Cutis

Interest in hidradenitis suppurativa (HS) has exploded in the last few years. A PubMed search of articles indexed for MEDLINE using the MeSH term hidradenitis suppurativa yielded more than 900 articles on HS since 1947, with a sharp increase in publications over the last few years and 119 articles published in 2015 alone. In addition to publications, we recently saw adalimumab become the first and only US Food and Drug Administration–approved treatment of moderate to severe HS.

With new treatment options and enthusiasm for HS, further attention needs to be paid to the scoring systems or outcome measures that clinicians use to grade HS severity and disease. Utilization of validated outcome measures allows for comparability between treatment effects, which is essential for clinical trials, meta-analyses, and monitoring of treatment response in daily clinical practice. Designing a scoring scale for any dermatologic disease is challenging; however, as we move forward with value-based reimbursement models, we likely will encounter quality reporting guidelines that mandate providers demonstrate the positive impact of treatment. Thus, scoring systems for HS, particularly ones that accurately assess this impact of treatment, are essential. For psoriasis, the physician global assessment (PGA) and psoriasis area and severity index are standard outcome measures of disease severity in clinical trials. The PGA also can be used in a clinical setting to longitudinally track patient treatment outcomes.¹ Both the psoriasis area and severity index and PGA were cited as acceptable scoring tools for Medicare’s Physician Quality Reporting System quality metrics reporting (Measure #410: Psoriasis: Clinical Response to Oral Systemic or Biologic Medications). Unfortunately, no such outcome measures consensus currently exists for scoring systems in HS.

Many scoring systems have been proposed for HS. The most well known is the Hurley staging system. Developed in 1989 for surgical approaches, it is a straightforward tool to categorize disease severity but does not emphasize the inflammatory component of HS. Recently, a refined Hurley stage classification system was proposed. This 3-step algorithm expanded the Hurley stage classification to incorporate disease extensiveness, degree of inflammation, and presence of sinus tracts.² The modified Sartorius score (also known as the modified HS score) is a more detailed scoring system for assessing disease activity that requires measurements and precise counting of lesions.³ The HS-PGA is an ordinal scale specific to HS that categorizes patients into clear, minimal, mild, moderate, severe, or very severe disease, and it was used successfully in a phase 2 interventional clinical trial.⁴ The HS clinical response (HiSCR) score is an HS-specific, binary scoring system for patients with 3 or more abscesses or inflammatory nodules. It was engineered using raw data and outcomes from a large clinical trial, and subsequently was employed as the primary end point in 2 randomized controlled trials.^5,6 It is the only HS scoring system to undergo an extensive validation process of both physician- and patient-reported measures for assessment of therapeutic response in controlling the inflammatory manifestations of HS.

Designing a scoring system for clinical trials can be complicated. Sample sizes are dependent on the delta, or change, in efficacy or variation in response, and the design of the score will affect how easy it is to detect a statistically meaningful difference. These choices are a critical part of the design of small studies, particularly if obtaining enough statistical power can be challenging. Additionally, it is easier to detect change in more homogenous populations where we expect a more consistent response. Hidradenitis suppurativa is not a particularly homogenous disease, which furthers the risk of designing a trial that cannot detect important differences. The PGA often is required by the US Food and Drug Administration and has the major advantage that it is easy to understand, but the categories can sometimes be too broad to detect change easily, and more granular data can provide the basis for more in-depth analyses. An ideal outcome measure is a simplified scoring system that assesses disease severity and responsiveness to treatment while accurately serving as a surrogate for patient-reported outcomes, such as the dermatology life quality index, visual analog scale for HS skin pain, the work productivity and activity impairment questionnaire (specific health problem), or the patient global assessment. Validation processes for outcome measures, such as the one that HiSCR underwent, are essential to ensure that the proposed scoring system has clinical meaningfulness to both the physician and patient.

