5 years prior, and a biopsy performed at the time led to a diagnosis of leukocytoclastic vasculitis (LCV). The rash affected her ability to work, as her job involved standing for prolonged periods of time. If she stood for more than 2 hours, she experienced leg pain and worsening of the rash. The rash also was exacerbated by nonsteroidal anti-inflammatory drugs but improved with multiple days of rest. She had been on dapsone 75 mg daily, but the dose was reduced to 50 mg daily after elevated liver enzymes were noted. This regimen had improved her rash for 4 years until she experienced breakthrough symptoms, leading to her re-evaluation. Prior outside therapies included systemic steroids with limited response, then oral dapsone.

Upon our initial evaluation, laboratory tests were notable for an elevated ESR of 43 mm/h. Results of antinuclear antibody (ANA), anti–double-stranded DNA, extractable nuclear antigen, RF, HIV, cryoglobulin, hepatitis panel, serum protein electrophoresis, complete blood count, basic metabolic panel, urinalysis, and thyroid-stimulating hormone testing were within reference range. Physical examination revealed scattered pinpoint violaceous papules on the lower extremities. Photographs on the patient’s phone from 2 months prior showed a more robust manifestation with diffuse palpable purpura on the lower extremities.

At 3-year follow-up, laboratory evaluation including ESR, IgA, IgG, IgM, serum protein electrophoresis with reflex immunofixation, and Mycoplasma pneumoniae IgM/IgG showed elevated ESR (29 mm/h) and IgG (1654 mg), with otherwise unremarkable results. Because of the extended period of time since the previous biopsy, a repeat biopsy with hematoxylin and eosin staining and direct immunofluorescence was performed. Biopsy from the left calf demonstrated a perivascular and interstitial infiltrate with lymphocytes and neutrophils with nuclear debris and hemorrhage (Figure 1). Direct immunofluorescence was positive for IgA, C3, and fibrin within vessel walls (Figure 2).

Overall the features of recurrent dependent palpable purpura and the pathology findings were consistent with evolving LCV. Given the chronic nature of her symptoms; flares with prolonged standing; presence of polyclonol hypergammaglobulinemia; and negative evaluation for underling autoimmune disease, infection, and malignancy, the clinicopathologic correlation was most consistent with primary HGPW. The patient was treated with colchicine 0.6 mg twice daily and continued on dapsone 50 mg daily. The colchicine was reduced to once daily due to diarrhea. Nonetheless, the patient had less frequent and less intense flares. On follow-up examination 4 months later, she was satisfied with her current level of control and did not wish to escalate her treatment.

Patient 2

A 53-year-old woman with a 1-year history of sicca symptoms presented for evaluation of a transient rash on the legs and feet of 2 months’ duration. At that time, the heels began to feel swollen. The rash was painful on the feet and caused calf myalgias. She did not endorse pruritus or pain elsewhere. The rash was not associated with prolonged standing, walking, or wearing tight socks. She had no fevers, chills, or joint pain. Flares would come and go within a week.

Laboratory evaluation was notable for an ANA of 1:1280 (reference range, 1:80) with positive anti-Ro/SS-A and anti-La/SS-B. Rheumatology evaluation confirmed the diagnosis of Sjögren syndrome. Physical examination revealed minimal petechiae on the heel of the left foot. Photographs from the previous month provided by the patient revealed linear petechiae of the lower extremities with postinflammatory hyperpigmentation (Figure 3). An additional photograph from the prior week revealed more diffuse erythematous plaques without secondary changes on the feet up to the ankles (Figure 4).

The patient experienced a recurrence of the rash within a month and had an expedited visit for biopsies, which demonstrated mixed inflammation with neutrophils, nuclear debris, hemorrhage, and C3 and fibrin immunoreactants within vessel walls. As with patient 1, the features were consistent with LCV.

In the context of Sjögren syndrome and elevated IgG and RF, the patient’s symptoms were consistent with secondary HGPW. Rheumatology prescribed hydroxychloroquine 400 mg daily alternating every other day with 300 mg and 0.6 mg of colchicine. The rash cleared within approximately 1 month.

Comment

Also known as benign hypergammaglobulinemic purpura, HGPW is a rare purpuric eruption that is exacerbated with prolonged standing and increased hydrostatic pressure.³ First described in 1943, HGPW is characterized by recurrent petechiae, purpuric macules, or palpable purpura, depending on the degree of inflammation.^1,4,5 It typically is distributed on the bilateral lower extremities or trunk. Chronic postinflammatory hyperpigmentation with hemosiderin deposition also can be observed. The lesions last for up to 1 week at a time and are frequently asymmetrically distributed.²

Patient 1 demonstrated the typical clinical manifestations and laboratory findings of HGPW. The eruption often is asymptomatic, and patients report that the skin worsens with prolonged immobilization, walking, and wearing of tight clothing.^2,6-8 Increased hydrostatic pressure is thought to cause the erythrocyte extravasation, resulting in the purpuric lesions. However, patient 2 was less typical, presenting with prominent skin pain and myalgias. Some patients experience discomfort, burning dysesthesia, pruritus, and swelling of the affected area.¹ Hypergammaglobulinemic purpura of Waldenström is a chronic condition. Recurrent episodes can occur yearly or as frequently as multiple times per week.⁸

Women are most commonly diagnosed with HGPW, but many cases have been reported in children.^9,10 In spite of the “condition being considered largely benign,” women with a diagnosis of HGPW require preconception counseling due to risks for congenital heart block, neonatal lupus, intrauterine growth restriction, intrauterine demise, and preterm birth.^7,9,11,12

The etiology of the rash remains undefined. It is hypothesized that it develops due to underlying immune dysregulation with associated immune complex formation and deposition in the blood vessel wall.¹ Small circulating immune complexes containing IgG or IgA RF are a specific finding in patients with HGPW. These highly soluble autoantibodies are hypothesized to influence the rapid appearance and disappearance of lesions.¹

The role of hypergammaglobulinemia in the pathogenesis of HGPW is unknown.¹³ Serum IgG levels do not correlate with the appearance and regression of lesions.¹³ Additionally, hypergammaglobulinemia can be found in autoimmune connective tissue diseases such as Sjögren syndrome without resulting cutaneous vasculitis.¹³

Characteristic laboratory abnormalities include polyclonal hypergammaglobulinemia, elevated ESR, and elevated IgA and IgG RF. Positive ANA and anti-Ro/SS-A and anti-La/SS-B indicate a potential to develop autoimmune connective tissue diseases, including Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis.^1,14 Additional recommended workup includes complete blood counts, metabolic panel, complement levels, urinalysis, and urine protein/creatinine ratio.⁹ Repeat monitoring for antibodies, inflammatory markers, immunoglobulins, and RF should be completed 3 months after initial evaluation. Patients with symptoms of systemic disease should have laboratory evaluation repeated.

