Case Letter

To the Editor:

Segmental vitiligo (SV) accounts for a minority of vitiligo cases and most frequently occurs in children.¹ It characteristically manifests unilaterally and affects a single body area with a sharp midline demarcation. In contrast to nonsegmental vitiligo (NSV), SV typically stabilizes early in the disease progression.¹ The pathophysiology of this vitiligo subtype is not well established, but possible autoinflammatory mechanisms associated with somatic mosaicism, neuronal mechanisms, and/or microvascular skin-homing have been proposed.² We present the case of a pediatric patient with segmental vitiligo of the right hemiface treated with a combination of a topical calcineurin inhibitor and narrow-band UVB (NB-UVB) phototherapy.

An otherwise healthy 7-year-old boy presented to the dermatology department for evaluation of depigmented macules and patches affecting the right hemiface (temporal, periorbital, malar, perioral, preauricular, and mandibular regions) and neck associated with homolateral leukotrichia of the scalp and facial hair as well as the eyelashes of 5 years’ duration. The findings were consistent with SV (Figure 1). The patient previously had been diagnosed based on the clinical findings and treated with continuous application of topical calcineurin inhibitors plus oral cyclosporine (3 mg/kg/d) for 1 year, but the response was poor. The condition had a severe impact on the patient’s quality of life and social relationships. Therapeutic options were discussed with the patient’s caregivers, and ultimately NB-UVB phototherapy was started twice weekly with 10% increases in the dose at each treatment. Topical tacrolimus ointment (1 mg/g) also was started, and the cyclosporine was stopped. Evaluation of treatment progress occurred every 3 months, with progressive repigmentation of the patches following a perifollicular pattern. After 6 months of phototherapy, there was notable repigmentation of the affected areas, particularly in the malar, perioral, and perinasal regions (Figure 2) and the therapeutic response improved after 1 year of treatment (Figure 3). No adverse events were noted during the treatment period.

Segmental vitiligo lacks consistently effective treatment options. This subtype of vitiligo is classically resistant to conventional therapeutic options. Surgery may be a more effective and long-lasting treatment option but is not suitable for every patient.^1,3 Janus kinase (JAK) inhibitors are the newest treatment options being explored for topical and systemic treatment of vitiligo, with promising results in active and stable NSV lesions^4,5; however, SV rarely is represented in case reports and clinical trials. The topical JAK inhibitor ruxolitinib has been approved for use in NSV,⁵ and a phase 2 trial with oral ritlecitinib only included patients with NSV.⁴ Furthermore, JAK inhibitors have been studied and approved for children aged 12 years or older as well as for adults,^4,5 but younger age groups (4-10 years)—in whom SV most frequently manifests, as in our patient—have been excluded from these studies.¹ We present a novel case of SV of the right hemiface in a child that was successfully treated with NB-UVB phototherapy in association with topical calcineurin inhibitors.

The role of phototherapy for the treatment of vitiligo has been well documented, and it frequently is combined with other therapeutic modalities, such as topical anti-inflammatory drugs or, most recently, laser and micrografting techniques.^6,7 The most frequently used modality is NB-UVB. In the active phase, it performs an immunomodulatory role, while in the stable phase, it stimulates migration and activity of perilesional and hair follicle melanocytes.⁸ Initiating therapy early is advisable, particularly during the first 6 months of progression, as there is a higher probability of response^1,3,8; nevertheless, a good response was achieved despite the 5-year evolution of vitiligo in our patient. This is a safe option for a skin condition that may begin early in life and require long-term treatment.⁸ A main concern would be an increased risk for skin cancer associated with repeated NB-UVB exposure, which has not been verified in a recent analysis.⁹

Segmental vitiligo can considerably impact the patient’s quality of life, affecting social interactions and self-perception, particularly in younger patients with facial involvement; thus, effective and safe therapeutic strategies adapted to the individual and their vitiligo lesions should be discussed. Classical treatment options remain valid and provide good results for some patients; therefore, they should not be disregarded even with the rise of innovative therapies.

To the Editor:

Segmental vitiligo (SV) accounts for a minority of vitiligo cases and most frequently occurs in children.¹ It characteristically manifests unilaterally and affects a single body area with a sharp midline demarcation. In contrast to nonsegmental vitiligo (NSV), SV typically stabilizes early in the disease progression.¹ The pathophysiology of this vitiligo subtype is not well established, but possible autoinflammatory mechanisms associated with somatic mosaicism, neuronal mechanisms, and/or microvascular skin-homing have been proposed.² We present the case of a pediatric patient with segmental vitiligo of the right hemiface treated with a combination of a topical calcineurin inhibitor and narrow-band UVB (NB-UVB) phototherapy.

An otherwise healthy 7-year-old boy presented to the dermatology department for evaluation of depigmented macules and patches affecting the right hemiface (temporal, periorbital, malar, perioral, preauricular, and mandibular regions) and neck associated with homolateral leukotrichia of the scalp and facial hair as well as the eyelashes of 5 years’ duration. The findings were consistent with SV (Figure 1). The patient previously had been diagnosed based on the clinical findings and treated with continuous application of topical calcineurin inhibitors plus oral cyclosporine (3 mg/kg/d) for 1 year, but the response was poor. The condition had a severe impact on the patient’s quality of life and social relationships. Therapeutic options were discussed with the patient’s caregivers, and ultimately NB-UVB phototherapy was started twice weekly with 10% increases in the dose at each treatment. Topical tacrolimus ointment (1 mg/g) also was started, and the cyclosporine was stopped. Evaluation of treatment progress occurred every 3 months, with progressive repigmentation of the patches following a perifollicular pattern. After 6 months of phototherapy, there was notable repigmentation of the affected areas, particularly in the malar, perioral, and perinasal regions (Figure 2) and the therapeutic response improved after 1 year of treatment (Figure 3). No adverse events were noted during the treatment period.

Segmental vitiligo lacks consistently effective treatment options. This subtype of vitiligo is classically resistant to conventional therapeutic options. Surgery may be a more effective and long-lasting treatment option but is not suitable for every patient.^1,3 Janus kinase (JAK) inhibitors are the newest treatment options being explored for topical and systemic treatment of vitiligo, with promising results in active and stable NSV lesions^4,5; however, SV rarely is represented in case reports and clinical trials. The topical JAK inhibitor ruxolitinib has been approved for use in NSV,⁵ and a phase 2 trial with oral ritlecitinib only included patients with NSV.⁴ Furthermore, JAK inhibitors have been studied and approved for children aged 12 years or older as well as for adults,^4,5 but younger age groups (4-10 years)—in whom SV most frequently manifests, as in our patient—have been excluded from these studies.¹ We present a novel case of SV of the right hemiface in a child that was successfully treated with NB-UVB phototherapy in association with topical calcineurin inhibitors.

The role of phototherapy for the treatment of vitiligo has been well documented, and it frequently is combined with other therapeutic modalities, such as topical anti-inflammatory drugs or, most recently, laser and micrografting techniques.^6,7 The most frequently used modality is NB-UVB. In the active phase, it performs an immunomodulatory role, while in the stable phase, it stimulates migration and activity of perilesional and hair follicle melanocytes.⁸ Initiating therapy early is advisable, particularly during the first 6 months of progression, as there is a higher probability of response^1,3,8; nevertheless, a good response was achieved despite the 5-year evolution of vitiligo in our patient. This is a safe option for a skin condition that may begin early in life and require long-term treatment.⁸ A main concern would be an increased risk for skin cancer associated with repeated NB-UVB exposure, which has not been verified in a recent analysis.⁹

Segmental vitiligo can considerably impact the patient’s quality of life, affecting social interactions and self-perception, particularly in younger patients with facial involvement; thus, effective and safe therapeutic strategies adapted to the individual and their vitiligo lesions should be discussed. Classical treatment options remain valid and provide good results for some patients; therefore, they should not be disregarded even with the rise of innovative therapies.

To the Editor:

Segmental vitiligo (SV) accounts for a minority of vitiligo cases and most frequently occurs in children.¹ It characteristically manifests unilaterally and affects a single body area with a sharp midline demarcation. In contrast to nonsegmental vitiligo (NSV), SV typically stabilizes early in the disease progression.¹ The pathophysiology of this vitiligo subtype is not well established, but possible autoinflammatory mechanisms associated with somatic mosaicism, neuronal mechanisms, and/or microvascular skin-homing have been proposed.² We present the case of a pediatric patient with segmental vitiligo of the right hemiface treated with a combination of a topical calcineurin inhibitor and narrow-band UVB (NB-UVB) phototherapy.

An otherwise healthy 7-year-old boy presented to the dermatology department for evaluation of depigmented macules and patches affecting the right hemiface (temporal, periorbital, malar, perioral, preauricular, and mandibular regions) and neck associated with homolateral leukotrichia of the scalp and facial hair as well as the eyelashes of 5 years’ duration. The findings were consistent with SV (Figure 1). The patient previously had been diagnosed based on the clinical findings and treated with continuous application of topical calcineurin inhibitors plus oral cyclosporine (3 mg/kg/d) for 1 year, but the response was poor. The condition had a severe impact on the patient’s quality of life and social relationships. Therapeutic options were discussed with the patient’s caregivers, and ultimately NB-UVB phototherapy was started twice weekly with 10% increases in the dose at each treatment. Topical tacrolimus ointment (1 mg/g) also was started, and the cyclosporine was stopped. Evaluation of treatment progress occurred every 3 months, with progressive repigmentation of the patches following a perifollicular pattern. After 6 months of phototherapy, there was notable repigmentation of the affected areas, particularly in the malar, perioral, and perinasal regions (Figure 2) and the therapeutic response improved after 1 year of treatment (Figure 3). No adverse events were noted during the treatment period.

Segmental vitiligo lacks consistently effective treatment options. This subtype of vitiligo is classically resistant to conventional therapeutic options. Surgery may be a more effective and long-lasting treatment option but is not suitable for every patient.^1,3 Janus kinase (JAK) inhibitors are the newest treatment options being explored for topical and systemic treatment of vitiligo, with promising results in active and stable NSV lesions^4,5; however, SV rarely is represented in case reports and clinical trials. The topical JAK inhibitor ruxolitinib has been approved for use in NSV,⁵ and a phase 2 trial with oral ritlecitinib only included patients with NSV.⁴ Furthermore, JAK inhibitors have been studied and approved for children aged 12 years or older as well as for adults,^4,5 but younger age groups (4-10 years)—in whom SV most frequently manifests, as in our patient—have been excluded from these studies.¹ We present a novel case of SV of the right hemiface in a child that was successfully treated with NB-UVB phototherapy in association with topical calcineurin inhibitors.

The role of phototherapy for the treatment of vitiligo has been well documented, and it frequently is combined with other therapeutic modalities, such as topical anti-inflammatory drugs or, most recently, laser and micrografting techniques.^6,7 The most frequently used modality is NB-UVB. In the active phase, it performs an immunomodulatory role, while in the stable phase, it stimulates migration and activity of perilesional and hair follicle melanocytes.⁸ Initiating therapy early is advisable, particularly during the first 6 months of progression, as there is a higher probability of response^1,3,8; nevertheless, a good response was achieved despite the 5-year evolution of vitiligo in our patient. This is a safe option for a skin condition that may begin early in life and require long-term treatment.⁸ A main concern would be an increased risk for skin cancer associated with repeated NB-UVB exposure, which has not been verified in a recent analysis.⁹

Segmental vitiligo can considerably impact the patient’s quality of life, affecting social interactions and self-perception, particularly in younger patients with facial involvement; thus, effective and safe therapeutic strategies adapted to the individual and their vitiligo lesions should be discussed. Classical treatment options remain valid and provide good results for some patients; therefore, they should not be disregarded even with the rise of innovative therapies.

To the Editor:

A 23-year-old man with plaque psoriasis experienced a flare after a 3-month interruption in his secukinumab therapy. The patient’s psoriasis previously was well controlled with secukinumab 300 mg every 4 weeks. Due to social impairment from the current flare, he received a one-time 100-mg dose of sample guselkumab. Secukinumab therapy was resumed 3 weeks later at 300 mg every 4 weeks. Improvement was gradual; 3 weeks after receiving guselkumab, plaques remained on the bilateral dorsal forearms and the lower abdomen. By 2 months posttreatment, there was decreased erythema and reduced scaling with the continued secukinumab therapy (eFigure 1). The patient reported complete clearance of the plaques 4 months after receiving guselkumab but experienced a brief recurrence at month 5. By month 6, his psoriasis returned to its prior baseline of mild disease. In this 6-month period after resuming treatment, the patient reported subjective improvement in itch and quality of life. He reported no infection or other adverse effects from the additional therapy.

Psoriasis is driven by the interleukin (IL)-23–­tyrosine kinase (TYK) 2–IL-17 axis.¹ Guselkumab, an IL-23 inhibitor, and secukinumab, an IL-17A inhibitor, target distinct yet interconnected pathways in the pathogenesis of psoriasis.¹ A key upstream regulator of the IL-17 pathway, IL-23 drives the expansion and survival of T helper 17 cells, which in turn produce IL-17A and IL-17F—cytokines involved in psoriatic inflammation.¹ While monotherapy with either IL-23 or IL-17A inhibition generally is safe and highly effective, it does not always provide adequate disease control. By simultaneously inhibiting IL-23 and IL-17A, a combined approach may offer enhanced disease control compared to monotherapy.