A 2016 Cochrane review of interventions for HS included 12 randomized controlled trials that employed a total of 30 different outcome measures instruments. Because use of multiple scoring systems makes it difficult to compare analyses of treatment, the authors concluded that there was a need for improved validation of HS outcome measures for future clinical trials.⁷ Schmitt et al⁸ recognized that atopic dermatitis also was in a similar predicament; they noted that more than 20 outcome measures were employed to assess disease severity in clinical trials. The authors called this situation “a significant threat to evidence-based health care” and outlined the Harmonizing Outcome Measures for Eczema (HOME) research initiative’s methodology for creation of core outcome sets for any dermatologic disease. Their consensus process involved first identifying what to measure, termed outcome domains, followed by developing how to measure these domains through outcome measures instruments, which would be assessed for validity, reliability, sensitivity to change, and feasibility.⁸

Using the framework set forth by the HOME initiative and data from the 2016 Cochrane review,⁷ a recent review of all outcome measures instruments currently employed in HS found that 90% (27/30) were not validated.⁹ Even those that were validated still could not be fully recommended by the authors. The authors identified 10 potential outcome domains for measurement, including quality of life, pain, lesion count, PGA, patient global self-assessment, recurrence rate, overall satisfaction with treatment, impairment of function, cosmesis, and duration of recovery. They recommended a further consensus process to better define these outcomes.⁹

Measuring all of these variables seems daunting, but as the speed of HS research rapidly progresses, we would greatly benefit from employing a standard validated scoring system that captures both disease severity and activity. Several groups are working to improve our current tools, but we will need to move quickly to a common approach so we can better compare treatment effects and build an evidence base for treatment decisions. For now, the HiSCR is the most validated clinical trials instrument, but it may not be ideal for the clinical setting. In our practice, we grade all patients each visit with Hurley staging, the validated HS-PGA scoring system to track improvement in inflammatory lesions, and a 10-point pain scale to monitor disease activity and severity. We have found these tools to be quick and effective for measuring treatment response and would recommend employment of these scoring systems as a standard measure in clinical practice until further consensus is reached.

Interest in hidradenitis suppurativa (HS) has exploded in the last few years. A PubMed search of articles indexed for MEDLINE using the MeSH term hidradenitis suppurativa yielded more than 900 articles on HS since 1947, with a sharp increase in publications over the last few years and 119 articles published in 2015 alone. In addition to publications, we recently saw adalimumab become the first and only US Food and Drug Administration–approved treatment of moderate to severe HS.

With new treatment options and enthusiasm for HS, further attention needs to be paid to the scoring systems or outcome measures that clinicians use to grade HS severity and disease. Utilization of validated outcome measures allows for comparability between treatment effects, which is essential for clinical trials, meta-analyses, and monitoring of treatment response in daily clinical practice. Designing a scoring scale for any dermatologic disease is challenging; however, as we move forward with value-based reimbursement models, we likely will encounter quality reporting guidelines that mandate providers demonstrate the positive impact of treatment. Thus, scoring systems for HS, particularly ones that accurately assess this impact of treatment, are essential. For psoriasis, the physician global assessment (PGA) and psoriasis area and severity index are standard outcome measures of disease severity in clinical trials. The PGA also can be used in a clinical setting to longitudinally track patient treatment outcomes.¹ Both the psoriasis area and severity index and PGA were cited as acceptable scoring tools for Medicare’s Physician Quality Reporting System quality metrics reporting (Measure #410: Psoriasis: Clinical Response to Oral Systemic or Biologic Medications). Unfortunately, no such outcome measures consensus currently exists for scoring systems in HS.

Many scoring systems have been proposed for HS. The most well known is the Hurley staging system. Developed in 1989 for surgical approaches, it is a straightforward tool to categorize disease severity but does not emphasize the inflammatory component of HS. Recently, a refined Hurley stage classification system was proposed. This 3-step algorithm expanded the Hurley stage classification to incorporate disease extensiveness, degree of inflammation, and presence of sinus tracts.² The modified Sartorius score (also known as the modified HS score) is a more detailed scoring system for assessing disease activity that requires measurements and precise counting of lesions.³ The HS-PGA is an ordinal scale specific to HS that categorizes patients into clear, minimal, mild, moderate, severe, or very severe disease, and it was used successfully in a phase 2 interventional clinical trial.⁴ The HS clinical response (HiSCR) score is an HS-specific, binary scoring system for patients with 3 or more abscesses or inflammatory nodules. It was engineered using raw data and outcomes from a large clinical trial, and subsequently was employed as the primary end point in 2 randomized controlled trials.^5,6 It is the only HS scoring system to undergo an extensive validation process of both physician- and patient-reported measures for assessment of therapeutic response in controlling the inflammatory manifestations of HS.