Erythrocyte sedimentation rate abnormalities are a defining feature of HGPW. Erythrocyte sedimentation rate is an inexpensive and commonly ordered inflammatory marker that measures settling of erythrocytes within 1 hour and can be elevated by plasma proteins such as gamma globulins. Erythrocyte sedimentation rate is nonspecific and is not sensitive as a general screening test. It can be elevated by autoimmune connective tissue disease, infection, and malignancy.¹⁵ Notably, ESR is not specific to inflammation. Confounding factors include red blood cell abnormalities, physiologic factors, and the quantity of plasma proteins such as fibrinogen.¹⁶ These positively charged plasma proteins neutralize the negative surface charge of erythrocytes, resulting in erythrocytes that are prone to rouleaux formation.¹⁷

The utility of the ESR is to expedite the diagnostic process and indicate the need for further workup.¹⁶ Patients with mild to moderate elevation in ESR without an identified etiology should have repeat testing to confirm the validity of the laboratory value. Patients with an ESR higher than 100 mm/h are more likely have an infectious cause, collagen vascular disease, or underlying malignancy.¹⁵ Elevation of ESR in HGPW is likely a result of increased immunoglobulins and acute phase proteins.¹⁷

The histopathology of HGPW is nonspecific and may show LCV or erythrocyte extravasation with mild perivascular lymphocytic infiltrates.^1,9 Direct immunofluorescence testing may show immune-complex deposition.⁵ For patients with evidence of LCV, the biopsy of a fresh but well-developed lesion is important in confirming the presence of vasculitis.¹ Incorrect sampling may lead to underreporting of LCV with HGPW.³

Associated underlying conditions include Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, hepatitis C, and hematologic malignancies.^1,3 Our patients demonstrated primary and secondary causes of HGPW. Patient 1’s case was not associated with any autoimmune disease but demonstrated chronic recurrence. Patient 2’s case was secondary to Sjögren syndrome.

In patients with suspected HGPW, differential diagnoses to consider include IgA vasculitis, cutaneous small vessel vasculitis, pigmented purpuric dermatoses, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and scurvy.^1,4

For patients with primary disease, treatment is focused on symptom management with compression stockings and avoidance of triggers. Compression stockings may exacerbate purpura but can provide symptom relief in some individuals.¹⁴ Patients with frequent or painful episodes can benefit from systemic treatment. In patients with an underlying disease, systemic therapies include prednisone, hydroxychloroquine, indomethacin, colchicine, chlorambucil, mycophenolate mofetil, rituximab, and plasmapheresis. Dapsone, a treatment for LCV, has been reported to be beneficial in patients with a neutrophilic infiltrate.¹⁸

Hypergammaglobulinemic purpura of Waldenström requires a thorough evaluation due to its association with underlying systemic disease. Patients without evidence of systemic disease should receive long-term monitoring and coordination of care with rheumatology, as systemic manifestations can develop years after the initial cutaneous manifestation. Dermatologists should consider HGPW in the differential diagnosis for cutaneous vasculitides.

Hypergammaglobulinemic purpura of Waldenström (HGPW) is a rare chronic skin condition characterized by recurrent petechiae and purpura on the lower legs, elevated erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia, and elevated titers of IgG and IgA rheumatoid factor (RF).^1,2 This condition can be a primary (idiopathic) syndrome or secondary to an autoimmune connective tissue disease. We report 2 cases of patients with episodic skin eruptions that were consistent with HGPW.

Patient 1

A 41-year-old woman presented to our clinic with a rash on the legs of 20 years’ duration. She had first been evaluated at an outside dermatology clinic 5 years prior, and a biopsy performed at the time led to a diagnosis of leukocytoclastic vasculitis (LCV). The rash affected her ability to work, as her job involved standing for prolonged periods of time. If she stood for more than 2 hours, she experienced leg pain and worsening of the rash. The rash also was exacerbated by nonsteroidal anti-inflammatory drugs but improved with multiple days of rest. She had been on dapsone 75 mg daily, but the dose was reduced to 50 mg daily after elevated liver enzymes were noted. This regimen had improved her rash for 4 years until she experienced breakthrough symptoms, leading to her re-evaluation. Prior outside therapies included systemic steroids with limited response, then oral dapsone.

Upon our initial evaluation, laboratory tests were notable for an elevated ESR of 43 mm/h. Results of antinuclear antibody (ANA), anti–double-stranded DNA, extractable nuclear antigen, RF, HIV, cryoglobulin, hepatitis panel, serum protein electrophoresis, complete blood count, basic metabolic panel, urinalysis, and thyroid-stimulating hormone testing were within reference range. Physical examination revealed scattered pinpoint violaceous papules on the lower extremities. Photographs on the patient’s phone from 2 months prior showed a more robust manifestation with diffuse palpable purpura on the lower extremities.

At 3-year follow-up, laboratory evaluation including ESR, IgA, IgG, IgM, serum protein electrophoresis with reflex immunofixation, and Mycoplasma pneumoniae IgM/IgG showed elevated ESR (29 mm/h) and IgG (1654 mg), with otherwise unremarkable results. Because of the extended period of time since the previous biopsy, a repeat biopsy with hematoxylin and eosin staining and direct immunofluorescence was performed. Biopsy from the left calf demonstrated a perivascular and interstitial infiltrate with lymphocytes and neutrophils with nuclear debris and hemorrhage (Figure 1). Direct immunofluorescence was positive for IgA, C3, and fibrin within vessel walls (Figure 2).

Overall the features of recurrent dependent palpable purpura and the pathology findings were consistent with evolving LCV. Given the chronic nature of her symptoms; flares with prolonged standing; presence of polyclonol hypergammaglobulinemia; and negative evaluation for underling autoimmune disease, infection, and malignancy, the clinicopathologic correlation was most consistent with primary HGPW. The patient was treated with colchicine 0.6 mg twice daily and continued on dapsone 50 mg daily. The colchicine was reduced to once daily due to diarrhea. Nonetheless, the patient had less frequent and less intense flares. On follow-up examination 4 months later, she was satisfied with her current level of control and did not wish to escalate her treatment.

Patient 2

A 53-year-old woman with a 1-year history of sicca symptoms presented for evaluation of a transient rash on the legs and feet of 2 months’ duration. At that time, the heels began to feel swollen. The rash was painful on the feet and caused calf myalgias. She did not endorse pruritus or pain elsewhere. The rash was not associated with prolonged standing, walking, or wearing tight socks. She had no fevers, chills, or joint pain. Flares would come and go within a week.

Laboratory evaluation was notable for an ANA of 1:1280 (reference range, 1:80) with positive anti-Ro/SS-A and anti-La/SS-B. Rheumatology evaluation confirmed the diagnosis of Sjögren syndrome. Physical examination revealed minimal petechiae on the heel of the left foot. Photographs from the previous month provided by the patient revealed linear petechiae of the lower extremities with postinflammatory hyperpigmentation (Figure 3). An additional photograph from the prior week revealed more diffuse erythematous plaques without secondary changes on the feet up to the ankles (Figure 4).