Combined therapy with a single 100-mg dose of guselkumab and secukinumab 300 mg every 4 weeks may be effective for short-term control in patients who experience psoriasis flares. Although guselkumab has a half-life of approximately 15 to 18 days, its effects may extend beyond 4 to 5 half-lives, as improvement was seen in our case for 57 to 180 days. Although we did not test for the development of antidrug antibodies to secukinumab, there is evidence that the incidence of such development is exceedingly low and not correlated with clinical efficacy.² We cannot exclude the possibility that the single dose of guselkumab may have been responsible for the entirety of our patient’s improvement, as up to 46% of patients treated with 12 months of guselkumab continued to experience remission at 6 months after discontinuation.³ Population data suggest a longer duration of activity or disease-modifying potential of guselkumab; however, affected patients had a longer duration of initial treatment before cessation.³

While data on the safety of dual cytokine inhibition in psoriasis are limited, patients in clinical trials for psoriatic arthritis often are treated with a biologic and methotrexate and/or oral corticosteroids; the safety of biologics even with such a combination is excellent.⁴ Combination biologic therapy with ustekinumab and etanercept in refractory psoriasis caused few adverse events.^4,5 Combination tumor necrosis factor α and IL-12/23 inhibition is comparatively more immunosuppressive than combination IL-23 and IL-17 inhibition. Additionally, there may be redundancies in the immune system to the IL-23–TYK-2–IL-17 axis.¹ While inhibition of both IL-17A and IL-17F increases cutaneous candidiasis risk, inhibiting IL-23 or IL-17A alone is associated with less risk for candidal infection.^6,7 This suggests that redundancy via IL-17F derived from non-IL-23–dependent pathways may offer protection during dual inhibition (eFigure 2). Our patient experienced no adverse effects with a single 100-mg dose of guselkumab, suggesting that at least short-term combination therapy may be well tolerated.

The safety profile seen in our case supports forgoing a washout period when switching between biologics, which can delay access to much-needed therapy and induce flares. Our patient had no adverse events, which provides anecdotal evidence supporting initiation of new biologics without delay. It is possible that the risks of overlapping two low-risk biologics may be lower than combining one biologic with a more immunosuppressive oral immunomodulator.

Combining standard-therapy secukinumab with a one-time dose of guselkumab may provide a synergistic effect by targeting different cytokines involved in the pathogenesis of psoriasis. Using 2 monoclonal antibodies with complementary targets may offer a strategy for rapid control of severe psoriasis that is refractory to single biologics.

To the Editor:

A 23-year-old man with plaque psoriasis experienced a flare after a 3-month interruption in his secukinumab therapy. The patient’s psoriasis previously was well controlled with secukinumab 300 mg every 4 weeks. Due to social impairment from the current flare, he received a one-time 100-mg dose of sample guselkumab. Secukinumab therapy was resumed 3 weeks later at 300 mg every 4 weeks. Improvement was gradual; 3 weeks after receiving guselkumab, plaques remained on the bilateral dorsal forearms and the lower abdomen. By 2 months posttreatment, there was decreased erythema and reduced scaling with the continued secukinumab therapy (eFigure 1). The patient reported complete clearance of the plaques 4 months after receiving guselkumab but experienced a brief recurrence at month 5. By month 6, his psoriasis returned to its prior baseline of mild disease. In this 6-month period after resuming treatment, the patient reported subjective improvement in itch and quality of life. He reported no infection or other adverse effects from the additional therapy.

Psoriasis is driven by the interleukin (IL)-23–­tyrosine kinase (TYK) 2–IL-17 axis.¹ Guselkumab, an IL-23 inhibitor, and secukinumab, an IL-17A inhibitor, target distinct yet interconnected pathways in the pathogenesis of psoriasis.¹ A key upstream regulator of the IL-17 pathway, IL-23 drives the expansion and survival of T helper 17 cells, which in turn produce IL-17A and IL-17F—cytokines involved in psoriatic inflammation.¹ While monotherapy with either IL-23 or IL-17A inhibition generally is safe and highly effective, it does not always provide adequate disease control. By simultaneously inhibiting IL-23 and IL-17A, a combined approach may offer enhanced disease control compared to monotherapy.

Combined therapy with a single 100-mg dose of guselkumab and secukinumab 300 mg every 4 weeks may be effective for short-term control in patients who experience psoriasis flares. Although guselkumab has a half-life of approximately 15 to 18 days, its effects may extend beyond 4 to 5 half-lives, as improvement was seen in our case for 57 to 180 days. Although we did not test for the development of antidrug antibodies to secukinumab, there is evidence that the incidence of such development is exceedingly low and not correlated with clinical efficacy.² We cannot exclude the possibility that the single dose of guselkumab may have been responsible for the entirety of our patient’s improvement, as up to 46% of patients treated with 12 months of guselkumab continued to experience remission at 6 months after discontinuation.³ Population data suggest a longer duration of activity or disease-modifying potential of guselkumab; however, affected patients had a longer duration of initial treatment before cessation.³

While data on the safety of dual cytokine inhibition in psoriasis are limited, patients in clinical trials for psoriatic arthritis often are treated with a biologic and methotrexate and/or oral corticosteroids; the safety of biologics even with such a combination is excellent.⁴ Combination biologic therapy with ustekinumab and etanercept in refractory psoriasis caused few adverse events.^4,5 Combination tumor necrosis factor α and IL-12/23 inhibition is comparatively more immunosuppressive than combination IL-23 and IL-17 inhibition. Additionally, there may be redundancies in the immune system to the IL-23–TYK-2–IL-17 axis.¹ While inhibition of both IL-17A and IL-17F increases cutaneous candidiasis risk, inhibiting IL-23 or IL-17A alone is associated with less risk for candidal infection.^6,7 This suggests that redundancy via IL-17F derived from non-IL-23–dependent pathways may offer protection during dual inhibition (eFigure 2). Our patient experienced no adverse effects with a single 100-mg dose of guselkumab, suggesting that at least short-term combination therapy may be well tolerated.

The safety profile seen in our case supports forgoing a washout period when switching between biologics, which can delay access to much-needed therapy and induce flares. Our patient had no adverse events, which provides anecdotal evidence supporting initiation of new biologics without delay. It is possible that the risks of overlapping two low-risk biologics may be lower than combining one biologic with a more immunosuppressive oral immunomodulator.

Combining standard-therapy secukinumab with a one-time dose of guselkumab may provide a synergistic effect by targeting different cytokines involved in the pathogenesis of psoriasis. Using 2 monoclonal antibodies with complementary targets may offer a strategy for rapid control of severe psoriasis that is refractory to single biologics.

To the Editor:

A 23-year-old man with plaque psoriasis experienced a flare after a 3-month interruption in his secukinumab therapy. The patient’s psoriasis previously was well controlled with secukinumab 300 mg every 4 weeks. Due to social impairment from the current flare, he received a one-time 100-mg dose of sample guselkumab. Secukinumab therapy was resumed 3 weeks later at 300 mg every 4 weeks. Improvement was gradual; 3 weeks after receiving guselkumab, plaques remained on the bilateral dorsal forearms and the lower abdomen. By 2 months posttreatment, there was decreased erythema and reduced scaling with the continued secukinumab therapy (eFigure 1). The patient reported complete clearance of the plaques 4 months after receiving guselkumab but experienced a brief recurrence at month 5. By month 6, his psoriasis returned to its prior baseline of mild disease. In this 6-month period after resuming treatment, the patient reported subjective improvement in itch and quality of life. He reported no infection or other adverse effects from the additional therapy.

Psoriasis is driven by the interleukin (IL)-23–­tyrosine kinase (TYK) 2–IL-17 axis.¹ Guselkumab, an IL-23 inhibitor, and secukinumab, an IL-17A inhibitor, target distinct yet interconnected pathways in the pathogenesis of psoriasis.¹ A key upstream regulator of the IL-17 pathway, IL-23 drives the expansion and survival of T helper 17 cells, which in turn produce IL-17A and IL-17F—cytokines involved in psoriatic inflammation.¹ While monotherapy with either IL-23 or IL-17A inhibition generally is safe and highly effective, it does not always provide adequate disease control. By simultaneously inhibiting IL-23 and IL-17A, a combined approach may offer enhanced disease control compared to monotherapy.

Combined therapy with a single 100-mg dose of guselkumab and secukinumab 300 mg every 4 weeks may be effective for short-term control in patients who experience psoriasis flares. Although guselkumab has a half-life of approximately 15 to 18 days, its effects may extend beyond 4 to 5 half-lives, as improvement was seen in our case for 57 to 180 days. Although we did not test for the development of antidrug antibodies to secukinumab, there is evidence that the incidence of such development is exceedingly low and not correlated with clinical efficacy.² We cannot exclude the possibility that the single dose of guselkumab may have been responsible for the entirety of our patient’s improvement, as up to 46% of patients treated with 12 months of guselkumab continued to experience remission at 6 months after discontinuation.³ Population data suggest a longer duration of activity or disease-modifying potential of guselkumab; however, affected patients had a longer duration of initial treatment before cessation.³

While data on the safety of dual cytokine inhibition in psoriasis are limited, patients in clinical trials for psoriatic arthritis often are treated with a biologic and methotrexate and/or oral corticosteroids; the safety of biologics even with such a combination is excellent.⁴ Combination biologic therapy with ustekinumab and etanercept in refractory psoriasis caused few adverse events.^4,5 Combination tumor necrosis factor α and IL-12/23 inhibition is comparatively more immunosuppressive than combination IL-23 and IL-17 inhibition. Additionally, there may be redundancies in the immune system to the IL-23–TYK-2–IL-17 axis.¹ While inhibition of both IL-17A and IL-17F increases cutaneous candidiasis risk, inhibiting IL-23 or IL-17A alone is associated with less risk for candidal infection.^6,7 This suggests that redundancy via IL-17F derived from non-IL-23–dependent pathways may offer protection during dual inhibition (eFigure 2). Our patient experienced no adverse effects with a single 100-mg dose of guselkumab, suggesting that at least short-term combination therapy may be well tolerated.

The safety profile seen in our case supports forgoing a washout period when switching between biologics, which can delay access to much-needed therapy and induce flares. Our patient had no adverse events, which provides anecdotal evidence supporting initiation of new biologics without delay. It is possible that the risks of overlapping two low-risk biologics may be lower than combining one biologic with a more immunosuppressive oral immunomodulator.

Combining standard-therapy secukinumab with a one-time dose of guselkumab may provide a synergistic effect by targeting different cytokines involved in the pathogenesis of psoriasis. Using 2 monoclonal antibodies with complementary targets may offer a strategy for rapid control of severe psoriasis that is refractory to single biologics.

To the Editor:

A 22-year-old man presented to our clinic with a history of longstanding widespread recalcitrant atopic dermatitis (AD) since early childhood. He had been treated by an outside physician with topical steroids and nonsteroidal medications without notable improvement as well as with dupilumab, which was discontinued due to the development of severe head and neck dermatitis. Given the severity of his AD on presentation, we initiated treatment with upadacitinib 15 mg/d, which resulted in partial improvement. The dose was increased to 30 mg/d at 3 months with further clinical improvement.

Ten months after the patient was started on upadacitinib, he presented for a follow-up evaluation and reported a new nontender nodule on the scalp. A punch biopsy revealed a dense dermal and subcutaneous lymphoid infiltrate (Figure 1) composed of many large atypical CD2+/CD5+/CD45+ T cells with partial loss of CD3 expression (Figure 2). The atypical cells demonstrated diffuse CD30+ expression (Figure 3) and a CD4:CD8 ratio of greater than 50:1 (Figures 4 and 5). He was diagnosed with anaplastic large cell lymphoma (ALCL), and the upadacitinib was discontinued. No additional therapies directed toward ALCL were initiated.

Over the next 2 weeks, the patient developed additional nodules on the postauricular skin and trunk that demonstrated similar histopathology and immunophenotype to the original scalp nodule. T-cell receptor gene rearrangement studies demonstrated shared clonal peaks in these subsequent nodules. A concurrent biopsy of an eczematous plaque on the back showed spongiotic dermatitis without evidence of cutaneous T-cell lymphoma; gene rearrangement studies from this site were negative. A positron emission tomography–computed tomography scan showed mildly hypermetabolic cervical, axillary, and inguinal lymph nodes, which were favored to be reactive. Narrow-band UVB phototherapy was initiated for management of the AD, and no additional nodules developed over the subsequent months.