Designing a scoring system for clinical trials can be complicated. Sample sizes are dependent on the delta, or change, in efficacy or variation in response, and the design of the score will affect how easy it is to detect a statistically meaningful difference. These choices are a critical part of the design of small studies, particularly if obtaining enough statistical power can be challenging. Additionally, it is easier to detect change in more homogenous populations where we expect a more consistent response. Hidradenitis suppurativa is not a particularly homogenous disease, which furthers the risk of designing a trial that cannot detect important differences. The PGA often is required by the US Food and Drug Administration and has the major advantage that it is easy to understand, but the categories can sometimes be too broad to detect change easily, and more granular data can provide the basis for more in-depth analyses. An ideal outcome measure is a simplified scoring system that assesses disease severity and responsiveness to treatment while accurately serving as a surrogate for patient-reported outcomes, such as the dermatology life quality index, visual analog scale for HS skin pain, the work productivity and activity impairment questionnaire (specific health problem), or the patient global assessment. Validation processes for outcome measures, such as the one that HiSCR underwent, are essential to ensure that the proposed scoring system has clinical meaningfulness to both the physician and patient.

A 2016 Cochrane review of interventions for HS included 12 randomized controlled trials that employed a total of 30 different outcome measures instruments. Because use of multiple scoring systems makes it difficult to compare analyses of treatment, the authors concluded that there was a need for improved validation of HS outcome measures for future clinical trials.⁷ Schmitt et al⁸ recognized that atopic dermatitis also was in a similar predicament; they noted that more than 20 outcome measures were employed to assess disease severity in clinical trials. The authors called this situation “a significant threat to evidence-based health care” and outlined the Harmonizing Outcome Measures for Eczema (HOME) research initiative’s methodology for creation of core outcome sets for any dermatologic disease. Their consensus process involved first identifying what to measure, termed outcome domains, followed by developing how to measure these domains through outcome measures instruments, which would be assessed for validity, reliability, sensitivity to change, and feasibility.⁸

Using the framework set forth by the HOME initiative and data from the 2016 Cochrane review,⁷ a recent review of all outcome measures instruments currently employed in HS found that 90% (27/30) were not validated.⁹ Even those that were validated still could not be fully recommended by the authors. The authors identified 10 potential outcome domains for measurement, including quality of life, pain, lesion count, PGA, patient global self-assessment, recurrence rate, overall satisfaction with treatment, impairment of function, cosmesis, and duration of recovery. They recommended a further consensus process to better define these outcomes.⁹

Measuring all of these variables seems daunting, but as the speed of HS research rapidly progresses, we would greatly benefit from employing a standard validated scoring system that captures both disease severity and activity. Several groups are working to improve our current tools, but we will need to move quickly to a common approach so we can better compare treatment effects and build an evidence base for treatment decisions. For now, the HiSCR is the most validated clinical trials instrument, but it may not be ideal for the clinical setting. In our practice, we grade all patients each visit with Hurley staging, the validated HS-PGA scoring system to track improvement in inflammatory lesions, and a 10-point pain scale to monitor disease activity and severity. We have found these tools to be quick and effective for measuring treatment response and would recommend employment of these scoring systems as a standard measure in clinical practice until further consensus is reached.

Interest in hidradenitis suppurativa (HS) has exploded in the last few years. A PubMed search of articles indexed for MEDLINE using the MeSH term hidradenitis suppurativa yielded more than 900 articles on HS since 1947, with a sharp increase in publications over the last few years and 119 articles published in 2015 alone. In addition to publications, we recently saw adalimumab become the first and only US Food and Drug Administration–approved treatment of moderate to severe HS.