The patient experienced a recurrence of the rash within a month and had an expedited visit for biopsies, which demonstrated mixed inflammation with neutrophils, nuclear debris, hemorrhage, and C3 and fibrin immunoreactants within vessel walls. As with patient 1, the features were consistent with LCV.

In the context of Sjögren syndrome and elevated IgG and RF, the patient’s symptoms were consistent with secondary HGPW. Rheumatology prescribed hydroxychloroquine 400 mg daily alternating every other day with 300 mg and 0.6 mg of colchicine. The rash cleared within approximately 1 month.

Comment

Also known as benign hypergammaglobulinemic purpura, HGPW is a rare purpuric eruption that is exacerbated with prolonged standing and increased hydrostatic pressure.³ First described in 1943, HGPW is characterized by recurrent petechiae, purpuric macules, or palpable purpura, depending on the degree of inflammation.^1,4,5 It typically is distributed on the bilateral lower extremities or trunk. Chronic postinflammatory hyperpigmentation with hemosiderin deposition also can be observed. The lesions last for up to 1 week at a time and are frequently asymmetrically distributed.²

Patient 1 demonstrated the typical clinical manifestations and laboratory findings of HGPW. The eruption often is asymptomatic, and patients report that the skin worsens with prolonged immobilization, walking, and wearing of tight clothing.^2,6-8 Increased hydrostatic pressure is thought to cause the erythrocyte extravasation, resulting in the purpuric lesions. However, patient 2 was less typical, presenting with prominent skin pain and myalgias. Some patients experience discomfort, burning dysesthesia, pruritus, and swelling of the affected area.¹ Hypergammaglobulinemic purpura of Waldenström is a chronic condition. Recurrent episodes can occur yearly or as frequently as multiple times per week.⁸

Women are most commonly diagnosed with HGPW, but many cases have been reported in children.^9,10 In spite of the “condition being considered largely benign,” women with a diagnosis of HGPW require preconception counseling due to risks for congenital heart block, neonatal lupus, intrauterine growth restriction, intrauterine demise, and preterm birth.^7,9,11,12

The etiology of the rash remains undefined. It is hypothesized that it develops due to underlying immune dysregulation with associated immune complex formation and deposition in the blood vessel wall.¹ Small circulating immune complexes containing IgG or IgA RF are a specific finding in patients with HGPW. These highly soluble autoantibodies are hypothesized to influence the rapid appearance and disappearance of lesions.¹

The role of hypergammaglobulinemia in the pathogenesis of HGPW is unknown.¹³ Serum IgG levels do not correlate with the appearance and regression of lesions.¹³ Additionally, hypergammaglobulinemia can be found in autoimmune connective tissue diseases such as Sjögren syndrome without resulting cutaneous vasculitis.¹³

Characteristic laboratory abnormalities include polyclonal hypergammaglobulinemia, elevated ESR, and elevated IgA and IgG RF. Positive ANA and anti-Ro/SS-A and anti-La/SS-B indicate a potential to develop autoimmune connective tissue diseases, including Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis.^1,14 Additional recommended workup includes complete blood counts, metabolic panel, complement levels, urinalysis, and urine protein/creatinine ratio.⁹ Repeat monitoring for antibodies, inflammatory markers, immunoglobulins, and RF should be completed 3 months after initial evaluation. Patients with symptoms of systemic disease should have laboratory evaluation repeated.

Erythrocyte sedimentation rate abnormalities are a defining feature of HGPW. Erythrocyte sedimentation rate is an inexpensive and commonly ordered inflammatory marker that measures settling of erythrocytes within 1 hour and can be elevated by plasma proteins such as gamma globulins. Erythrocyte sedimentation rate is nonspecific and is not sensitive as a general screening test. It can be elevated by autoimmune connective tissue disease, infection, and malignancy.¹⁵ Notably, ESR is not specific to inflammation. Confounding factors include red blood cell abnormalities, physiologic factors, and the quantity of plasma proteins such as fibrinogen.¹⁶ These positively charged plasma proteins neutralize the negative surface charge of erythrocytes, resulting in erythrocytes that are prone to rouleaux formation.¹⁷

The utility of the ESR is to expedite the diagnostic process and indicate the need for further workup.¹⁶ Patients with mild to moderate elevation in ESR without an identified etiology should have repeat testing to confirm the validity of the laboratory value. Patients with an ESR higher than 100 mm/h are more likely have an infectious cause, collagen vascular disease, or underlying malignancy.¹⁵ Elevation of ESR in HGPW is likely a result of increased immunoglobulins and acute phase proteins.¹⁷

The histopathology of HGPW is nonspecific and may show LCV or erythrocyte extravasation with mild perivascular lymphocytic infiltrates.^1,9 Direct immunofluorescence testing may show immune-complex deposition.⁵ For patients with evidence of LCV, the biopsy of a fresh but well-developed lesion is important in confirming the presence of vasculitis.¹ Incorrect sampling may lead to underreporting of LCV with HGPW.³

Associated underlying conditions include Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, hepatitis C, and hematologic malignancies.^1,3 Our patients demonstrated primary and secondary causes of HGPW. Patient 1’s case was not associated with any autoimmune disease but demonstrated chronic recurrence. Patient 2’s case was secondary to Sjögren syndrome.

In patients with suspected HGPW, differential diagnoses to consider include IgA vasculitis, cutaneous small vessel vasculitis, pigmented purpuric dermatoses, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and scurvy.^1,4

For patients with primary disease, treatment is focused on symptom management with compression stockings and avoidance of triggers. Compression stockings may exacerbate purpura but can provide symptom relief in some individuals.¹⁴ Patients with frequent or painful episodes can benefit from systemic treatment. In patients with an underlying disease, systemic therapies include prednisone, hydroxychloroquine, indomethacin, colchicine, chlorambucil, mycophenolate mofetil, rituximab, and plasmapheresis. Dapsone, a treatment for LCV, has been reported to be beneficial in patients with a neutrophilic infiltrate.¹⁸

Hypergammaglobulinemic purpura of Waldenström requires a thorough evaluation due to its association with underlying systemic disease. Patients without evidence of systemic disease should receive long-term monitoring and coordination of care with rheumatology, as systemic manifestations can develop years after the initial cutaneous manifestation. Dermatologists should consider HGPW in the differential diagnosis for cutaneous vasculitides.

THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease

The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.

Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman¹ as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.^2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.^3,4

Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.⁵ Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.⁶ Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.^7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.^9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.

Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.^12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.¹² Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.

Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.⁵ Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.⁶

The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.^14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.^14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.¹⁵ While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.^14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.^7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.^20,21

Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.^22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.²⁴ Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.^4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.⁵ There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.²²

THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease

The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.

Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman¹ as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.^2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.^3,4

Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.⁵ Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.⁶ Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.^7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.^9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.

Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.^12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.¹² Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.

Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.⁵ Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.⁶

The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.^14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.^14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.¹⁵ While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.^14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.^7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.^20,21

Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.^22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.²⁴ Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.^4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.⁵ There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.²²

THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease

The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.

Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman¹ as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.^2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.^3,4

Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.⁵ Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.⁶ Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.^7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.^9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.

Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.^12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.¹² Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.

Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.⁵ Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.⁶

The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.^14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.^14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.¹⁵ While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.^14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.^7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.^20,21

Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.^22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.²⁴ Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.^4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.⁵ There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.²²

To the Editor:

Xylazine, commonly referred to by its street name tranq, is a veterinary tranquilizer that has recently gained attention due to its increasing misuse in human populations. It often is combined with recreational drugs like fentanyl to extend the duration of drug effects. As a partial α₂ receptor agonist, xylazine acts by reducing dopamine and norepinephrine release, resulting in sedative effects. This case report highlights xylazine skin necrosis manifesting as wrist drop and chronic wounds in a patient with a history of intravenous (IV) drug use.

A 35-year-old man with a history of IV drug use presented to the emergency department with a nonprogressive right wrist drop that had persisted for 2 weeks, along with new-onset left wrist drop of 1 day’s duration. The patient did not report any sensory symptoms or pain. Physical examination revealed an ulcerated necrotic plaque with hemorrhagic crust and focal areas of scarring on the right posterior forearm (Figure 1). The left hand exhibited a well-healed pink scar symmetric to the ulcer on the right forearm. The patient reported a history of a similar ulcer on the left hand that had resolved after discontinuation of IV drug use in that arm. He denied any history of trauma to the area.

The patient’s laboratory results demonstrated elevated inflammatory markers, including an erythrocyte sedimentation rate of 105 mm/h (reference range, <15 mm/h in men younger than 50 years) and a C-reactive protein level of 7.7 mg/dL (reference range, <0.9 mg/dL). Additionally, antinuclear antibody and antineutrophil cytoplasmic antibody tests were positive. A urine drug screen returned positive results for various substances, including cocaine, cocaine metabolites, fentanyl, norfentanyl, β-hydroxyfentanyl or fentanyl metabolite, caffeine, caffeine metabolite or theophylline, nicotine metabolite, and xylazine. Magnetic resonance imaging of the right upper extremity excluded osteomyelitis but revealed multiple subepidermal abscesses.

A punch biopsy from the right forearm demonstrated an ulcer with a mixed infiltrate, dermal necrosis, and clusters of Gram-positive cocci, indicating a bacterial infection. There was no evidence of leukocytoclastic vasculitis (Figures 2 and 3). Electromyography confirmed mononeuritis multiplex as the cause of the right wrist drop. The patient was found to have cytoplasmic antineutrophil cytoplasmic antibody–positive vasculitis in the setting of levamisole-adulterated cocaine use. Since no vasculitis was identified on histopathology of the ulcer and xylazine was detected on drug screening, a diagnosis of xylazine-induced skin necrosis was made. In our case, the patient did not show evidence of active osteomyelitis or sepsis and left the hospital against medical advice without adequate wound debridement.

Our case highlights xylazine-induced skin necrosis that can occur in individuals who use IV drugs. The combination of xylazine with other recreational drugs such as fentanyl poses unique challenges for clinicians. Xylazine has been increasingly found in cases of overdose-related mortality¹ and recently has been reported to induce skin ulcers.² Xylazine intoxication, though uncommon, can result in distinct clinical presentations, including recalcitrant skin ulcers and deep necrotizing wounds.

The precise mechanism behind these wounds remains unclear. Xylazine is a partial α₂ receptor agonist, and it is postulated that the necrotic wounds develop secondary to local vasoconstriction, leading to decreased skin perfusion.³ A recent study found that xylazine used in combination with cocaine or an active metabolite in heroin can cause cytotoxicity to vascular endothelial cells, which can lead to dysregulation of vascular tone.⁴ Decreased perfusion and impaired wound healing put patients at risk for secondary infections, infected ulcers, osteomyelitis, and sepsis.

In patients with known fentanyl use in conjunction with skin necrosis, a high degree of suspicion for xylazine intoxication should be employed. Ruling out vasculitis (via serologic markers and skin biopsy) as well as atypical skin infections is important in these patients to identify potential cases of xylazine-induced skin necrosis. Other IV drugs such as krokodil (desomorphine) can cause severe skin necrosis and therefore should be considered in these patients. Early detection of these skin ulcers is imperative, as delayed diagnosis increases the risk for osteomyelitis and/or the need for amputation.

This case emphasizes the importance of health care providers remaining vigilant about emerging trends in drug misuse. Early recognition of xylazine intoxication and its potential complications is crucial for timely intervention and appropriate management, which may include wound debridement and antibiotic therapy. In addition, proper counseling regarding discontinuation of drug use is important in wound healing, though this poses a challenging conversation with the patient. Increased awareness among health care professionals and continued research in illicit drug–induced skin necrosis will aid in better understanding and addressing the growing issue of xylazine misuse.

To the Editor:

Xylazine, commonly referred to by its street name tranq, is a veterinary tranquilizer that has recently gained attention due to its increasing misuse in human populations. It often is combined with recreational drugs like fentanyl to extend the duration of drug effects. As a partial α₂ receptor agonist, xylazine acts by reducing dopamine and norepinephrine release, resulting in sedative effects. This case report highlights xylazine skin necrosis manifesting as wrist drop and chronic wounds in a patient with a history of intravenous (IV) drug use.

A 35-year-old man with a history of IV drug use presented to the emergency department with a nonprogressive right wrist drop that had persisted for 2 weeks, along with new-onset left wrist drop of 1 day’s duration. The patient did not report any sensory symptoms or pain. Physical examination revealed an ulcerated necrotic plaque with hemorrhagic crust and focal areas of scarring on the right posterior forearm (Figure 1). The left hand exhibited a well-healed pink scar symmetric to the ulcer on the right forearm. The patient reported a history of a similar ulcer on the left hand that had resolved after discontinuation of IV drug use in that arm. He denied any history of trauma to the area.

The patient’s laboratory results demonstrated elevated inflammatory markers, including an erythrocyte sedimentation rate of 105 mm/h (reference range, <15 mm/h in men younger than 50 years) and a C-reactive protein level of 7.7 mg/dL (reference range, <0.9 mg/dL). Additionally, antinuclear antibody and antineutrophil cytoplasmic antibody tests were positive. A urine drug screen returned positive results for various substances, including cocaine, cocaine metabolites, fentanyl, norfentanyl, β-hydroxyfentanyl or fentanyl metabolite, caffeine, caffeine metabolite or theophylline, nicotine metabolite, and xylazine. Magnetic resonance imaging of the right upper extremity excluded osteomyelitis but revealed multiple subepidermal abscesses.