Janus kinase (JAK) inhibitors are immunomodulatory small molecules that interfere with JAK–signal transducer and activator of transcription signaling involving 1 or more isoforms (eg, JAK1, JAK2, JAK3, tyrosine kinase 2) and have been used to treat various inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and AD.¹ Upadacitinib is an oral selective JAK1 inhibitor approved by the US Food and Drug Administration for treatment of moderate to severe AD in adults and children aged 12 years and older.² A search of PubMed using the terms upadacitinib or Rinvoq and anaplastic large cell lymphoma did not identify any cases of cutaneous ALCL arising after treatment with upadacitinib. However, a case of lymphomatoid papulosis after initiation of upadacitinib for the treatment of rheumatoid arthritis in a 74-year-old Japanese woman has been described,³ and the JAK/signal transducer and activator of transcription pathway has been implicated in the development of other CD30+ lymphoproliferative disorders.^4,5

An association between JAK inhibitors and aggressive B-cell lymphomas has been described. In an observational study of 626 patients with myeloproliferative neoplasia by Porpaczy et al,⁶ 4 of 69 (5.8%) patients treated with JAK inhibitors developed an aggressive B-cell lymphoma, whereas only 2 of 557 (0.36%) patients who did not receive JAK-inhibitor therapy developed an aggressive B-cell lymphoma. In contrast, a retrospective analysis of 2583 patients with myeloproliferative neoplasia by Pemmaraju et al⁷ found no significant increase in lymphoma rates in the JAK inhibitor–treated population as compared with the non-JAK inhibitor–treated group; 9 (0.56%) cases of lymphoma occurred in 1617 patients with myelofibrosis, of which 6 had exposure to JAK inhibitor therapy and 3 had no exposure to JAK inhibitor therapy (P=.082) and 5 (0.52%) cases of lymphoma occurred in 966 patients with essential thrombocythemia or polycythemia vera, none of whom had exposure to JAK inhibitor therapy.Finally, some evidence suggests the use of JAK inhibitors may be associated with an elevated risk of malignancies overall. The ORAL Surveillance study found the incidence of all cancers, excluding nonmelanoma skin cancer (NMSC), in patients treated with tofacitinib to be 4.2% (122/2911) compared with 2.9% (42/1451) in patients treated with tumor necrosis factor α inhibitors; it should be noted that the patients in this study were restricted to adults aged 50 years and older who were undergoing treatment for rheumatoid arthritis.⁸ In a safety profile study for upadacitinib, a higher rate of malignancies, excluding NMSC, was found in patients with AD treated with upadacitinib 30 mg/d than in patients treated with 15 mg/d; however, the overall rates of malignancies, excluding NMSC, in patients treated with upadacitinib were comparable to the standard incidence rates of malignancies in the general population derived from Surveillance, Epidemiology, and End Results data.⁹

In summary, we present a case of cutaneous ALCL arising after treatment with upadacitinib for AD. While some literature suggests AD may independently predispose patients to the development of CD30+ lymphoproliferative disorders, the onset of our patient’s cutaneous ALCL 10 months after initiation of upadacitinib is suggestive of an association between his lymphoproliferative disorder and JAK inhibition. Further studies are needed to better characterize the risk of lymphoproliferative disorders and other malignancies in patients treated with JAK inhibitors.

To the Editor:

A 22-year-old man presented to our clinic with a history of longstanding widespread recalcitrant atopic dermatitis (AD) since early childhood. He had been treated by an outside physician with topical steroids and nonsteroidal medications without notable improvement as well as with dupilumab, which was discontinued due to the development of severe head and neck dermatitis. Given the severity of his AD on presentation, we initiated treatment with upadacitinib 15 mg/d, which resulted in partial improvement. The dose was increased to 30 mg/d at 3 months with further clinical improvement.

Ten months after the patient was started on upadacitinib, he presented for a follow-up evaluation and reported a new nontender nodule on the scalp. A punch biopsy revealed a dense dermal and subcutaneous lymphoid infiltrate (Figure 1) composed of many large atypical CD2+/CD5+/CD45+ T cells with partial loss of CD3 expression (Figure 2). The atypical cells demonstrated diffuse CD30+ expression (Figure 3) and a CD4:CD8 ratio of greater than 50:1 (Figures 4 and 5). He was diagnosed with anaplastic large cell lymphoma (ALCL), and the upadacitinib was discontinued. No additional therapies directed toward ALCL were initiated.

Over the next 2 weeks, the patient developed additional nodules on the postauricular skin and trunk that demonstrated similar histopathology and immunophenotype to the original scalp nodule. T-cell receptor gene rearrangement studies demonstrated shared clonal peaks in these subsequent nodules. A concurrent biopsy of an eczematous plaque on the back showed spongiotic dermatitis without evidence of cutaneous T-cell lymphoma; gene rearrangement studies from this site were negative. A positron emission tomography–computed tomography scan showed mildly hypermetabolic cervical, axillary, and inguinal lymph nodes, which were favored to be reactive. Narrow-band UVB phototherapy was initiated for management of the AD, and no additional nodules developed over the subsequent months.

Janus kinase (JAK) inhibitors are immunomodulatory small molecules that interfere with JAK–signal transducer and activator of transcription signaling involving 1 or more isoforms (eg, JAK1, JAK2, JAK3, tyrosine kinase 2) and have been used to treat various inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and AD.¹ Upadacitinib is an oral selective JAK1 inhibitor approved by the US Food and Drug Administration for treatment of moderate to severe AD in adults and children aged 12 years and older.² A search of PubMed using the terms upadacitinib or Rinvoq and anaplastic large cell lymphoma did not identify any cases of cutaneous ALCL arising after treatment with upadacitinib. However, a case of lymphomatoid papulosis after initiation of upadacitinib for the treatment of rheumatoid arthritis in a 74-year-old Japanese woman has been described,³ and the JAK/signal transducer and activator of transcription pathway has been implicated in the development of other CD30+ lymphoproliferative disorders.^4,5

An association between JAK inhibitors and aggressive B-cell lymphomas has been described. In an observational study of 626 patients with myeloproliferative neoplasia by Porpaczy et al,⁶ 4 of 69 (5.8%) patients treated with JAK inhibitors developed an aggressive B-cell lymphoma, whereas only 2 of 557 (0.36%) patients who did not receive JAK-inhibitor therapy developed an aggressive B-cell lymphoma. In contrast, a retrospective analysis of 2583 patients with myeloproliferative neoplasia by Pemmaraju et al⁷ found no significant increase in lymphoma rates in the JAK inhibitor–treated population as compared with the non-JAK inhibitor–treated group; 9 (0.56%) cases of lymphoma occurred in 1617 patients with myelofibrosis, of which 6 had exposure to JAK inhibitor therapy and 3 had no exposure to JAK inhibitor therapy (P=.082) and 5 (0.52%) cases of lymphoma occurred in 966 patients with essential thrombocythemia or polycythemia vera, none of whom had exposure to JAK inhibitor therapy.Finally, some evidence suggests the use of JAK inhibitors may be associated with an elevated risk of malignancies overall. The ORAL Surveillance study found the incidence of all cancers, excluding nonmelanoma skin cancer (NMSC), in patients treated with tofacitinib to be 4.2% (122/2911) compared with 2.9% (42/1451) in patients treated with tumor necrosis factor α inhibitors; it should be noted that the patients in this study were restricted to adults aged 50 years and older who were undergoing treatment for rheumatoid arthritis.⁸ In a safety profile study for upadacitinib, a higher rate of malignancies, excluding NMSC, was found in patients with AD treated with upadacitinib 30 mg/d than in patients treated with 15 mg/d; however, the overall rates of malignancies, excluding NMSC, in patients treated with upadacitinib were comparable to the standard incidence rates of malignancies in the general population derived from Surveillance, Epidemiology, and End Results data.⁹

In summary, we present a case of cutaneous ALCL arising after treatment with upadacitinib for AD. While some literature suggests AD may independently predispose patients to the development of CD30+ lymphoproliferative disorders, the onset of our patient’s cutaneous ALCL 10 months after initiation of upadacitinib is suggestive of an association between his lymphoproliferative disorder and JAK inhibition. Further studies are needed to better characterize the risk of lymphoproliferative disorders and other malignancies in patients treated with JAK inhibitors.

To the Editor:

A 22-year-old man presented to our clinic with a history of longstanding widespread recalcitrant atopic dermatitis (AD) since early childhood. He had been treated by an outside physician with topical steroids and nonsteroidal medications without notable improvement as well as with dupilumab, which was discontinued due to the development of severe head and neck dermatitis. Given the severity of his AD on presentation, we initiated treatment with upadacitinib 15 mg/d, which resulted in partial improvement. The dose was increased to 30 mg/d at 3 months with further clinical improvement.

Ten months after the patient was started on upadacitinib, he presented for a follow-up evaluation and reported a new nontender nodule on the scalp. A punch biopsy revealed a dense dermal and subcutaneous lymphoid infiltrate (Figure 1) composed of many large atypical CD2+/CD5+/CD45+ T cells with partial loss of CD3 expression (Figure 2). The atypical cells demonstrated diffuse CD30+ expression (Figure 3) and a CD4:CD8 ratio of greater than 50:1 (Figures 4 and 5). He was diagnosed with anaplastic large cell lymphoma (ALCL), and the upadacitinib was discontinued. No additional therapies directed toward ALCL were initiated.

Over the next 2 weeks, the patient developed additional nodules on the postauricular skin and trunk that demonstrated similar histopathology and immunophenotype to the original scalp nodule. T-cell receptor gene rearrangement studies demonstrated shared clonal peaks in these subsequent nodules. A concurrent biopsy of an eczematous plaque on the back showed spongiotic dermatitis without evidence of cutaneous T-cell lymphoma; gene rearrangement studies from this site were negative. A positron emission tomography–computed tomography scan showed mildly hypermetabolic cervical, axillary, and inguinal lymph nodes, which were favored to be reactive. Narrow-band UVB phototherapy was initiated for management of the AD, and no additional nodules developed over the subsequent months.

Janus kinase (JAK) inhibitors are immunomodulatory small molecules that interfere with JAK–signal transducer and activator of transcription signaling involving 1 or more isoforms (eg, JAK1, JAK2, JAK3, tyrosine kinase 2) and have been used to treat various inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and AD.¹ Upadacitinib is an oral selective JAK1 inhibitor approved by the US Food and Drug Administration for treatment of moderate to severe AD in adults and children aged 12 years and older.² A search of PubMed using the terms upadacitinib or Rinvoq and anaplastic large cell lymphoma did not identify any cases of cutaneous ALCL arising after treatment with upadacitinib. However, a case of lymphomatoid papulosis after initiation of upadacitinib for the treatment of rheumatoid arthritis in a 74-year-old Japanese woman has been described,³ and the JAK/signal transducer and activator of transcription pathway has been implicated in the development of other CD30+ lymphoproliferative disorders.^4,5

An association between JAK inhibitors and aggressive B-cell lymphomas has been described. In an observational study of 626 patients with myeloproliferative neoplasia by Porpaczy et al,⁶ 4 of 69 (5.8%) patients treated with JAK inhibitors developed an aggressive B-cell lymphoma, whereas only 2 of 557 (0.36%) patients who did not receive JAK-inhibitor therapy developed an aggressive B-cell lymphoma. In contrast, a retrospective analysis of 2583 patients with myeloproliferative neoplasia by Pemmaraju et al⁷ found no significant increase in lymphoma rates in the JAK inhibitor–treated population as compared with the non-JAK inhibitor–treated group; 9 (0.56%) cases of lymphoma occurred in 1617 patients with myelofibrosis, of which 6 had exposure to JAK inhibitor therapy and 3 had no exposure to JAK inhibitor therapy (P=.082) and 5 (0.52%) cases of lymphoma occurred in 966 patients with essential thrombocythemia or polycythemia vera, none of whom had exposure to JAK inhibitor therapy.Finally, some evidence suggests the use of JAK inhibitors may be associated with an elevated risk of malignancies overall. The ORAL Surveillance study found the incidence of all cancers, excluding nonmelanoma skin cancer (NMSC), in patients treated with tofacitinib to be 4.2% (122/2911) compared with 2.9% (42/1451) in patients treated with tumor necrosis factor α inhibitors; it should be noted that the patients in this study were restricted to adults aged 50 years and older who were undergoing treatment for rheumatoid arthritis.⁸ In a safety profile study for upadacitinib, a higher rate of malignancies, excluding NMSC, was found in patients with AD treated with upadacitinib 30 mg/d than in patients treated with 15 mg/d; however, the overall rates of malignancies, excluding NMSC, in patients treated with upadacitinib were comparable to the standard incidence rates of malignancies in the general population derived from Surveillance, Epidemiology, and End Results data.⁹

In summary, we present a case of cutaneous ALCL arising after treatment with upadacitinib for AD. While some literature suggests AD may independently predispose patients to the development of CD30+ lymphoproliferative disorders, the onset of our patient’s cutaneous ALCL 10 months after initiation of upadacitinib is suggestive of an association between his lymphoproliferative disorder and JAK inhibition. Further studies are needed to better characterize the risk of lymphoproliferative disorders and other malignancies in patients treated with JAK inhibitors.

To the Editor:

Primary cutaneous B-cell lymphomas (pcBCLs) can clinically mimic basal cell carcinomas (BCCs); however, histopathologic examination typically demonstrates features of lymphoma without evidence of an epithelial tumor. We present the case of a patient who demonstrated histologic features of both pcBCL and BCC in the same lesion, which was discovered during Mohs micrographic surgery.

An 84-year-old man presented for Mohs surgery for a biopsy-proven nodular and infiltrative BCC on the right superior helix of the ear of 1 year’s duration. Physical examination of the ear revealed a 1.0×1.3–cm ulcerated indurated plaque with rolled borders and a central hyperkeratotic crust (Figure 1). Frozen sections from the first Mohs stage demonstrated residual superficial, infiltrative, and basosquamous BCC (Figure 2). In addition, there was a brisk inflammatory infiltrate throughout the deep margins. The second stage showed no residual BCC, but there still was a brisk atypical lymphocytic infiltrate, with some areas showing lymphocytes in a linear cordlike distribution (Figure 3). Permanent sections demonstrated infiltration of small to medium lymphoid cells. Immunohistochemistry stains were positive for CD20 and BCL2 and negative for CD5, CD10, BCL6, and CD43; a low Ki-67 proliferation fraction also was observed. B-cell clonality studies and polymerase chain reaction demonstrated rearrangements of the IgH and IgK genes, consistent with primary cutaneous marginal zone lymphoma (pcMZL). Positron emission tomography showed no spread of malignancy; therefore, medical oncology recommended observation and close monitoring.