With new treatment options and enthusiasm for HS, further attention needs to be paid to the scoring systems or outcome measures that clinicians use to grade HS severity and disease. Utilization of validated outcome measures allows for comparability between treatment effects, which is essential for clinical trials, meta-analyses, and monitoring of treatment response in daily clinical practice. Designing a scoring scale for any dermatologic disease is challenging; however, as we move forward with value-based reimbursement models, we likely will encounter quality reporting guidelines that mandate providers demonstrate the positive impact of treatment. Thus, scoring systems for HS, particularly ones that accurately assess this impact of treatment, are essential. For psoriasis, the physician global assessment (PGA) and psoriasis area and severity index are standard outcome measures of disease severity in clinical trials. The PGA also can be used in a clinical setting to longitudinally track patient treatment outcomes.¹ Both the psoriasis area and severity index and PGA were cited as acceptable scoring tools for Medicare’s Physician Quality Reporting System quality metrics reporting (Measure #410: Psoriasis: Clinical Response to Oral Systemic or Biologic Medications). Unfortunately, no such outcome measures consensus currently exists for scoring systems in HS.

Many scoring systems have been proposed for HS. The most well known is the Hurley staging system. Developed in 1989 for surgical approaches, it is a straightforward tool to categorize disease severity but does not emphasize the inflammatory component of HS. Recently, a refined Hurley stage classification system was proposed. This 3-step algorithm expanded the Hurley stage classification to incorporate disease extensiveness, degree of inflammation, and presence of sinus tracts.² The modified Sartorius score (also known as the modified HS score) is a more detailed scoring system for assessing disease activity that requires measurements and precise counting of lesions.³ The HS-PGA is an ordinal scale specific to HS that categorizes patients into clear, minimal, mild, moderate, severe, or very severe disease, and it was used successfully in a phase 2 interventional clinical trial.⁴ The HS clinical response (HiSCR) score is an HS-specific, binary scoring system for patients with 3 or more abscesses or inflammatory nodules. It was engineered using raw data and outcomes from a large clinical trial, and subsequently was employed as the primary end point in 2 randomized controlled trials.^5,6 It is the only HS scoring system to undergo an extensive validation process of both physician- and patient-reported measures for assessment of therapeutic response in controlling the inflammatory manifestations of HS.

Designing a scoring system for clinical trials can be complicated. Sample sizes are dependent on the delta, or change, in efficacy or variation in response, and the design of the score will affect how easy it is to detect a statistically meaningful difference. These choices are a critical part of the design of small studies, particularly if obtaining enough statistical power can be challenging. Additionally, it is easier to detect change in more homogenous populations where we expect a more consistent response. Hidradenitis suppurativa is not a particularly homogenous disease, which furthers the risk of designing a trial that cannot detect important differences. The PGA often is required by the US Food and Drug Administration and has the major advantage that it is easy to understand, but the categories can sometimes be too broad to detect change easily, and more granular data can provide the basis for more in-depth analyses. An ideal outcome measure is a simplified scoring system that assesses disease severity and responsiveness to treatment while accurately serving as a surrogate for patient-reported outcomes, such as the dermatology life quality index, visual analog scale for HS skin pain, the work productivity and activity impairment questionnaire (specific health problem), or the patient global assessment. Validation processes for outcome measures, such as the one that HiSCR underwent, are essential to ensure that the proposed scoring system has clinical meaningfulness to both the physician and patient.