A punch biopsy from the right forearm demonstrated an ulcer with a mixed infiltrate, dermal necrosis, and clusters of Gram-positive cocci, indicating a bacterial infection. There was no evidence of leukocytoclastic vasculitis (Figures 2 and 3). Electromyography confirmed mononeuritis multiplex as the cause of the right wrist drop. The patient was found to have cytoplasmic antineutrophil cytoplasmic antibody–positive vasculitis in the setting of levamisole-adulterated cocaine use. Since no vasculitis was identified on histopathology of the ulcer and xylazine was detected on drug screening, a diagnosis of xylazine-induced skin necrosis was made. In our case, the patient did not show evidence of active osteomyelitis or sepsis and left the hospital against medical advice without adequate wound debridement.

Our case highlights xylazine-induced skin necrosis that can occur in individuals who use IV drugs. The combination of xylazine with other recreational drugs such as fentanyl poses unique challenges for clinicians. Xylazine has been increasingly found in cases of overdose-related mortality¹ and recently has been reported to induce skin ulcers.² Xylazine intoxication, though uncommon, can result in distinct clinical presentations, including recalcitrant skin ulcers and deep necrotizing wounds.

The precise mechanism behind these wounds remains unclear. Xylazine is a partial α₂ receptor agonist, and it is postulated that the necrotic wounds develop secondary to local vasoconstriction, leading to decreased skin perfusion.³ A recent study found that xylazine used in combination with cocaine or an active metabolite in heroin can cause cytotoxicity to vascular endothelial cells, which can lead to dysregulation of vascular tone.⁴ Decreased perfusion and impaired wound healing put patients at risk for secondary infections, infected ulcers, osteomyelitis, and sepsis.

In patients with known fentanyl use in conjunction with skin necrosis, a high degree of suspicion for xylazine intoxication should be employed. Ruling out vasculitis (via serologic markers and skin biopsy) as well as atypical skin infections is important in these patients to identify potential cases of xylazine-induced skin necrosis. Other IV drugs such as krokodil (desomorphine) can cause severe skin necrosis and therefore should be considered in these patients. Early detection of these skin ulcers is imperative, as delayed diagnosis increases the risk for osteomyelitis and/or the need for amputation.

This case emphasizes the importance of health care providers remaining vigilant about emerging trends in drug misuse. Early recognition of xylazine intoxication and its potential complications is crucial for timely intervention and appropriate management, which may include wound debridement and antibiotic therapy. In addition, proper counseling regarding discontinuation of drug use is important in wound healing, though this poses a challenging conversation with the patient. Increased awareness among health care professionals and continued research in illicit drug–induced skin necrosis will aid in better understanding and addressing the growing issue of xylazine misuse.

To the Editor:

Xylazine, commonly referred to by its street name tranq, is a veterinary tranquilizer that has recently gained attention due to its increasing misuse in human populations. It often is combined with recreational drugs like fentanyl to extend the duration of drug effects. As a partial α₂ receptor agonist, xylazine acts by reducing dopamine and norepinephrine release, resulting in sedative effects. This case report highlights xylazine skin necrosis manifesting as wrist drop and chronic wounds in a patient with a history of intravenous (IV) drug use.

A 35-year-old man with a history of IV drug use presented to the emergency department with a nonprogressive right wrist drop that had persisted for 2 weeks, along with new-onset left wrist drop of 1 day’s duration. The patient did not report any sensory symptoms or pain. Physical examination revealed an ulcerated necrotic plaque with hemorrhagic crust and focal areas of scarring on the right posterior forearm (Figure 1). The left hand exhibited a well-healed pink scar symmetric to the ulcer on the right forearm. The patient reported a history of a similar ulcer on the left hand that had resolved after discontinuation of IV drug use in that arm. He denied any history of trauma to the area.

The patient’s laboratory results demonstrated elevated inflammatory markers, including an erythrocyte sedimentation rate of 105 mm/h (reference range, <15 mm/h in men younger than 50 years) and a C-reactive protein level of 7.7 mg/dL (reference range, <0.9 mg/dL). Additionally, antinuclear antibody and antineutrophil cytoplasmic antibody tests were positive. A urine drug screen returned positive results for various substances, including cocaine, cocaine metabolites, fentanyl, norfentanyl, β-hydroxyfentanyl or fentanyl metabolite, caffeine, caffeine metabolite or theophylline, nicotine metabolite, and xylazine. Magnetic resonance imaging of the right upper extremity excluded osteomyelitis but revealed multiple subepidermal abscesses.

A punch biopsy from the right forearm demonstrated an ulcer with a mixed infiltrate, dermal necrosis, and clusters of Gram-positive cocci, indicating a bacterial infection. There was no evidence of leukocytoclastic vasculitis (Figures 2 and 3). Electromyography confirmed mononeuritis multiplex as the cause of the right wrist drop. The patient was found to have cytoplasmic antineutrophil cytoplasmic antibody–positive vasculitis in the setting of levamisole-adulterated cocaine use. Since no vasculitis was identified on histopathology of the ulcer and xylazine was detected on drug screening, a diagnosis of xylazine-induced skin necrosis was made. In our case, the patient did not show evidence of active osteomyelitis or sepsis and left the hospital against medical advice without adequate wound debridement.

Our case highlights xylazine-induced skin necrosis that can occur in individuals who use IV drugs. The combination of xylazine with other recreational drugs such as fentanyl poses unique challenges for clinicians. Xylazine has been increasingly found in cases of overdose-related mortality¹ and recently has been reported to induce skin ulcers.² Xylazine intoxication, though uncommon, can result in distinct clinical presentations, including recalcitrant skin ulcers and deep necrotizing wounds.

The precise mechanism behind these wounds remains unclear. Xylazine is a partial α₂ receptor agonist, and it is postulated that the necrotic wounds develop secondary to local vasoconstriction, leading to decreased skin perfusion.³ A recent study found that xylazine used in combination with cocaine or an active metabolite in heroin can cause cytotoxicity to vascular endothelial cells, which can lead to dysregulation of vascular tone.⁴ Decreased perfusion and impaired wound healing put patients at risk for secondary infections, infected ulcers, osteomyelitis, and sepsis.

In patients with known fentanyl use in conjunction with skin necrosis, a high degree of suspicion for xylazine intoxication should be employed. Ruling out vasculitis (via serologic markers and skin biopsy) as well as atypical skin infections is important in these patients to identify potential cases of xylazine-induced skin necrosis. Other IV drugs such as krokodil (desomorphine) can cause severe skin necrosis and therefore should be considered in these patients. Early detection of these skin ulcers is imperative, as delayed diagnosis increases the risk for osteomyelitis and/or the need for amputation.

This case emphasizes the importance of health care providers remaining vigilant about emerging trends in drug misuse. Early recognition of xylazine intoxication and its potential complications is crucial for timely intervention and appropriate management, which may include wound debridement and antibiotic therapy. In addition, proper counseling regarding discontinuation of drug use is important in wound healing, though this poses a challenging conversation with the patient. Increased awareness among health care professionals and continued research in illicit drug–induced skin necrosis will aid in better understanding and addressing the growing issue of xylazine misuse.