Primary cutaneous B-cell lymphoma accounts for approximately 25% of all cutaneous lymphomas.¹ Three main cutaneous subtypes exist: pcMZL; primary cutaneous follicular center lymphoma; and primary cutaneous diffuse large B-cell lymphoma, leg type. The second most common type of cutaneous lymphoma, pcMZL, accounts for 25% of cases of pcBCL.¹ Primary cutaneous follicular center lymphoma makes up 60% of cutaneous lymphomas, and the remainder are primary cutaneous diffuse large B-cell lymphoma, leg type. All share a notable male predominance and onset most commonly in the sixth through eighth decades of life, although they also can occur in younger patients.¹

Histologically, pcMZL has 2 distinct subtypes: one resembling mucosal-associated lymphoid tissue lymphomas and a more clinically aggressive subtype with heavy chain class switching, although intermediate forms also exist. Both are characterized by diffuse and/or nodular infiltrates in the subcutis and dermis with sparing of the epidermis. Often, these infiltrates are more prominent in the deeper sections examined, and occasionally they may be accompanied by germinal center follicles. Immunohistochemical stains are key in determining the pcBCL subtype. Primary cutaneous marginal zone lymphoma will most commonly show a BCL2+, BCL6–, CD20+, and CD10– immunophenotype, as in our case. If a majority of cells have undergone plasmacytoid differentiation, loss of CD20 can occur, but retention of other B-cell markers, such as CD79a and CD19, will be seen. Proliferation fraction via Ki-67 commonly is low, reflecting the indolence of this subtype of lymphoma.¹

Monoclonal rearrangement of immunoglobulins also can occur, with IgH rearrangements detected in 60% to 80% of cases of pcMZL. Translocations are not a reliable method of diagnosis for pcMZL but can be present in a variable manner, with t(14;18), t(3;14), and t(11;18) reported in a subset of cases.² Leukemic infiltrates encountered on frozen sections should prompt the Mohs surgeon to consider the possibility of a concomitant leukemia or lymphoma. In one study, 36% (20/55) of patients with chronic lymphocytic leukemia (CLL) were found to have predominantly leukemic B-cell infiltrates on frozen sections.³ Numerous reports also exist of asymptomatic patients being diagnosed with CLL due to leukemic infiltrates identified during Mohs surgery.^4,5 Patients with systemic hematologic malignancies, including CLL and non-Hodgkin lymphoma, also are known to be at an increased risk for skin cancers, including keratinocyte cancers, melanoma, and Merkel cell carcinoma. This can be attributed partially to immunosuppression, a well-known risk factor for development of cutaneous malignancies.⁵ Padgett et al⁵ speculated that local immune suppression due to underlying pcBCL and reaction of lymphocytes to tumor antigens could have played a role in the development of BCC at this site. If a leukemic infiltrate is demonstrated, the surgeon should consider sending tissue for permanent section and immunostaining. This can be helpful to determine if it is a reactive or neoplastic process and aid in characterizing the leukemic infiltrate if it is suspected to be neoplastic in nature.

There are numerous reports of pcBCL imitating the cutaneous findings of BCC clinically, but this is quite uncommon on histopathology. As in our case, findings of sheets of dense, monomorphic lymphocytes; inability to clear inflammation on deeper Mohs sections; presence of primordial follicles; and atypical cytology, including predominance of blastic forms, plasmacytoid cells, or cleaved lymphocytes, should give the clinician pause to consider further evaluation through permanent sections as well as genetic and immunoglobulin studies by a dermatopathologist. This case highlights the importance of further evaluation when an atypical finding is encountered during Mohs surgery.

To the Editor:

Primary cutaneous B-cell lymphomas (pcBCLs) can clinically mimic basal cell carcinomas (BCCs); however, histopathologic examination typically demonstrates features of lymphoma without evidence of an epithelial tumor. We present the case of a patient who demonstrated histologic features of both pcBCL and BCC in the same lesion, which was discovered during Mohs micrographic surgery.

An 84-year-old man presented for Mohs surgery for a biopsy-proven nodular and infiltrative BCC on the right superior helix of the ear of 1 year’s duration. Physical examination of the ear revealed a 1.0×1.3–cm ulcerated indurated plaque with rolled borders and a central hyperkeratotic crust (Figure 1). Frozen sections from the first Mohs stage demonstrated residual superficial, infiltrative, and basosquamous BCC (Figure 2). In addition, there was a brisk inflammatory infiltrate throughout the deep margins. The second stage showed no residual BCC, but there still was a brisk atypical lymphocytic infiltrate, with some areas showing lymphocytes in a linear cordlike distribution (Figure 3). Permanent sections demonstrated infiltration of small to medium lymphoid cells. Immunohistochemistry stains were positive for CD20 and BCL2 and negative for CD5, CD10, BCL6, and CD43; a low Ki-67 proliferation fraction also was observed. B-cell clonality studies and polymerase chain reaction demonstrated rearrangements of the IgH and IgK genes, consistent with primary cutaneous marginal zone lymphoma (pcMZL). Positron emission tomography showed no spread of malignancy; therefore, medical oncology recommended observation and close monitoring.

Primary cutaneous B-cell lymphoma accounts for approximately 25% of all cutaneous lymphomas.¹ Three main cutaneous subtypes exist: pcMZL; primary cutaneous follicular center lymphoma; and primary cutaneous diffuse large B-cell lymphoma, leg type. The second most common type of cutaneous lymphoma, pcMZL, accounts for 25% of cases of pcBCL.¹ Primary cutaneous follicular center lymphoma makes up 60% of cutaneous lymphomas, and the remainder are primary cutaneous diffuse large B-cell lymphoma, leg type. All share a notable male predominance and onset most commonly in the sixth through eighth decades of life, although they also can occur in younger patients.¹

Histologically, pcMZL has 2 distinct subtypes: one resembling mucosal-associated lymphoid tissue lymphomas and a more clinically aggressive subtype with heavy chain class switching, although intermediate forms also exist. Both are characterized by diffuse and/or nodular infiltrates in the subcutis and dermis with sparing of the epidermis. Often, these infiltrates are more prominent in the deeper sections examined, and occasionally they may be accompanied by germinal center follicles. Immunohistochemical stains are key in determining the pcBCL subtype. Primary cutaneous marginal zone lymphoma will most commonly show a BCL2+, BCL6–, CD20+, and CD10– immunophenotype, as in our case. If a majority of cells have undergone plasmacytoid differentiation, loss of CD20 can occur, but retention of other B-cell markers, such as CD79a and CD19, will be seen. Proliferation fraction via Ki-67 commonly is low, reflecting the indolence of this subtype of lymphoma.¹

Monoclonal rearrangement of immunoglobulins also can occur, with IgH rearrangements detected in 60% to 80% of cases of pcMZL. Translocations are not a reliable method of diagnosis for pcMZL but can be present in a variable manner, with t(14;18), t(3;14), and t(11;18) reported in a subset of cases.² Leukemic infiltrates encountered on frozen sections should prompt the Mohs surgeon to consider the possibility of a concomitant leukemia or lymphoma. In one study, 36% (20/55) of patients with chronic lymphocytic leukemia (CLL) were found to have predominantly leukemic B-cell infiltrates on frozen sections.³ Numerous reports also exist of asymptomatic patients being diagnosed with CLL due to leukemic infiltrates identified during Mohs surgery.^4,5 Patients with systemic hematologic malignancies, including CLL and non-Hodgkin lymphoma, also are known to be at an increased risk for skin cancers, including keratinocyte cancers, melanoma, and Merkel cell carcinoma. This can be attributed partially to immunosuppression, a well-known risk factor for development of cutaneous malignancies.⁵ Padgett et al⁵ speculated that local immune suppression due to underlying pcBCL and reaction of lymphocytes to tumor antigens could have played a role in the development of BCC at this site. If a leukemic infiltrate is demonstrated, the surgeon should consider sending tissue for permanent section and immunostaining. This can be helpful to determine if it is a reactive or neoplastic process and aid in characterizing the leukemic infiltrate if it is suspected to be neoplastic in nature.

There are numerous reports of pcBCL imitating the cutaneous findings of BCC clinically, but this is quite uncommon on histopathology. As in our case, findings of sheets of dense, monomorphic lymphocytes; inability to clear inflammation on deeper Mohs sections; presence of primordial follicles; and atypical cytology, including predominance of blastic forms, plasmacytoid cells, or cleaved lymphocytes, should give the clinician pause to consider further evaluation through permanent sections as well as genetic and immunoglobulin studies by a dermatopathologist. This case highlights the importance of further evaluation when an atypical finding is encountered during Mohs surgery.

To the Editor:

Primary cutaneous B-cell lymphomas (pcBCLs) can clinically mimic basal cell carcinomas (BCCs); however, histopathologic examination typically demonstrates features of lymphoma without evidence of an epithelial tumor. We present the case of a patient who demonstrated histologic features of both pcBCL and BCC in the same lesion, which was discovered during Mohs micrographic surgery.

An 84-year-old man presented for Mohs surgery for a biopsy-proven nodular and infiltrative BCC on the right superior helix of the ear of 1 year’s duration. Physical examination of the ear revealed a 1.0×1.3–cm ulcerated indurated plaque with rolled borders and a central hyperkeratotic crust (Figure 1). Frozen sections from the first Mohs stage demonstrated residual superficial, infiltrative, and basosquamous BCC (Figure 2). In addition, there was a brisk inflammatory infiltrate throughout the deep margins. The second stage showed no residual BCC, but there still was a brisk atypical lymphocytic infiltrate, with some areas showing lymphocytes in a linear cordlike distribution (Figure 3). Permanent sections demonstrated infiltration of small to medium lymphoid cells. Immunohistochemistry stains were positive for CD20 and BCL2 and negative for CD5, CD10, BCL6, and CD43; a low Ki-67 proliferation fraction also was observed. B-cell clonality studies and polymerase chain reaction demonstrated rearrangements of the IgH and IgK genes, consistent with primary cutaneous marginal zone lymphoma (pcMZL). Positron emission tomography showed no spread of malignancy; therefore, medical oncology recommended observation and close monitoring.

Primary cutaneous B-cell lymphoma accounts for approximately 25% of all cutaneous lymphomas.¹ Three main cutaneous subtypes exist: pcMZL; primary cutaneous follicular center lymphoma; and primary cutaneous diffuse large B-cell lymphoma, leg type. The second most common type of cutaneous lymphoma, pcMZL, accounts for 25% of cases of pcBCL.¹ Primary cutaneous follicular center lymphoma makes up 60% of cutaneous lymphomas, and the remainder are primary cutaneous diffuse large B-cell lymphoma, leg type. All share a notable male predominance and onset most commonly in the sixth through eighth decades of life, although they also can occur in younger patients.¹

Histologically, pcMZL has 2 distinct subtypes: one resembling mucosal-associated lymphoid tissue lymphomas and a more clinically aggressive subtype with heavy chain class switching, although intermediate forms also exist. Both are characterized by diffuse and/or nodular infiltrates in the subcutis and dermis with sparing of the epidermis. Often, these infiltrates are more prominent in the deeper sections examined, and occasionally they may be accompanied by germinal center follicles. Immunohistochemical stains are key in determining the pcBCL subtype. Primary cutaneous marginal zone lymphoma will most commonly show a BCL2+, BCL6–, CD20+, and CD10– immunophenotype, as in our case. If a majority of cells have undergone plasmacytoid differentiation, loss of CD20 can occur, but retention of other B-cell markers, such as CD79a and CD19, will be seen. Proliferation fraction via Ki-67 commonly is low, reflecting the indolence of this subtype of lymphoma.¹

Monoclonal rearrangement of immunoglobulins also can occur, with IgH rearrangements detected in 60% to 80% of cases of pcMZL. Translocations are not a reliable method of diagnosis for pcMZL but can be present in a variable manner, with t(14;18), t(3;14), and t(11;18) reported in a subset of cases.² Leukemic infiltrates encountered on frozen sections should prompt the Mohs surgeon to consider the possibility of a concomitant leukemia or lymphoma. In one study, 36% (20/55) of patients with chronic lymphocytic leukemia (CLL) were found to have predominantly leukemic B-cell infiltrates on frozen sections.³ Numerous reports also exist of asymptomatic patients being diagnosed with CLL due to leukemic infiltrates identified during Mohs surgery.^4,5 Patients with systemic hematologic malignancies, including CLL and non-Hodgkin lymphoma, also are known to be at an increased risk for skin cancers, including keratinocyte cancers, melanoma, and Merkel cell carcinoma. This can be attributed partially to immunosuppression, a well-known risk factor for development of cutaneous malignancies.⁵ Padgett et al⁵ speculated that local immune suppression due to underlying pcBCL and reaction of lymphocytes to tumor antigens could have played a role in the development of BCC at this site. If a leukemic infiltrate is demonstrated, the surgeon should consider sending tissue for permanent section and immunostaining. This can be helpful to determine if it is a reactive or neoplastic process and aid in characterizing the leukemic infiltrate if it is suspected to be neoplastic in nature.