A 2016 Cochrane review of interventions for HS included 12 randomized controlled trials that employed a total of 30 different outcome measures instruments. Because use of multiple scoring systems makes it difficult to compare analyses of treatment, the authors concluded that there was a need for improved validation of HS outcome measures for future clinical trials.⁷ Schmitt et al⁸ recognized that atopic dermatitis also was in a similar predicament; they noted that more than 20 outcome measures were employed to assess disease severity in clinical trials. The authors called this situation “a significant threat to evidence-based health care” and outlined the Harmonizing Outcome Measures for Eczema (HOME) research initiative’s methodology for creation of core outcome sets for any dermatologic disease. Their consensus process involved first identifying what to measure, termed outcome domains, followed by developing how to measure these domains through outcome measures instruments, which would be assessed for validity, reliability, sensitivity to change, and feasibility.⁸

Using the framework set forth by the HOME initiative and data from the 2016 Cochrane review,⁷ a recent review of all outcome measures instruments currently employed in HS found that 90% (27/30) were not validated.⁹ Even those that were validated still could not be fully recommended by the authors. The authors identified 10 potential outcome domains for measurement, including quality of life, pain, lesion count, PGA, patient global self-assessment, recurrence rate, overall satisfaction with treatment, impairment of function, cosmesis, and duration of recovery. They recommended a further consensus process to better define these outcomes.⁹

Measuring all of these variables seems daunting, but as the speed of HS research rapidly progresses, we would greatly benefit from employing a standard validated scoring system that captures both disease severity and activity. Several groups are working to improve our current tools, but we will need to move quickly to a common approach so we can better compare treatment effects and build an evidence base for treatment decisions. For now, the HiSCR is the most validated clinical trials instrument, but it may not be ideal for the clinical setting. In our practice, we grade all patients each visit with Hurley staging, the validated HS-PGA scoring system to track improvement in inflammatory lesions, and a 10-point pain scale to monitor disease activity and severity. We have found these tools to be quick and effective for measuring treatment response and would recommend employment of these scoring systems as a standard measure in clinical practice until further consensus is reached.

Imatinib mesylate is a tyrosine kinase inhibitor initially approved by the US Food and Drug Administration in 2001 for chronic myeloid leukemia (CML). The indications for imatinib have expanded since its initial approval. It is increasingly important that dermatologists recognize adverse cutaneous manifestations associated with imatinib and are aware of their management and outcomes to avoid unnecessarily discontinuing a potentially lifesaving medication.

Adverse cutaneous manifestations in response to imatinib are not infrequent, accounting for 7% to 21% of all side effects.¹ The most frequent cutaneous manifestations of imatinib are dry skin, alopecia, facial edema, and photosensitivity rash, respectively.¹ Other less common manifestations include exfoliative dermatitis, nail disorders, psoriasis, folliculitis, hypotrichosis, urticaria, petechiae, Stevens-Johnson syndrome, erythema multiforme, Sweet syndrome, and leukocytoclastic vasculitis.

We report a case of imatinib-induced lichenoid drug eruption (LDE), a rare cutaneous side effect of imatinib use, along with a review of the literature.

Case Report

An 86-year-old man with a history of gastrointestinal stromal tumors (GISTs) and myelodysplastic syndrome presented with diffuse hyperpigmented skin lesions on the trunk, arms, legs, and lower lip of 2 weeks’ duration. He had been taking imatinib 400 mg once daily for 5 months for GIST. Although the oncologist stopped the medication 2 weeks prior, the lesions were persistent and gradually expanded to involve the trunk, arms, legs, and lower lip. He denied any pain or pruritus. Physical examination revealed multiple ill-defined, brown to violaceous, slightly scaly macules and patches on the trunk (Figures 1A and 1B), arms, and legs (Figure 1C), as well as violaceous to erythematous patches on the mucosal aspect of the lower lip (Figure 2). Two 4-mm punch biopsies were performed from the chest and back, which revealed an atrophic epidermis, lichenoid infiltration, and multiple melanophages in the upper dermis consistent with LDE (Figure 3). Direct immunofluorescence was negative. Therefore, based on the clinicopathologic correlation, the diagnosis of imatinib-induced LDE was made. He was treated with clobetasol ointment twice daily for 3 weeks with some improvement. His GIST was stable on follow-up computed tomography 3 months after presentation, and imatinib was resumed 1 month later with continued rash that was stable with topical corticosteroid treatment.