THE DIAGNOSIS: Demodicosis

Direct microscopic examination of the purulent fluid revealed a considerable number of actively motile Demodex mites (Figure). Based on the microscopy results and the patient’s history of prolonged topical immunosuppressive therapy, a known risk factor for Demodex overgrowth, a diagnosis of demodicosis was made. The patient was prescribed a single dose of oral metronidazole 2 g as well as metronidazole solution 0.5% to be applied 3 times daily. The folliculitis gradually improved and eventually resolved completely.

Demodex is a parasitic mite inhabiting the pilosebaceous units of human skin. Evidence suggests the vast majority of adults carry these mites. Demodex mites maintain a balance with the human immune system in appropriate microenvironments, with the immune system controlling their numbers without eliciting an inflammatory response; however, immunosuppression, as induced by topical corticosteroids and other immunomodulators, can lead to an increase in Demodex mite populations on facial skin. Clinical manifestations and severity of demodicosis are highly variable, ranging from nonspecific dry, sensitive skin and papules to nodules or granulomas, depending on mite density, the cutaneous microenvironment, and the host immune response.¹ Consequently, demodicosis often is mistaken for other dermatologic conditions with similar skin lesions.

High Demodex mite density is considered a pathogenic factor in demodicosis; therefore, determining Demodex mite density is essential to the diagnosis of demodicosis. Standard skin surface biopsy and direct microscopic examination commonly are used methods for measuring Demodex mite density; however, the accuracy of these methods is subject to the technical proficiency of the investigator. Noninvasive examination tools like dermoscopy and confocal laser scanning also offer advantages in diagnosing demodicosis. Dermoscopy, by direct contact with skin lesions, typically reveals gelatinous filaments extending from the follicular openings.

Importantly, Demodex mite density alone does not determine the severity of clinical symptoms. In addition, mites may migrate to the skin surface or reside deep within follicles, rendering them difficult to detect with standard examination methods.¹ Therefore, diagnostic criteria should extend beyond mite proliferation to include characteristic clinical lesions, response to acaricidal therapy, and normalization of mite density.

Rosacea was included in the differential diagnosis for our patient, but it typically manifests in the central facial area (eg, forehead, nose, chin). Patients may have a history of facial flushing associated with alcohol consumption, heat exposure, or emotional stress.² Additionally, rosacea typically has an insidious onset and does not erupt suddenly within a short period of time; however, our patient presented with a sudden onset of widespread papules and pustules on the face without facial flushing, and there was no exacerbation upon exposure to heat or emotional stress. Furthermore, rosacea tends to be recurrent and challenging to cure, whereas our patient responded rapidly to treatment without recurrence. Therefore, the likelihood of rosacea was minimal. Histopathologic examination also can differentiate between rosacea and demodicosis. Histologically, the features of rosacea include dilated blood and lymphatic vessels and infiltration of T lymphocytes, macrophages, and mast cells around blood vessels, often with increased solar elastosis and dermal edema.³ Demodicosis can reveal Demodex mites within the infundibulum of hair follicles, with dense neutrophil and monocyte infiltration around and between the infundibula.⁴

Bacterial folliculitis is primarily characterized by perifollicular erythema, papules, and pustules, often accompanied by pain. Positive bacterial culture of purulent fluid is indicative.⁵ Our patient’s lesions shared certain similarities with bacterial folliculitis but lacked the characteristic pain, instead exhibiting pronounced pruritus. Remarkable therapeutic efficacy was observed following topical acaricidal treatment, thus rendering the diagnosis of bacterial folliculitis less probable.

Acne vulgaris is a noninfectious folliculitis caused by follicular occlusion. Abnormal keratinization leads to the obstruction of follicles by keratin, hindering the outflow of sebum from the follicles. Sebum accumulation within the follicles provides a rich substrate for Propionibacterium acnes, which metabolizes sebum into proinflammatory free fatty acids, resulting in the formation of comedones, papules, and pustules.⁵ Our patient did not exhibit comedonal lesions on the face and lacked a seborrheic complexion, hence diminishing the likelihood of acne vulgaris.

Tinea corporis is another intensely pruritic condition, especially in areas subjected to prolonged use of topical immunosuppressants. It is caused by dermatophyte fungi and typically manifests as erythematous pruritic patches, often presenting as ring-shaped lesions with active margins and sometimes accompanied by scaling.⁶ While long-term use of immunosuppressants may be a risk factor for fungal infections and increase the probability of tinea corporis, our patient’s presentation of papules and pustules without a ring-shaped configuration or scaling diminished the likelihood of tinea corporis.

Our patient represents an intriguing case of an eruptive form of demodicosis induced by long-term intermittent and inconsistent application of topical immunosuppressive agents. Demodicosis encompasses a spectrum of clinical presentations, including pityriasis folliculorum, rosacealike, folliculitislike, and perioral dermatitis–like forms.¹ It is prone to misdiagnosis, as it is clinically similar to other conditions, such as acne, rosacea, or bacterial folliculitis, and it also is susceptible to missed diagnosis. Demodicosis tends to erupt in immunocompromised individuals, and the use of topical immunosuppressive and corticosteroid medications can exacerbate Demodex activity. Dermatologists should be aware that demodicosis is not a rare skin disorder, and timely identification and diagnosis can reduce the incidence of disease and improve quality of life for affected patients. Conversely, the consequences of misdiagnosis can be severe, with inappropriate treatment potentially exacerbating the condition.

THE DIAGNOSIS: Demodicosis

Direct microscopic examination of the purulent fluid revealed a considerable number of actively motile Demodex mites (Figure). Based on the microscopy results and the patient’s history of prolonged topical immunosuppressive therapy, a known risk factor for Demodex overgrowth, a diagnosis of demodicosis was made. The patient was prescribed a single dose of oral metronidazole 2 g as well as metronidazole solution 0.5% to be applied 3 times daily. The folliculitis gradually improved and eventually resolved completely.

Demodex is a parasitic mite inhabiting the pilosebaceous units of human skin. Evidence suggests the vast majority of adults carry these mites. Demodex mites maintain a balance with the human immune system in appropriate microenvironments, with the immune system controlling their numbers without eliciting an inflammatory response; however, immunosuppression, as induced by topical corticosteroids and other immunomodulators, can lead to an increase in Demodex mite populations on facial skin. Clinical manifestations and severity of demodicosis are highly variable, ranging from nonspecific dry, sensitive skin and papules to nodules or granulomas, depending on mite density, the cutaneous microenvironment, and the host immune response.¹ Consequently, demodicosis often is mistaken for other dermatologic conditions with similar skin lesions.