There are numerous reports of pcBCL imitating the cutaneous findings of BCC clinically, but this is quite uncommon on histopathology. As in our case, findings of sheets of dense, monomorphic lymphocytes; inability to clear inflammation on deeper Mohs sections; presence of primordial follicles; and atypical cytology, including predominance of blastic forms, plasmacytoid cells, or cleaved lymphocytes, should give the clinician pause to consider further evaluation through permanent sections as well as genetic and immunoglobulin studies by a dermatopathologist. This case highlights the importance of further evaluation when an atypical finding is encountered during Mohs surgery.

To the Editor:

In dermatology, rupioid describes ­dirty-appearing scale. The term is derived from the Greek word rhupos, which translates to “dirty” or “filthy.” This type of scale also is called ostraceous, owing to its resemblance to an oyster shell. Histopathologically, rupioid or ostraceous scale corresponds to epidermal hyperplasia and hyperkeratosis. Therefore, the presence of rupioid scale is believed to reflect an exuberant inflammatory response. Several dermatologic conditions have been associated with rupioid scale, including psoriasis, secondary syphilis, reactive arthritis, histoplasmosis, and Norwegian scabies.^1-4 Peripheral eosinophilia has been reported in eczematous dermatoses such as atopic dermatitis and contact dermatitis,^5,6 but our review of the literature did not find it described in the context of id reactions. We report the case of a patient who developed a rupioid id reaction with peripheral eosinophilia.

An otherwise healthy 40-year-old woman presented with a generalized pruritic eruption of 1 month’s duration. Prior to onset, she was bitten by a bug on the left arm and covered the site with a bandage. She subsequently noticed an erythematous papulopustular rash corresponding to the shape of the bandage adhesive. Shortly thereafter, a generalized eruption developed, prompting the patient to present for evaluation 1 month later. A review of systems was negative for fevers, chills, headaches, vision changes, and joint symptoms. She denied having a history of atopy.

Physical examination revealed numerous pink papules and plaques with rupioid scale scattered over the trunk and extremities (Figure). The palms, soles, and mucous membranes were spared. Laboratory studies revealed peripheral eosinophilia (9% eosinophils [reference range, 1%-6%] and an absolute eosinophil count of 600/µL [reference range, 0-400/µL]). A 3-mm punch biopsy of a representative lesion revealed a superficial perivascular infiltrate of lymphocytes, histiocytes, and eosinophils along with epidermal hyperplasia, spongiosis, and mounds of parakeratosis. Clinicopathologic correlation led to the diagnosis of a rupioid id reaction secondary to an arthropod assault and/or a reaction to the bandage adhesive.

Treatment with topical corticosteroids was avoided at the patient’s request. Instead, a ceramide-based emollient and oral antihistamines (fexofenadine 180 mg in the morning and cetirizine 10 mg in the evening) were recommended and resulted in resolution of the eruption with postinflammatory hyperpigmentation at 2-week follow-up. The patient was advised to avoid further exposure to bandage adhesives.

An id reaction, or autoeczematization, is a cutaneous immunologic response to antigen(s) released from an initial, often distant site of inflammation.^7,8 Clinically, it typically manifests as a pruritic, symmetrically distributed papulovesicular eruption. Although the pathogenesis of id reactions is uncertain, overactivation of T lymphocytes responding to the initial inflammatory insult has been implicated.⁷ A variety of noninfectious (eg, stasis dermatitis, contact dermatitis) and infectious dermatoses (eg, fungal, bacterial, viral, parasitic) may trigger id reactions.^7,9-13 In this case, we believe an arthropod assault and/or reaction to the bandage adhesive was the primary insult, and the id reaction that ensued was so exuberant that it resulted not only in rupioid scale but also in peripheral eosinophilia—similar to how more severe forms of atopic dermatitis have been associated with peripheral eosinophilia.⁵ As such presentations of id reactions not have been widely described in the literature, this report expands our understanding of this condition to include rupioid scale and peripheral eosinophilia.

To the Editor:

In dermatology, rupioid describes ­dirty-appearing scale. The term is derived from the Greek word rhupos, which translates to “dirty” or “filthy.” This type of scale also is called ostraceous, owing to its resemblance to an oyster shell. Histopathologically, rupioid or ostraceous scale corresponds to epidermal hyperplasia and hyperkeratosis. Therefore, the presence of rupioid scale is believed to reflect an exuberant inflammatory response. Several dermatologic conditions have been associated with rupioid scale, including psoriasis, secondary syphilis, reactive arthritis, histoplasmosis, and Norwegian scabies.^1-4 Peripheral eosinophilia has been reported in eczematous dermatoses such as atopic dermatitis and contact dermatitis,^5,6 but our review of the literature did not find it described in the context of id reactions. We report the case of a patient who developed a rupioid id reaction with peripheral eosinophilia.

An otherwise healthy 40-year-old woman presented with a generalized pruritic eruption of 1 month’s duration. Prior to onset, she was bitten by a bug on the left arm and covered the site with a bandage. She subsequently noticed an erythematous papulopustular rash corresponding to the shape of the bandage adhesive. Shortly thereafter, a generalized eruption developed, prompting the patient to present for evaluation 1 month later. A review of systems was negative for fevers, chills, headaches, vision changes, and joint symptoms. She denied having a history of atopy.

Physical examination revealed numerous pink papules and plaques with rupioid scale scattered over the trunk and extremities (Figure). The palms, soles, and mucous membranes were spared. Laboratory studies revealed peripheral eosinophilia (9% eosinophils [reference range, 1%-6%] and an absolute eosinophil count of 600/µL [reference range, 0-400/µL]). A 3-mm punch biopsy of a representative lesion revealed a superficial perivascular infiltrate of lymphocytes, histiocytes, and eosinophils along with epidermal hyperplasia, spongiosis, and mounds of parakeratosis. Clinicopathologic correlation led to the diagnosis of a rupioid id reaction secondary to an arthropod assault and/or a reaction to the bandage adhesive.

Treatment with topical corticosteroids was avoided at the patient’s request. Instead, a ceramide-based emollient and oral antihistamines (fexofenadine 180 mg in the morning and cetirizine 10 mg in the evening) were recommended and resulted in resolution of the eruption with postinflammatory hyperpigmentation at 2-week follow-up. The patient was advised to avoid further exposure to bandage adhesives.

An id reaction, or autoeczematization, is a cutaneous immunologic response to antigen(s) released from an initial, often distant site of inflammation.^7,8 Clinically, it typically manifests as a pruritic, symmetrically distributed papulovesicular eruption. Although the pathogenesis of id reactions is uncertain, overactivation of T lymphocytes responding to the initial inflammatory insult has been implicated.⁷ A variety of noninfectious (eg, stasis dermatitis, contact dermatitis) and infectious dermatoses (eg, fungal, bacterial, viral, parasitic) may trigger id reactions.^7,9-13 In this case, we believe an arthropod assault and/or reaction to the bandage adhesive was the primary insult, and the id reaction that ensued was so exuberant that it resulted not only in rupioid scale but also in peripheral eosinophilia—similar to how more severe forms of atopic dermatitis have been associated with peripheral eosinophilia.⁵ As such presentations of id reactions not have been widely described in the literature, this report expands our understanding of this condition to include rupioid scale and peripheral eosinophilia.

To the Editor:

In dermatology, rupioid describes ­dirty-appearing scale. The term is derived from the Greek word rhupos, which translates to “dirty” or “filthy.” This type of scale also is called ostraceous, owing to its resemblance to an oyster shell. Histopathologically, rupioid or ostraceous scale corresponds to epidermal hyperplasia and hyperkeratosis. Therefore, the presence of rupioid scale is believed to reflect an exuberant inflammatory response. Several dermatologic conditions have been associated with rupioid scale, including psoriasis, secondary syphilis, reactive arthritis, histoplasmosis, and Norwegian scabies.^1-4 Peripheral eosinophilia has been reported in eczematous dermatoses such as atopic dermatitis and contact dermatitis,^5,6 but our review of the literature did not find it described in the context of id reactions. We report the case of a patient who developed a rupioid id reaction with peripheral eosinophilia.

An otherwise healthy 40-year-old woman presented with a generalized pruritic eruption of 1 month’s duration. Prior to onset, she was bitten by a bug on the left arm and covered the site with a bandage. She subsequently noticed an erythematous papulopustular rash corresponding to the shape of the bandage adhesive. Shortly thereafter, a generalized eruption developed, prompting the patient to present for evaluation 1 month later. A review of systems was negative for fevers, chills, headaches, vision changes, and joint symptoms. She denied having a history of atopy.

Physical examination revealed numerous pink papules and plaques with rupioid scale scattered over the trunk and extremities (Figure). The palms, soles, and mucous membranes were spared. Laboratory studies revealed peripheral eosinophilia (9% eosinophils [reference range, 1%-6%] and an absolute eosinophil count of 600/µL [reference range, 0-400/µL]). A 3-mm punch biopsy of a representative lesion revealed a superficial perivascular infiltrate of lymphocytes, histiocytes, and eosinophils along with epidermal hyperplasia, spongiosis, and mounds of parakeratosis. Clinicopathologic correlation led to the diagnosis of a rupioid id reaction secondary to an arthropod assault and/or a reaction to the bandage adhesive.

Treatment with topical corticosteroids was avoided at the patient’s request. Instead, a ceramide-based emollient and oral antihistamines (fexofenadine 180 mg in the morning and cetirizine 10 mg in the evening) were recommended and resulted in resolution of the eruption with postinflammatory hyperpigmentation at 2-week follow-up. The patient was advised to avoid further exposure to bandage adhesives.

An id reaction, or autoeczematization, is a cutaneous immunologic response to antigen(s) released from an initial, often distant site of inflammation.^7,8 Clinically, it typically manifests as a pruritic, symmetrically distributed papulovesicular eruption. Although the pathogenesis of id reactions is uncertain, overactivation of T lymphocytes responding to the initial inflammatory insult has been implicated.⁷ A variety of noninfectious (eg, stasis dermatitis, contact dermatitis) and infectious dermatoses (eg, fungal, bacterial, viral, parasitic) may trigger id reactions.^7,9-13 In this case, we believe an arthropod assault and/or reaction to the bandage adhesive was the primary insult, and the id reaction that ensued was so exuberant that it resulted not only in rupioid scale but also in peripheral eosinophilia—similar to how more severe forms of atopic dermatitis have been associated with peripheral eosinophilia.⁵ As such presentations of id reactions not have been widely described in the literature, this report expands our understanding of this condition to include rupioid scale and peripheral eosinophilia.

To the Editor:

Millipedes do not have nearly as many feet as their name would suggest; most have fewer than 100.¹ They are not actually insects; they are a wormlike arthropod in the Diplopoda class. Generally these harmless animals can be a welcome resident in gardens because they break down decaying plant material and rejuvenate the soil.¹ However, they are less welcome in the home or underfoot because of what happens when these invertebrates are threatened or crushed.²

Millipedes, which typically have at least 30 pairs of legs, have 2 defense mechanisms: (1) body coiling to withstand external pressure, and (2) secretion of fluids with insecticidal properties from specialized glands distributed along their body.³ These secretions, which are used by the millipede to defend against predators, contain organic compounds including benzoquinone. When these secretions come into contact with skin, pigmentary changes resembling a burn or necrosis and irritation to the skin (pain, burning, itching) occur.^4,5

Millipedes typically are found in tropical and temperate regions worldwide, such as the Amazon rainforest, Southeast Asia, tropical areas of Africa, forests, grasslands, and gardens in North America and Europe.⁶ They also are found in every US state as well as Puerto Rico.¹ Millipedes are nocturnal, favor dark places, and can make their way into residential areas, including homes, basements, gardens, and yards.^2,6 Although millipede burns commonly are reported in tropical regions, we present a case in China.⁶A 33-year-old woman presented with purplish-red discoloration on all 5 toes on the left foot. The patient recounted that she discovered a millipede in her shoe earlier in the day, removed it, and crushed it with her bare foot. That night, while taking a bath, she noticed that the toes had turned purplish-red (Figure 1). The patient brought the crushed millipede with her to the emergency department where she sought treatment. The dermatologist confirmed that it was a millipede; however, the team was unable to determine the specific species because it had been crushed (Figure 2).

Physical examination of the affected toes showed a clear boundary and iodinelike staining. The patient did not report pain. The stained skin had a normal temperature, pulse, texture, and sensation. Dermoscopy revealed multiple black-brown patches on the toes (Figure 3). The pigmented area gradually faded over a 1-month period. Superficial damage to the toenail revealed evidence of black-brown pigmentation on both the nail and the skin underneath. The diagnosis in the dermoscopy report suggested exogenous pigmentation of the toes. The patient was advised that no treatment was needed and that the condition would resolve on its own. At 1-month follow-up, the patient’s toes had returned to their normal color (Figure 4).

The feet are common sites of millipede burns; other exposed areas, such as the arms, face, and eyes, also are potential sites of involvement.⁵ The cutaneous pigmentary changes seen on our patient’s foot were a result of the millipede’s defense mechanism—secreted toxic chemicals that stained the foot. It is important to note that the pigmentation was not associated with the death of the millipede, as the millipede was still alive upon initial contact with the patient’s foot in her shoe. 