Comment

In addition to CML, imatinib has been approved for acute lymphoblastic leukemia, myelodysplastic syndromes, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, and GIST. Moreover, off-label use of imatinib for various other tyrosine kinase–positive cancers and rheumatologic conditions have been documented.^2,3 With the expanding use of imatinib, there will be more occasions for dermatologists to encounter cutaneous manifestations associated with its use.

According to a PubMed search of articles indexed for MEDLINE using the terms imatinib mesylate lichenoid drug, there have been few case reports of LDE associated with imatinib in the literature (eTable).^4-24 Compared to classic LDE, imatinib-induced LDE has a few characteristic findings. Classic LDE frequently spares the oral mucosa and genitalia, but imatinib-induced LDE with manifestations on the oral mucosa and genitalia as well as cutaneous eruptions have been reported.^4-9 In fact, the first known case of imatinib-induced LDE was an oral eruption in a patient with CML.⁴ In patients with oral involvement, lesions have been described as lacy reticular macules and violaceous papules, erosions, and ulcers.^4,5,12 Interestingly, of those cases manifesting as concomitant oral and cutaneous LDE, the oral eruptions recurred more frequently, with 3 of 12 patients having recurrence of oral lesions after the cutaneous manifestations resolved.^8,16 Genital manifestations of imatinib-induced LDE were much less common.^9,11

To date, subsequent reports of imatinib-induced LDE have documented skin manifestations consistent with classic LDE occurring in a diffuse, bilateral, photodistributed pattern.^10,15,16 One case presented with diffuse hyperpigmentation associated with LDE in a Japanese patient.²⁰ The authors suggested this finding may be more prominent in patients with skin of color,²⁰ which is consistent with the current case. Nail findings such as subungual hyperkeratosis and longitudinal ridging also have been reported.^9,11

The latency period between initiation of imat-inib and onset of LDE generally ranges from 1 to 12 months, with onset most commonly occurring between 2 to 5 months or with dosage increase (eTable). Imatinib-induced LDE primarily has been documented with a 400-mg dose, with 1 case of a 600-mg dose and 1 case of an 800-mg dose, which suggests dose dependency. Furthermore, reports exist of several patients responding well to dose reduction with subsequent recurrence on dose reescalation.^13,15

Historically, LDE resolves with discontinuation of the drug after a few weeks to months. When discontinuation of imatinib is unfavorable or patients report symptoms including severe pruritus or pain, treatment should be considered. Topical or oral corticosteroids can be used to treat imatinib-induced LDE, similar to lichen planus. When oral corticosteroids are contraindicated (eg, due to poor patient tolerance), oral acitretin at 25 to 35 mg once daily for 6 to 12 weeks has been reported as an alternative treatment.²⁵

In the majority of cases of imatinib-induced LDE, it was undesirable to stop imatinib (eTable). Notably, in half the reported cases, imatinib was able to be continued and patients were treated symptomatically with either oral and/or topical steroids and/or acitretin with complete remission or tolerable recurrences. Dalmau et al⁹ reported 3 patients who responded poorly to topical and oral steroids and were subsequently treated with acitretin 25 mg once daily; 2 of 3 patients responded favorably to treatment and imatinib was able to be continued. In the current case imatinib initially helped, but because his rash was relatively asymptomatic, imatinib was restarted with control of rash with topical steroids. He developed some pancytopenia, which required intermittent stoppage of the imatinib.

Conclusion

We present a case of imatinib-induced cutaneous and oral LDE in a patient with GIST. Topical corticosteroids, oral acitretin, and oral steroids all may be reasonable treatment options if discontinuing imatinib is not possible in a symptomatic patient. If these therapies fail and the eruption is extensive or intolerable, dosage adjustment is another option to consider before discontinuation of imatinib.

Imatinib mesylate is a tyrosine kinase inhibitor initially approved by the US Food and Drug Administration in 2001 for chronic myeloid leukemia (CML). The indications for imatinib have expanded since its initial approval. It is increasingly important that dermatologists recognize adverse cutaneous manifestations associated with imatinib and are aware of their management and outcomes to avoid unnecessarily discontinuing a potentially lifesaving medication.