High Demodex mite density is considered a pathogenic factor in demodicosis; therefore, determining Demodex mite density is essential to the diagnosis of demodicosis. Standard skin surface biopsy and direct microscopic examination commonly are used methods for measuring Demodex mite density; however, the accuracy of these methods is subject to the technical proficiency of the investigator. Noninvasive examination tools like dermoscopy and confocal laser scanning also offer advantages in diagnosing demodicosis. Dermoscopy, by direct contact with skin lesions, typically reveals gelatinous filaments extending from the follicular openings.

Importantly, Demodex mite density alone does not determine the severity of clinical symptoms. In addition, mites may migrate to the skin surface or reside deep within follicles, rendering them difficult to detect with standard examination methods.¹ Therefore, diagnostic criteria should extend beyond mite proliferation to include characteristic clinical lesions, response to acaricidal therapy, and normalization of mite density.

Rosacea was included in the differential diagnosis for our patient, but it typically manifests in the central facial area (eg, forehead, nose, chin). Patients may have a history of facial flushing associated with alcohol consumption, heat exposure, or emotional stress.² Additionally, rosacea typically has an insidious onset and does not erupt suddenly within a short period of time; however, our patient presented with a sudden onset of widespread papules and pustules on the face without facial flushing, and there was no exacerbation upon exposure to heat or emotional stress. Furthermore, rosacea tends to be recurrent and challenging to cure, whereas our patient responded rapidly to treatment without recurrence. Therefore, the likelihood of rosacea was minimal. Histopathologic examination also can differentiate between rosacea and demodicosis. Histologically, the features of rosacea include dilated blood and lymphatic vessels and infiltration of T lymphocytes, macrophages, and mast cells around blood vessels, often with increased solar elastosis and dermal edema.³ Demodicosis can reveal Demodex mites within the infundibulum of hair follicles, with dense neutrophil and monocyte infiltration around and between the infundibula.⁴

Bacterial folliculitis is primarily characterized by perifollicular erythema, papules, and pustules, often accompanied by pain. Positive bacterial culture of purulent fluid is indicative.⁵ Our patient’s lesions shared certain similarities with bacterial folliculitis but lacked the characteristic pain, instead exhibiting pronounced pruritus. Remarkable therapeutic efficacy was observed following topical acaricidal treatment, thus rendering the diagnosis of bacterial folliculitis less probable.

Acne vulgaris is a noninfectious folliculitis caused by follicular occlusion. Abnormal keratinization leads to the obstruction of follicles by keratin, hindering the outflow of sebum from the follicles. Sebum accumulation within the follicles provides a rich substrate for Propionibacterium acnes, which metabolizes sebum into proinflammatory free fatty acids, resulting in the formation of comedones, papules, and pustules.⁵ Our patient did not exhibit comedonal lesions on the face and lacked a seborrheic complexion, hence diminishing the likelihood of acne vulgaris.

Tinea corporis is another intensely pruritic condition, especially in areas subjected to prolonged use of topical immunosuppressants. It is caused by dermatophyte fungi and typically manifests as erythematous pruritic patches, often presenting as ring-shaped lesions with active margins and sometimes accompanied by scaling.⁶ While long-term use of immunosuppressants may be a risk factor for fungal infections and increase the probability of tinea corporis, our patient’s presentation of papules and pustules without a ring-shaped configuration or scaling diminished the likelihood of tinea corporis.

Our patient represents an intriguing case of an eruptive form of demodicosis induced by long-term intermittent and inconsistent application of topical immunosuppressive agents. Demodicosis encompasses a spectrum of clinical presentations, including pityriasis folliculorum, rosacealike, folliculitislike, and perioral dermatitis–like forms.¹ It is prone to misdiagnosis, as it is clinically similar to other conditions, such as acne, rosacea, or bacterial folliculitis, and it also is susceptible to missed diagnosis. Demodicosis tends to erupt in immunocompromised individuals, and the use of topical immunosuppressive and corticosteroid medications can exacerbate Demodex activity. Dermatologists should be aware that demodicosis is not a rare skin disorder, and timely identification and diagnosis can reduce the incidence of disease and improve quality of life for affected patients. Conversely, the consequences of misdiagnosis can be severe, with inappropriate treatment potentially exacerbating the condition.

THE DIAGNOSIS: Demodicosis

Direct microscopic examination of the purulent fluid revealed a considerable number of actively motile Demodex mites (Figure). Based on the microscopy results and the patient’s history of prolonged topical immunosuppressive therapy, a known risk factor for Demodex overgrowth, a diagnosis of demodicosis was made. The patient was prescribed a single dose of oral metronidazole 2 g as well as metronidazole solution 0.5% to be applied 3 times daily. The folliculitis gradually improved and eventually resolved completely.

Demodex is a parasitic mite inhabiting the pilosebaceous units of human skin. Evidence suggests the vast majority of adults carry these mites. Demodex mites maintain a balance with the human immune system in appropriate microenvironments, with the immune system controlling their numbers without eliciting an inflammatory response; however, immunosuppression, as induced by topical corticosteroids and other immunomodulators, can lead to an increase in Demodex mite populations on facial skin. Clinical manifestations and severity of demodicosis are highly variable, ranging from nonspecific dry, sensitive skin and papules to nodules or granulomas, depending on mite density, the cutaneous microenvironment, and the host immune response.¹ Consequently, demodicosis often is mistaken for other dermatologic conditions with similar skin lesions.

High Demodex mite density is considered a pathogenic factor in demodicosis; therefore, determining Demodex mite density is essential to the diagnosis of demodicosis. Standard skin surface biopsy and direct microscopic examination commonly are used methods for measuring Demodex mite density; however, the accuracy of these methods is subject to the technical proficiency of the investigator. Noninvasive examination tools like dermoscopy and confocal laser scanning also offer advantages in diagnosing demodicosis. Dermoscopy, by direct contact with skin lesions, typically reveals gelatinous filaments extending from the follicular openings.

Importantly, Demodex mite density alone does not determine the severity of clinical symptoms. In addition, mites may migrate to the skin surface or reside deep within follicles, rendering them difficult to detect with standard examination methods.¹ Therefore, diagnostic criteria should extend beyond mite proliferation to include characteristic clinical lesions, response to acaricidal therapy, and normalization of mite density.

Rosacea was included in the differential diagnosis for our patient, but it typically manifests in the central facial area (eg, forehead, nose, chin). Patients may have a history of facial flushing associated with alcohol consumption, heat exposure, or emotional stress.² Additionally, rosacea typically has an insidious onset and does not erupt suddenly within a short period of time; however, our patient presented with a sudden onset of widespread papules and pustules on the face without facial flushing, and there was no exacerbation upon exposure to heat or emotional stress. Furthermore, rosacea tends to be recurrent and challenging to cure, whereas our patient responded rapidly to treatment without recurrence. Therefore, the likelihood of rosacea was minimal. Histopathologic examination also can differentiate between rosacea and demodicosis. Histologically, the features of rosacea include dilated blood and lymphatic vessels and infiltration of T lymphocytes, macrophages, and mast cells around blood vessels, often with increased solar elastosis and dermal edema.³ Demodicosis can reveal Demodex mites within the infundibulum of hair follicles, with dense neutrophil and monocyte infiltration around and between the infundibula.⁴

Bacterial folliculitis is primarily characterized by perifollicular erythema, papules, and pustules, often accompanied by pain. Positive bacterial culture of purulent fluid is indicative.⁵ Our patient’s lesions shared certain similarities with bacterial folliculitis but lacked the characteristic pain, instead exhibiting pronounced pruritus. Remarkable therapeutic efficacy was observed following topical acaricidal treatment, thus rendering the diagnosis of bacterial folliculitis less probable.