When a patient presents with pigmentary changes, several conditions must be ruled out—notably acute arterial thrombosis. Patients with this condition will describe acute pain and weakness in the area of involvement. Physicians inspecting the area will note coldness and pallor in the affected limb as well as a diminished or absent pulse. In severe cases, the skin may exhibit a purplish-red appearance.⁵ Millipede burns also should be distinguished from bacterial endocarditis and cryoglobulinemia.⁷ All 3 conditions can manifest with redness, swelling, blisters, and purpuralike changes. Positive blood culture is an important diagnostic basis for bacterial endocarditis; in addition, routine blood tests will demonstrate a decrease in red blood cells and hemoglobin, and routine urinalysis may show proteinuria and microscopic hematuria. Patients with cryoglobulinemia will have a positive cryoglobulin assay, increased IgM, and often decreased complement.⁷ It also is worth noting that millipede burns might resemble child abuse in pediatric patients, necessitating further evaluation.⁵ 

It is unusual to see a millipede burn in nontropical regions. Therefore, the identification of our patient’s millipede burn was notable and serves as a reminder to keep this diagnosis in the differential when caring for patients with pigmentary changes. An accurate diagnosis hinges on being alert to a millipede exposure history and recognizing the clinical manifestations. For affected patients, it may be beneficial to recommend they advise friends and relatives to avoid skin contact with millipedes and most importantly to avoid stepping on them with bare feet.

To the Editor:

Millipedes do not have nearly as many feet as their name would suggest; most have fewer than 100.¹ They are not actually insects; they are a wormlike arthropod in the Diplopoda class. Generally these harmless animals can be a welcome resident in gardens because they break down decaying plant material and rejuvenate the soil.¹ However, they are less welcome in the home or underfoot because of what happens when these invertebrates are threatened or crushed.²

Millipedes, which typically have at least 30 pairs of legs, have 2 defense mechanisms: (1) body coiling to withstand external pressure, and (2) secretion of fluids with insecticidal properties from specialized glands distributed along their body.³ These secretions, which are used by the millipede to defend against predators, contain organic compounds including benzoquinone. When these secretions come into contact with skin, pigmentary changes resembling a burn or necrosis and irritation to the skin (pain, burning, itching) occur.^4,5

Millipedes typically are found in tropical and temperate regions worldwide, such as the Amazon rainforest, Southeast Asia, tropical areas of Africa, forests, grasslands, and gardens in North America and Europe.⁶ They also are found in every US state as well as Puerto Rico.¹ Millipedes are nocturnal, favor dark places, and can make their way into residential areas, including homes, basements, gardens, and yards.^2,6 Although millipede burns commonly are reported in tropical regions, we present a case in China.⁶A 33-year-old woman presented with purplish-red discoloration on all 5 toes on the left foot. The patient recounted that she discovered a millipede in her shoe earlier in the day, removed it, and crushed it with her bare foot. That night, while taking a bath, she noticed that the toes had turned purplish-red (Figure 1). The patient brought the crushed millipede with her to the emergency department where she sought treatment. The dermatologist confirmed that it was a millipede; however, the team was unable to determine the specific species because it had been crushed (Figure 2).

Physical examination of the affected toes showed a clear boundary and iodinelike staining. The patient did not report pain. The stained skin had a normal temperature, pulse, texture, and sensation. Dermoscopy revealed multiple black-brown patches on the toes (Figure 3). The pigmented area gradually faded over a 1-month period. Superficial damage to the toenail revealed evidence of black-brown pigmentation on both the nail and the skin underneath. The diagnosis in the dermoscopy report suggested exogenous pigmentation of the toes. The patient was advised that no treatment was needed and that the condition would resolve on its own. At 1-month follow-up, the patient’s toes had returned to their normal color (Figure 4).

The feet are common sites of millipede burns; other exposed areas, such as the arms, face, and eyes, also are potential sites of involvement.⁵ The cutaneous pigmentary changes seen on our patient’s foot were a result of the millipede’s defense mechanism—secreted toxic chemicals that stained the foot. It is important to note that the pigmentation was not associated with the death of the millipede, as the millipede was still alive upon initial contact with the patient’s foot in her shoe. 

When a patient presents with pigmentary changes, several conditions must be ruled out—notably acute arterial thrombosis. Patients with this condition will describe acute pain and weakness in the area of involvement. Physicians inspecting the area will note coldness and pallor in the affected limb as well as a diminished or absent pulse. In severe cases, the skin may exhibit a purplish-red appearance.⁵ Millipede burns also should be distinguished from bacterial endocarditis and cryoglobulinemia.⁷ All 3 conditions can manifest with redness, swelling, blisters, and purpuralike changes. Positive blood culture is an important diagnostic basis for bacterial endocarditis; in addition, routine blood tests will demonstrate a decrease in red blood cells and hemoglobin, and routine urinalysis may show proteinuria and microscopic hematuria. Patients with cryoglobulinemia will have a positive cryoglobulin assay, increased IgM, and often decreased complement.⁷ It also is worth noting that millipede burns might resemble child abuse in pediatric patients, necessitating further evaluation.⁵ 

It is unusual to see a millipede burn in nontropical regions. Therefore, the identification of our patient’s millipede burn was notable and serves as a reminder to keep this diagnosis in the differential when caring for patients with pigmentary changes. An accurate diagnosis hinges on being alert to a millipede exposure history and recognizing the clinical manifestations. For affected patients, it may be beneficial to recommend they advise friends and relatives to avoid skin contact with millipedes and most importantly to avoid stepping on them with bare feet.

To the Editor:

Millipedes do not have nearly as many feet as their name would suggest; most have fewer than 100.¹ They are not actually insects; they are a wormlike arthropod in the Diplopoda class. Generally these harmless animals can be a welcome resident in gardens because they break down decaying plant material and rejuvenate the soil.¹ However, they are less welcome in the home or underfoot because of what happens when these invertebrates are threatened or crushed.²

Millipedes, which typically have at least 30 pairs of legs, have 2 defense mechanisms: (1) body coiling to withstand external pressure, and (2) secretion of fluids with insecticidal properties from specialized glands distributed along their body.³ These secretions, which are used by the millipede to defend against predators, contain organic compounds including benzoquinone. When these secretions come into contact with skin, pigmentary changes resembling a burn or necrosis and irritation to the skin (pain, burning, itching) occur.^4,5

Millipedes typically are found in tropical and temperate regions worldwide, such as the Amazon rainforest, Southeast Asia, tropical areas of Africa, forests, grasslands, and gardens in North America and Europe.⁶ They also are found in every US state as well as Puerto Rico.¹ Millipedes are nocturnal, favor dark places, and can make their way into residential areas, including homes, basements, gardens, and yards.^2,6 Although millipede burns commonly are reported in tropical regions, we present a case in China.⁶A 33-year-old woman presented with purplish-red discoloration on all 5 toes on the left foot. The patient recounted that she discovered a millipede in her shoe earlier in the day, removed it, and crushed it with her bare foot. That night, while taking a bath, she noticed that the toes had turned purplish-red (Figure 1). The patient brought the crushed millipede with her to the emergency department where she sought treatment. The dermatologist confirmed that it was a millipede; however, the team was unable to determine the specific species because it had been crushed (Figure 2).

Physical examination of the affected toes showed a clear boundary and iodinelike staining. The patient did not report pain. The stained skin had a normal temperature, pulse, texture, and sensation. Dermoscopy revealed multiple black-brown patches on the toes (Figure 3). The pigmented area gradually faded over a 1-month period. Superficial damage to the toenail revealed evidence of black-brown pigmentation on both the nail and the skin underneath. The diagnosis in the dermoscopy report suggested exogenous pigmentation of the toes. The patient was advised that no treatment was needed and that the condition would resolve on its own. At 1-month follow-up, the patient’s toes had returned to their normal color (Figure 4).

The feet are common sites of millipede burns; other exposed areas, such as the arms, face, and eyes, also are potential sites of involvement.⁵ The cutaneous pigmentary changes seen on our patient’s foot were a result of the millipede’s defense mechanism—secreted toxic chemicals that stained the foot. It is important to note that the pigmentation was not associated with the death of the millipede, as the millipede was still alive upon initial contact with the patient’s foot in her shoe. 

When a patient presents with pigmentary changes, several conditions must be ruled out—notably acute arterial thrombosis. Patients with this condition will describe acute pain and weakness in the area of involvement. Physicians inspecting the area will note coldness and pallor in the affected limb as well as a diminished or absent pulse. In severe cases, the skin may exhibit a purplish-red appearance.⁵ Millipede burns also should be distinguished from bacterial endocarditis and cryoglobulinemia.⁷ All 3 conditions can manifest with redness, swelling, blisters, and purpuralike changes. Positive blood culture is an important diagnostic basis for bacterial endocarditis; in addition, routine blood tests will demonstrate a decrease in red blood cells and hemoglobin, and routine urinalysis may show proteinuria and microscopic hematuria. Patients with cryoglobulinemia will have a positive cryoglobulin assay, increased IgM, and often decreased complement.⁷ It also is worth noting that millipede burns might resemble child abuse in pediatric patients, necessitating further evaluation.⁵ 

It is unusual to see a millipede burn in nontropical regions. Therefore, the identification of our patient’s millipede burn was notable and serves as a reminder to keep this diagnosis in the differential when caring for patients with pigmentary changes. An accurate diagnosis hinges on being alert to a millipede exposure history and recognizing the clinical manifestations. For affected patients, it may be beneficial to recommend they advise friends and relatives to avoid skin contact with millipedes and most importantly to avoid stepping on them with bare feet.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

To the Editor:

Necrobiotic xanthogranuloma (NXG) is classified as a cutaneous non–Langerhans cell histiocytosis, often seen with monoclonal gammopathy of undetermined significance or multiple myeloma.¹ Clinically, it appears as a red or yellow plaque with occasional ulceration and telangiectasias, most commonly seen periorbitally and on the trunk. On pathology, NXG appears as necrobiosis, giant cells, and various inflammatory cells extending into the subcutaneous tissue.² In this article, we describe a rare presentation of NXG in location and skin type.

A 52-year-old woman with a history of systemic lupus erythematosus (SLE) presented with alopecia and a tender lesion on the scalp of 5 years’ duration (Figure 1). The patient had no history of a similar lesion, and no other lesions were present. A biopsy performed at an outside clinic a few weeks to months prior to the initial presentation to our clinic showed NXG (Figure 2). Evaluation at our clinic revealed a 4x4-cm orange-brown annular plaque on the left parietal scalp. Serum and urine protein electrophoresis studies were negative. The patient reported she was up to date with recommended screenings such as mammography and colonoscopy. 

We started the patient on topical triamcinolone and topical ruxolitinib and administered intralesional triamcinolone. She was already taking hydroxychloroquine and leflunomide for SLE. Three weeks later, she returned with improved symptoms and appearance (Figure 1). She remained on intralesional triamcinolone and ruxolitinib and continues to experience improvement.

Necrobiotic xanthogranuloma is rare and typically is associated with monoclonal gammopathy.² In one study, 83 of 100 of patients with NXG presented with or were found to have a monoclonal gammopathy.² In another study, paraproteinemia was detected in 82.1% of patients.³ The majority of case reports and systematic reviews detail periorbital or thoracic lesions.⁴ The location on the scalp and lack of association with paraproteinemia make this a rare presentation of NXG. Studies may be warranted to explore any association of SLE with NXG if more cases present.

In a multicenter cross-sectional study and systematic review of 235 patients with NXG, 87% were White, 12% were Asian, and only 1% were Black or African American.³ The limited representation of skin of color raises concern for the possibility of missed diagnoses and delays in care. 

Treatment of NXG often is multimodal with use of intravenous immunoglobulin, oral steroids, chlorambucil, melphalan, and other alkylating agents, and response is variable.^3-6 Recent studies show treatment effectiveness with Janus kinase inhibitors in granulomatous dermatitides.^7-9 As our patient was not responding to prior treatments, we decided to try ruxolitinib, and she has continued to improve with it.^10,11 Interestingly, the patient experienced continued improvement with intralesional triamcinolone, which is not often reported in the literature.^2-6 Overall, NXG is an extremely rare condition that requires special care in workup to rule out paraproteinemia and a thoughtful approach to treatment modalities.

To the Editor:

Necrobiotic xanthogranuloma (NXG) is classified as a cutaneous non–Langerhans cell histiocytosis, often seen with monoclonal gammopathy of undetermined significance or multiple myeloma.¹ Clinically, it appears as a red or yellow plaque with occasional ulceration and telangiectasias, most commonly seen periorbitally and on the trunk. On pathology, NXG appears as necrobiosis, giant cells, and various inflammatory cells extending into the subcutaneous tissue.² In this article, we describe a rare presentation of NXG in location and skin type.

A 52-year-old woman with a history of systemic lupus erythematosus (SLE) presented with alopecia and a tender lesion on the scalp of 5 years’ duration (Figure 1). The patient had no history of a similar lesion, and no other lesions were present. A biopsy performed at an outside clinic a few weeks to months prior to the initial presentation to our clinic showed NXG (Figure 2). Evaluation at our clinic revealed a 4x4-cm orange-brown annular plaque on the left parietal scalp. Serum and urine protein electrophoresis studies were negative. The patient reported she was up to date with recommended screenings such as mammography and colonoscopy. 

We started the patient on topical triamcinolone and topical ruxolitinib and administered intralesional triamcinolone. She was already taking hydroxychloroquine and leflunomide for SLE. Three weeks later, she returned with improved symptoms and appearance (Figure 1). She remained on intralesional triamcinolone and ruxolitinib and continues to experience improvement.

Necrobiotic xanthogranuloma is rare and typically is associated with monoclonal gammopathy.² In one study, 83 of 100 of patients with NXG presented with or were found to have a monoclonal gammopathy.² In another study, paraproteinemia was detected in 82.1% of patients.³ The majority of case reports and systematic reviews detail periorbital or thoracic lesions.⁴ The location on the scalp and lack of association with paraproteinemia make this a rare presentation of NXG. Studies may be warranted to explore any association of SLE with NXG if more cases present.

In a multicenter cross-sectional study and systematic review of 235 patients with NXG, 87% were White, 12% were Asian, and only 1% were Black or African American.³ The limited representation of skin of color raises concern for the possibility of missed diagnoses and delays in care. 

Treatment of NXG often is multimodal with use of intravenous immunoglobulin, oral steroids, chlorambucil, melphalan, and other alkylating agents, and response is variable.^3-6 Recent studies show treatment effectiveness with Janus kinase inhibitors in granulomatous dermatitides.^7-9 As our patient was not responding to prior treatments, we decided to try ruxolitinib, and she has continued to improve with it.^10,11 Interestingly, the patient experienced continued improvement with intralesional triamcinolone, which is not often reported in the literature.^2-6 Overall, NXG is an extremely rare condition that requires special care in workup to rule out paraproteinemia and a thoughtful approach to treatment modalities.

To the Editor:

Necrobiotic xanthogranuloma (NXG) is classified as a cutaneous non–Langerhans cell histiocytosis, often seen with monoclonal gammopathy of undetermined significance or multiple myeloma.¹ Clinically, it appears as a red or yellow plaque with occasional ulceration and telangiectasias, most commonly seen periorbitally and on the trunk. On pathology, NXG appears as necrobiosis, giant cells, and various inflammatory cells extending into the subcutaneous tissue.² In this article, we describe a rare presentation of NXG in location and skin type.

A 52-year-old woman with a history of systemic lupus erythematosus (SLE) presented with alopecia and a tender lesion on the scalp of 5 years’ duration (Figure 1). The patient had no history of a similar lesion, and no other lesions were present. A biopsy performed at an outside clinic a few weeks to months prior to the initial presentation to our clinic showed NXG (Figure 2). Evaluation at our clinic revealed a 4x4-cm orange-brown annular plaque on the left parietal scalp. Serum and urine protein electrophoresis studies were negative. The patient reported she was up to date with recommended screenings such as mammography and colonoscopy. 

We started the patient on topical triamcinolone and topical ruxolitinib and administered intralesional triamcinolone. She was already taking hydroxychloroquine and leflunomide for SLE. Three weeks later, she returned with improved symptoms and appearance (Figure 1). She remained on intralesional triamcinolone and ruxolitinib and continues to experience improvement.

Necrobiotic xanthogranuloma is rare and typically is associated with monoclonal gammopathy.² In one study, 83 of 100 of patients with NXG presented with or were found to have a monoclonal gammopathy.² In another study, paraproteinemia was detected in 82.1% of patients.³ The majority of case reports and systematic reviews detail periorbital or thoracic lesions.⁴ The location on the scalp and lack of association with paraproteinemia make this a rare presentation of NXG. Studies may be warranted to explore any association of SLE with NXG if more cases present.

In a multicenter cross-sectional study and systematic review of 235 patients with NXG, 87% were White, 12% were Asian, and only 1% were Black or African American.³ The limited representation of skin of color raises concern for the possibility of missed diagnoses and delays in care. 

Treatment of NXG often is multimodal with use of intravenous immunoglobulin, oral steroids, chlorambucil, melphalan, and other alkylating agents, and response is variable.^3-6 Recent studies show treatment effectiveness with Janus kinase inhibitors in granulomatous dermatitides.^7-9 As our patient was not responding to prior treatments, we decided to try ruxolitinib, and she has continued to improve with it.^10,11 Interestingly, the patient experienced continued improvement with intralesional triamcinolone, which is not often reported in the literature.^2-6 Overall, NXG is an extremely rare condition that requires special care in workup to rule out paraproteinemia and a thoughtful approach to treatment modalities.

To the Editor:

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases and is characterized by age-related morphology and distribution of lesions. Although AD can manifest at any age, it often develops during childhood, with an estimated worldwide prevalence of 15% to 25% in children and 1% to 10% in adults.¹ Clinical manifestation includes chronic or recurrent xerosis, pruritic eczematous lesions involving the flexural and extensor areas, and cutaneous infections. Immediate skin test reactivity and elevated total IgE levels can be found in up to 80% of patients.²

Although the pathogenesis of AD is complex, multifactorial, and not completely understood, some studies have highlighted the central role of a type 2 immune response, resulting in skin barrier dysfunction, cutaneous inflammation, and neuroimmune dysregulation.^3,4 The primary goals of treatment are to mitigate these factors through improvement of symptoms and long-term disease control. Topical emollients are used to repair the epidermal barrier, and topical anti-inflammatory therapy with corticosteroids or calcineurin inhibitors might be applied during flares; however, systemic treatment is essential for patients with moderate to severe AD that is not controlled with topical treatment or phototherapy.⁵

Until recently, systemic immunosuppressant agents such as corticosteroids, cyclosporine, and methotrexate were the only systemic treatment options for severe AD; however, their effectiveness is limited and they may cause serious long-term adverse events, limiting their regular usage, especially in children.⁶

Therapies that target type 2 immune responses include anti–IL-4/IL-13, anti–IL-13, and anti–IL-31 biologics. Dupilumab is a fully human monoclonal antibody targeting the type 2 immune response. This biologic directly binds to IL-4Rα,which prevents signaling by both the IL-4 and IL-13 pathways. Dupilumab was the first biologic approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe AD, with demonstrated efficacy and a favorable safety profile.⁵

In addition to biologics, Janus kinase (JAK) inhibitors belong to the small-molecule class. These drugs block the JAK/STAT intracellular signaling pathway, leading to inhibition of downstream effects triggered by several cytokines related to AD pathogenesis. Upadacitinib is an oral JAK inhibitor that was approved by the FDA in 2022 for treatment of severe AD in adults and children aged 12 years and older. This drug promotes a selective and reversible JAK-1 inhibition and has demonstrated rapid onset of action and a sustained reduction in the signs and symptoms of AD.⁷ We report the case of a child with recalcitrant severe AD that showed significant clinical improvement following off-label treatment with upadacitinib after showing a poor clinical response to dupilumab.

A 9-year-old girl presented to our pediatrics department with progressive worsening of severe AD over the previous 2 years. The patient had been diagnosed with AD at 6 months old, at which time she was treated with several prescribed moisturizers, topical and systemic corticosteroids, and calcineurin inhibitors with no clinical improvement.

The patient initially presented to us for evaluation of severe pruritus and associated sleep loss at age 7 years; physical examination revealed severe xerosis and disseminated pruritic eczematous lesions. Her SCORAD (SCORing Atopic Dermatitis) score was 70 (range, 0-103), and laboratory testing showed a high eosinophil count (1.5×10³/μL [range, 0-0.6×10³], 13%) and IgE level (1686 κU/L [range, 0-90]); a skin prick test on the forearm was positive for Blomia tropicalis.

Following her presentation with severe AD at 7 years old, the patient was prescribed systemic treatments including methotrexate and cyclosporine. During treatment with these agents, she presented to our department with several bacterial skin infections that required oral and intravenous antibiotics for treatment. These agents ultimately were discontinued after 12 months due to the adverse effects and poor clinical improvement. At age 8 years, the patient received an initial 600-mg dose of dupilumab followed by 300 mg subcutaneously every 4 weeks for 6 months along with topical corticosteroids and emollients. During treatment with dupilumab, the patient showed no clinical improvement (SCORAD score, 62). Therefore, we decided to change the dose to 200 mg every 2 weeks. The patient still showed no improvement and presented at age 9 years with moderate conjunctivitis and oculocutaneous infection caused by herpes simplex virus, which required treatment with oral acyclovir (Figure 1).

Considering the severe and refractory clinical course and the poor response to the recommended treatments for the patient’s age, oral upadacitinib was administered off label at a dose of 15 mg once daily after informed consent was obtained from her parents. She returned for follow-up once weekly for 1 month. Three days after starting treatment with upadacitinib, she showed considerable improvement in itch, and her SCORAD score decreased from 62 to 31 after 15 days. After 2 months of treatment, she reported no pruritus or sleep loss, and her SCORAD score was 4.5 (Figure 2). The results of a complete blood count, coagulation function test, and liver and kidney function tests were normal at 6-month and 12-month follow-up during upadacitinib therapy. No adverse effects were observed. The patient currently has completed 18 months of treatment, and the disease remains in complete remission.

Atopic dermatitis is highly prevalent in children. According to the International Study of Asthma and Allergies in Childhood, the prevalence of eczema in 2009 was 8.2% among children aged 6 to 7 years and 5% among adolescents aged between 13 and 14 years in Brazil; severe AD was present in 1.5% of children in both age groups.⁸

The main systemic therapies currently available for patients with severe AD are immunosuppressants, biologics, and small-molecule drugs. The considerable adverse effects of immunosuppressants limit their application. Dupilumab is considered the first-line treatment for children with severe AD. Clinical trials and case reports have demonstrated that dupilumab is effective in patients with AD, promoting notable improvement of pruritic eczematous lesions and quality-of-life scores.⁹ Dupilumab has been approved by the FDA for children older than 6 months, and some studies have shown up to a 49% reduction of pruritus in this age group.⁹ The main reported adverse effects were mild conjunctivitis and oral herpes simplex virus infection.^9,10

Upadacitinib is a reversible and selective JAK-1 inhibitor approved by the FDA for treatment of severe AD in patients aged 12 years and older. A multicenter, randomized, double-blind, placebo-controlled trial evaluated adolescents (12-17 years) and adults (18-75 years) with moderate to severe AD who were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks.¹¹ A higher proportion of patients achieved an Eczema Area and Severity Index score of 75 at week 16 with both upadacitinib 15 mg daily (70%) and 30 mg daily (80%) compared to placebo. Improvements also were observed in both SCORAD and pruritus scores. The most commonly reported adverse events were acne, lipid profile abnormalities, and herpes zoster infection.¹¹

Our patient was a child with severe refractory AD that demonstrated a poor treatment response to dupilumab. When switched to off-label upadacitinib, her disease was effectively controlled; the treatment also was well tolerated with no adverse effects. Reports of upadacitinib used to treat AD in patients younger than 12 years are limited in the literature. One case report described a 9-year-old child with concurrent alopecia areata and severe AD who was successfully treated off label with upadacitinib.¹² A clinical trial also has evaluated the pharmacokinetics, safety, and tolerability of upadacitinib in children aged 2 to 12 years with severe AD (ClinicalTrials.gov Identifier: NCT03646604); although the trial was completed in 2024, at the time of this review (July 2025), the results have not been published.

Interestingly, there have been a few reports of adults with severe AD that failed to respond to treatment with immunosuppressants and dupilumab but showed notable clinical improvement when therapy was switched to upadacitinib,^13,14 as we noticed with our patient. These findings suggest that the JAK-STAT intracellular signaling pathway plays an important role in the pathogenesis of AD.

Continued development of safe and efficient targeted treatment for children with severe AD is critical. Upadacitinib was a safe and effective option for treatment of refractory and severe AD in our patient; however, further studies are needed to confirm both the efficacy and safety of JAK inhibitors in this age group.

To the Editor:

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases and is characterized by age-related morphology and distribution of lesions. Although AD can manifest at any age, it often develops during childhood, with an estimated worldwide prevalence of 15% to 25% in children and 1% to 10% in adults.¹ Clinical manifestation includes chronic or recurrent xerosis, pruritic eczematous lesions involving the flexural and extensor areas, and cutaneous infections. Immediate skin test reactivity and elevated total IgE levels can be found in up to 80% of patients.²

Although the pathogenesis of AD is complex, multifactorial, and not completely understood, some studies have highlighted the central role of a type 2 immune response, resulting in skin barrier dysfunction, cutaneous inflammation, and neuroimmune dysregulation.^3,4 The primary goals of treatment are to mitigate these factors through improvement of symptoms and long-term disease control. Topical emollients are used to repair the epidermal barrier, and topical anti-inflammatory therapy with corticosteroids or calcineurin inhibitors might be applied during flares; however, systemic treatment is essential for patients with moderate to severe AD that is not controlled with topical treatment or phototherapy.⁵

Until recently, systemic immunosuppressant agents such as corticosteroids, cyclosporine, and methotrexate were the only systemic treatment options for severe AD; however, their effectiveness is limited and they may cause serious long-term adverse events, limiting their regular usage, especially in children.⁶

Therapies that target type 2 immune responses include anti–IL-4/IL-13, anti–IL-13, and anti–IL-31 biologics. Dupilumab is a fully human monoclonal antibody targeting the type 2 immune response. This biologic directly binds to IL-4Rα,which prevents signaling by both the IL-4 and IL-13 pathways. Dupilumab was the first biologic approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe AD, with demonstrated efficacy and a favorable safety profile.⁵

In addition to biologics, Janus kinase (JAK) inhibitors belong to the small-molecule class. These drugs block the JAK/STAT intracellular signaling pathway, leading to inhibition of downstream effects triggered by several cytokines related to AD pathogenesis. Upadacitinib is an oral JAK inhibitor that was approved by the FDA in 2022 for treatment of severe AD in adults and children aged 12 years and older. This drug promotes a selective and reversible JAK-1 inhibition and has demonstrated rapid onset of action and a sustained reduction in the signs and symptoms of AD.⁷ We report the case of a child with recalcitrant severe AD that showed significant clinical improvement following off-label treatment with upadacitinib after showing a poor clinical response to dupilumab.