Acne vulgaris is a noninfectious folliculitis caused by follicular occlusion. Abnormal keratinization leads to the obstruction of follicles by keratin, hindering the outflow of sebum from the follicles. Sebum accumulation within the follicles provides a rich substrate for Propionibacterium acnes, which metabolizes sebum into proinflammatory free fatty acids, resulting in the formation of comedones, papules, and pustules.⁵ Our patient did not exhibit comedonal lesions on the face and lacked a seborrheic complexion, hence diminishing the likelihood of acne vulgaris.

Tinea corporis is another intensely pruritic condition, especially in areas subjected to prolonged use of topical immunosuppressants. It is caused by dermatophyte fungi and typically manifests as erythematous pruritic patches, often presenting as ring-shaped lesions with active margins and sometimes accompanied by scaling.⁶ While long-term use of immunosuppressants may be a risk factor for fungal infections and increase the probability of tinea corporis, our patient’s presentation of papules and pustules without a ring-shaped configuration or scaling diminished the likelihood of tinea corporis.

Our patient represents an intriguing case of an eruptive form of demodicosis induced by long-term intermittent and inconsistent application of topical immunosuppressive agents. Demodicosis encompasses a spectrum of clinical presentations, including pityriasis folliculorum, rosacealike, folliculitislike, and perioral dermatitis–like forms.¹ It is prone to misdiagnosis, as it is clinically similar to other conditions, such as acne, rosacea, or bacterial folliculitis, and it also is susceptible to missed diagnosis. Demodicosis tends to erupt in immunocompromised individuals, and the use of topical immunosuppressive and corticosteroid medications can exacerbate Demodex activity. Dermatologists should be aware that demodicosis is not a rare skin disorder, and timely identification and diagnosis can reduce the incidence of disease and improve quality of life for affected patients. Conversely, the consequences of misdiagnosis can be severe, with inappropriate treatment potentially exacerbating the condition.

The Cutis editorial staff is proud to announce that Vincent A. DeLeo, MD, Editor-in-Chief, was honored with the Master Dermatologist Award at the 2026 Annual Meeting of the American Academy of Dermatology (AAD) in Denver, Colorado.

Presented as part of the AAD’s “Stars of the Academy” program, this award is reserved for physicians whose careers have advanced dermatology through leadership, service, and meaningful contributions to patient care, education, and research. The award reflects Dr. DeLeo’s impact across the specialty.

“Vince’s passion for dermatology has impacted all aspects of our specialty. He has been at the forefront of basic science research, clinical dermatology, education, mentoring, and leadership of specialty organizations and societies.” –Susan C. Taylor, MD

During the presentation, outgoing AAD president Susan C. Taylor, MD, emphasized Dr. DeLeo’s wide-ranging influence, noting his reputation as a researcher, compassionate physician, and skilled diagnostician. He is adept at managing complex cases and improving patient outcomes. Dr. DeLeo is widely recognized for his expertise in contact dermatitis, photomedicine, and photoprotection, as well as for his contributions to dermatologic education.

Beyond his clinical and editorial leadership of Cutis for the past 25 years, Dr. DeLeo is committed to mentorship and leadership by serving on the AAD Board of Directors as well as other specialty organizations such as the American Contact Dermatitis Society.

We congratulate Dr. DeLeo on this well-deserved distinction and thank him for his continued vision and dedication to our readers and the specialty at large.

The Cutis editorial staff is proud to announce that Vincent A. DeLeo, MD, Editor-in-Chief, was honored with the Master Dermatologist Award at the 2026 Annual Meeting of the American Academy of Dermatology (AAD) in Denver, Colorado.

Presented as part of the AAD’s “Stars of the Academy” program, this award is reserved for physicians whose careers have advanced dermatology through leadership, service, and meaningful contributions to patient care, education, and research. The award reflects Dr. DeLeo’s impact across the specialty.

“Vince’s passion for dermatology has impacted all aspects of our specialty. He has been at the forefront of basic science research, clinical dermatology, education, mentoring, and leadership of specialty organizations and societies.” –Susan C. Taylor, MD

During the presentation, outgoing AAD president Susan C. Taylor, MD, emphasized Dr. DeLeo’s wide-ranging influence, noting his reputation as a researcher, compassionate physician, and skilled diagnostician. He is adept at managing complex cases and improving patient outcomes. Dr. DeLeo is widely recognized for his expertise in contact dermatitis, photomedicine, and photoprotection, as well as for his contributions to dermatologic education.

Beyond his clinical and editorial leadership of Cutis for the past 25 years, Dr. DeLeo is committed to mentorship and leadership by serving on the AAD Board of Directors as well as other specialty organizations such as the American Contact Dermatitis Society.

We congratulate Dr. DeLeo on this well-deserved distinction and thank him for his continued vision and dedication to our readers and the specialty at large.

The Cutis editorial staff is proud to announce that Vincent A. DeLeo, MD, Editor-in-Chief, was honored with the Master Dermatologist Award at the 2026 Annual Meeting of the American Academy of Dermatology (AAD) in Denver, Colorado.

Presented as part of the AAD’s “Stars of the Academy” program, this award is reserved for physicians whose careers have advanced dermatology through leadership, service, and meaningful contributions to patient care, education, and research. The award reflects Dr. DeLeo’s impact across the specialty.

“Vince’s passion for dermatology has impacted all aspects of our specialty. He has been at the forefront of basic science research, clinical dermatology, education, mentoring, and leadership of specialty organizations and societies.” –Susan C. Taylor, MD

During the presentation, outgoing AAD president Susan C. Taylor, MD, emphasized Dr. DeLeo’s wide-ranging influence, noting his reputation as a researcher, compassionate physician, and skilled diagnostician. He is adept at managing complex cases and improving patient outcomes. Dr. DeLeo is widely recognized for his expertise in contact dermatitis, photomedicine, and photoprotection, as well as for his contributions to dermatologic education.

Beyond his clinical and editorial leadership of Cutis for the past 25 years, Dr. DeLeo is committed to mentorship and leadership by serving on the AAD Board of Directors as well as other specialty organizations such as the American Contact Dermatitis Society.

We congratulate Dr. DeLeo on this well-deserved distinction and thank him for his continued vision and dedication to our readers and the specialty at large.