A 9-year-old girl presented to our pediatrics department with progressive worsening of severe AD over the previous 2 years. The patient had been diagnosed with AD at 6 months old, at which time she was treated with several prescribed moisturizers, topical and systemic corticosteroids, and calcineurin inhibitors with no clinical improvement.

The patient initially presented to us for evaluation of severe pruritus and associated sleep loss at age 7 years; physical examination revealed severe xerosis and disseminated pruritic eczematous lesions. Her SCORAD (SCORing Atopic Dermatitis) score was 70 (range, 0-103), and laboratory testing showed a high eosinophil count (1.5×10³/μL [range, 0-0.6×10³], 13%) and IgE level (1686 κU/L [range, 0-90]); a skin prick test on the forearm was positive for Blomia tropicalis.

Following her presentation with severe AD at 7 years old, the patient was prescribed systemic treatments including methotrexate and cyclosporine. During treatment with these agents, she presented to our department with several bacterial skin infections that required oral and intravenous antibiotics for treatment. These agents ultimately were discontinued after 12 months due to the adverse effects and poor clinical improvement. At age 8 years, the patient received an initial 600-mg dose of dupilumab followed by 300 mg subcutaneously every 4 weeks for 6 months along with topical corticosteroids and emollients. During treatment with dupilumab, the patient showed no clinical improvement (SCORAD score, 62). Therefore, we decided to change the dose to 200 mg every 2 weeks. The patient still showed no improvement and presented at age 9 years with moderate conjunctivitis and oculocutaneous infection caused by herpes simplex virus, which required treatment with oral acyclovir (Figure 1).

Considering the severe and refractory clinical course and the poor response to the recommended treatments for the patient’s age, oral upadacitinib was administered off label at a dose of 15 mg once daily after informed consent was obtained from her parents. She returned for follow-up once weekly for 1 month. Three days after starting treatment with upadacitinib, she showed considerable improvement in itch, and her SCORAD score decreased from 62 to 31 after 15 days. After 2 months of treatment, she reported no pruritus or sleep loss, and her SCORAD score was 4.5 (Figure 2). The results of a complete blood count, coagulation function test, and liver and kidney function tests were normal at 6-month and 12-month follow-up during upadacitinib therapy. No adverse effects were observed. The patient currently has completed 18 months of treatment, and the disease remains in complete remission.

Atopic dermatitis is highly prevalent in children. According to the International Study of Asthma and Allergies in Childhood, the prevalence of eczema in 2009 was 8.2% among children aged 6 to 7 years and 5% among adolescents aged between 13 and 14 years in Brazil; severe AD was present in 1.5% of children in both age groups.⁸

The main systemic therapies currently available for patients with severe AD are immunosuppressants, biologics, and small-molecule drugs. The considerable adverse effects of immunosuppressants limit their application. Dupilumab is considered the first-line treatment for children with severe AD. Clinical trials and case reports have demonstrated that dupilumab is effective in patients with AD, promoting notable improvement of pruritic eczematous lesions and quality-of-life scores.⁹ Dupilumab has been approved by the FDA for children older than 6 months, and some studies have shown up to a 49% reduction of pruritus in this age group.⁹ The main reported adverse effects were mild conjunctivitis and oral herpes simplex virus infection.^9,10

Upadacitinib is a reversible and selective JAK-1 inhibitor approved by the FDA for treatment of severe AD in patients aged 12 years and older. A multicenter, randomized, double-blind, placebo-controlled trial evaluated adolescents (12-17 years) and adults (18-75 years) with moderate to severe AD who were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks.¹¹ A higher proportion of patients achieved an Eczema Area and Severity Index score of 75 at week 16 with both upadacitinib 15 mg daily (70%) and 30 mg daily (80%) compared to placebo. Improvements also were observed in both SCORAD and pruritus scores. The most commonly reported adverse events were acne, lipid profile abnormalities, and herpes zoster infection.¹¹

Our patient was a child with severe refractory AD that demonstrated a poor treatment response to dupilumab. When switched to off-label upadacitinib, her disease was effectively controlled; the treatment also was well tolerated with no adverse effects. Reports of upadacitinib used to treat AD in patients younger than 12 years are limited in the literature. One case report described a 9-year-old child with concurrent alopecia areata and severe AD who was successfully treated off label with upadacitinib.¹² A clinical trial also has evaluated the pharmacokinetics, safety, and tolerability of upadacitinib in children aged 2 to 12 years with severe AD (ClinicalTrials.gov Identifier: NCT03646604); although the trial was completed in 2024, at the time of this review (July 2025), the results have not been published.

Interestingly, there have been a few reports of adults with severe AD that failed to respond to treatment with immunosuppressants and dupilumab but showed notable clinical improvement when therapy was switched to upadacitinib,^13,14 as we noticed with our patient. These findings suggest that the JAK-STAT intracellular signaling pathway plays an important role in the pathogenesis of AD.

Continued development of safe and efficient targeted treatment for children with severe AD is critical. Upadacitinib was a safe and effective option for treatment of refractory and severe AD in our patient; however, further studies are needed to confirm both the efficacy and safety of JAK inhibitors in this age group.

To the Editor:

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases and is characterized by age-related morphology and distribution of lesions. Although AD can manifest at any age, it often develops during childhood, with an estimated worldwide prevalence of 15% to 25% in children and 1% to 10% in adults.¹ Clinical manifestation includes chronic or recurrent xerosis, pruritic eczematous lesions involving the flexural and extensor areas, and cutaneous infections. Immediate skin test reactivity and elevated total IgE levels can be found in up to 80% of patients.²

Although the pathogenesis of AD is complex, multifactorial, and not completely understood, some studies have highlighted the central role of a type 2 immune response, resulting in skin barrier dysfunction, cutaneous inflammation, and neuroimmune dysregulation.^3,4 The primary goals of treatment are to mitigate these factors through improvement of symptoms and long-term disease control. Topical emollients are used to repair the epidermal barrier, and topical anti-inflammatory therapy with corticosteroids or calcineurin inhibitors might be applied during flares; however, systemic treatment is essential for patients with moderate to severe AD that is not controlled with topical treatment or phototherapy.⁵

Until recently, systemic immunosuppressant agents such as corticosteroids, cyclosporine, and methotrexate were the only systemic treatment options for severe AD; however, their effectiveness is limited and they may cause serious long-term adverse events, limiting their regular usage, especially in children.⁶

Therapies that target type 2 immune responses include anti–IL-4/IL-13, anti–IL-13, and anti–IL-31 biologics. Dupilumab is a fully human monoclonal antibody targeting the type 2 immune response. This biologic directly binds to IL-4Rα,which prevents signaling by both the IL-4 and IL-13 pathways. Dupilumab was the first biologic approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe AD, with demonstrated efficacy and a favorable safety profile.⁵

In addition to biologics, Janus kinase (JAK) inhibitors belong to the small-molecule class. These drugs block the JAK/STAT intracellular signaling pathway, leading to inhibition of downstream effects triggered by several cytokines related to AD pathogenesis. Upadacitinib is an oral JAK inhibitor that was approved by the FDA in 2022 for treatment of severe AD in adults and children aged 12 years and older. This drug promotes a selective and reversible JAK-1 inhibition and has demonstrated rapid onset of action and a sustained reduction in the signs and symptoms of AD.⁷ We report the case of a child with recalcitrant severe AD that showed significant clinical improvement following off-label treatment with upadacitinib after showing a poor clinical response to dupilumab.

A 9-year-old girl presented to our pediatrics department with progressive worsening of severe AD over the previous 2 years. The patient had been diagnosed with AD at 6 months old, at which time she was treated with several prescribed moisturizers, topical and systemic corticosteroids, and calcineurin inhibitors with no clinical improvement.

The patient initially presented to us for evaluation of severe pruritus and associated sleep loss at age 7 years; physical examination revealed severe xerosis and disseminated pruritic eczematous lesions. Her SCORAD (SCORing Atopic Dermatitis) score was 70 (range, 0-103), and laboratory testing showed a high eosinophil count (1.5×10³/μL [range, 0-0.6×10³], 13%) and IgE level (1686 κU/L [range, 0-90]); a skin prick test on the forearm was positive for Blomia tropicalis.

Following her presentation with severe AD at 7 years old, the patient was prescribed systemic treatments including methotrexate and cyclosporine. During treatment with these agents, she presented to our department with several bacterial skin infections that required oral and intravenous antibiotics for treatment. These agents ultimately were discontinued after 12 months due to the adverse effects and poor clinical improvement. At age 8 years, the patient received an initial 600-mg dose of dupilumab followed by 300 mg subcutaneously every 4 weeks for 6 months along with topical corticosteroids and emollients. During treatment with dupilumab, the patient showed no clinical improvement (SCORAD score, 62). Therefore, we decided to change the dose to 200 mg every 2 weeks. The patient still showed no improvement and presented at age 9 years with moderate conjunctivitis and oculocutaneous infection caused by herpes simplex virus, which required treatment with oral acyclovir (Figure 1).

Considering the severe and refractory clinical course and the poor response to the recommended treatments for the patient’s age, oral upadacitinib was administered off label at a dose of 15 mg once daily after informed consent was obtained from her parents. She returned for follow-up once weekly for 1 month. Three days after starting treatment with upadacitinib, she showed considerable improvement in itch, and her SCORAD score decreased from 62 to 31 after 15 days. After 2 months of treatment, she reported no pruritus or sleep loss, and her SCORAD score was 4.5 (Figure 2). The results of a complete blood count, coagulation function test, and liver and kidney function tests were normal at 6-month and 12-month follow-up during upadacitinib therapy. No adverse effects were observed. The patient currently has completed 18 months of treatment, and the disease remains in complete remission.

Atopic dermatitis is highly prevalent in children. According to the International Study of Asthma and Allergies in Childhood, the prevalence of eczema in 2009 was 8.2% among children aged 6 to 7 years and 5% among adolescents aged between 13 and 14 years in Brazil; severe AD was present in 1.5% of children in both age groups.⁸

The main systemic therapies currently available for patients with severe AD are immunosuppressants, biologics, and small-molecule drugs. The considerable adverse effects of immunosuppressants limit their application. Dupilumab is considered the first-line treatment for children with severe AD. Clinical trials and case reports have demonstrated that dupilumab is effective in patients with AD, promoting notable improvement of pruritic eczematous lesions and quality-of-life scores.⁹ Dupilumab has been approved by the FDA for children older than 6 months, and some studies have shown up to a 49% reduction of pruritus in this age group.⁹ The main reported adverse effects were mild conjunctivitis and oral herpes simplex virus infection.^9,10

Upadacitinib is a reversible and selective JAK-1 inhibitor approved by the FDA for treatment of severe AD in patients aged 12 years and older. A multicenter, randomized, double-blind, placebo-controlled trial evaluated adolescents (12-17 years) and adults (18-75 years) with moderate to severe AD who were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks.¹¹ A higher proportion of patients achieved an Eczema Area and Severity Index score of 75 at week 16 with both upadacitinib 15 mg daily (70%) and 30 mg daily (80%) compared to placebo. Improvements also were observed in both SCORAD and pruritus scores. The most commonly reported adverse events were acne, lipid profile abnormalities, and herpes zoster infection.¹¹

Our patient was a child with severe refractory AD that demonstrated a poor treatment response to dupilumab. When switched to off-label upadacitinib, her disease was effectively controlled; the treatment also was well tolerated with no adverse effects. Reports of upadacitinib used to treat AD in patients younger than 12 years are limited in the literature. One case report described a 9-year-old child with concurrent alopecia areata and severe AD who was successfully treated off label with upadacitinib.¹² A clinical trial also has evaluated the pharmacokinetics, safety, and tolerability of upadacitinib in children aged 2 to 12 years with severe AD (ClinicalTrials.gov Identifier: NCT03646604); although the trial was completed in 2024, at the time of this review (July 2025), the results have not been published.

Interestingly, there have been a few reports of adults with severe AD that failed to respond to treatment with immunosuppressants and dupilumab but showed notable clinical improvement when therapy was switched to upadacitinib,^13,14 as we noticed with our patient. These findings suggest that the JAK-STAT intracellular signaling pathway plays an important role in the pathogenesis of AD.

Continued development of safe and efficient targeted treatment for children with severe AD is critical. Upadacitinib was a safe and effective option for treatment of refractory and severe AD in our patient; however, further studies are needed to confirm both the efficacy and safety of JAK inhibitors in this age group.

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.