Adverse cutaneous manifestations in response to imatinib are not infrequent, accounting for 7% to 21% of all side effects.¹ The most frequent cutaneous manifestations of imatinib are dry skin, alopecia, facial edema, and photosensitivity rash, respectively.¹ Other less common manifestations include exfoliative dermatitis, nail disorders, psoriasis, folliculitis, hypotrichosis, urticaria, petechiae, Stevens-Johnson syndrome, erythema multiforme, Sweet syndrome, and leukocytoclastic vasculitis.

We report a case of imatinib-induced lichenoid drug eruption (LDE), a rare cutaneous side effect of imatinib use, along with a review of the literature.

Case Report

An 86-year-old man with a history of gastrointestinal stromal tumors (GISTs) and myelodysplastic syndrome presented with diffuse hyperpigmented skin lesions on the trunk, arms, legs, and lower lip of 2 weeks’ duration. He had been taking imatinib 400 mg once daily for 5 months for GIST. Although the oncologist stopped the medication 2 weeks prior, the lesions were persistent and gradually expanded to involve the trunk, arms, legs, and lower lip. He denied any pain or pruritus. Physical examination revealed multiple ill-defined, brown to violaceous, slightly scaly macules and patches on the trunk (Figures 1A and 1B), arms, and legs (Figure 1C), as well as violaceous to erythematous patches on the mucosal aspect of the lower lip (Figure 2). Two 4-mm punch biopsies were performed from the chest and back, which revealed an atrophic epidermis, lichenoid infiltration, and multiple melanophages in the upper dermis consistent with LDE (Figure 3). Direct immunofluorescence was negative. Therefore, based on the clinicopathologic correlation, the diagnosis of imatinib-induced LDE was made. He was treated with clobetasol ointment twice daily for 3 weeks with some improvement. His GIST was stable on follow-up computed tomography 3 months after presentation, and imatinib was resumed 1 month later with continued rash that was stable with topical corticosteroid treatment.

Comment

In addition to CML, imatinib has been approved for acute lymphoblastic leukemia, myelodysplastic syndromes, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, and GIST. Moreover, off-label use of imatinib for various other tyrosine kinase–positive cancers and rheumatologic conditions have been documented.^2,3 With the expanding use of imatinib, there will be more occasions for dermatologists to encounter cutaneous manifestations associated with its use.

According to a PubMed search of articles indexed for MEDLINE using the terms imatinib mesylate lichenoid drug, there have been few case reports of LDE associated with imatinib in the literature (eTable).^4-24 Compared to classic LDE, imatinib-induced LDE has a few characteristic findings. Classic LDE frequently spares the oral mucosa and genitalia, but imatinib-induced LDE with manifestations on the oral mucosa and genitalia as well as cutaneous eruptions have been reported.^4-9 In fact, the first known case of imatinib-induced LDE was an oral eruption in a patient with CML.⁴ In patients with oral involvement, lesions have been described as lacy reticular macules and violaceous papules, erosions, and ulcers.^4,5,12 Interestingly, of those cases manifesting as concomitant oral and cutaneous LDE, the oral eruptions recurred more frequently, with 3 of 12 patients having recurrence of oral lesions after the cutaneous manifestations resolved.^8,16 Genital manifestations of imatinib-induced LDE were much less common.^9,11

To date, subsequent reports of imatinib-induced LDE have documented skin manifestations consistent with classic LDE occurring in a diffuse, bilateral, photodistributed pattern.^10,15,16 One case presented with diffuse hyperpigmentation associated with LDE in a Japanese patient.²⁰ The authors suggested this finding may be more prominent in patients with skin of color,²⁰ which is consistent with the current case. Nail findings such as subungual hyperkeratosis and longitudinal ridging also have been reported.^9,11

The latency period between initiation of imat-inib and onset of LDE generally ranges from 1 to 12 months, with onset most commonly occurring between 2 to 5 months or with dosage increase (eTable). Imatinib-induced LDE primarily has been documented with a 400-mg dose, with 1 case of a 600-mg dose and 1 case of an 800-mg dose, which suggests dose dependency. Furthermore, reports exist of several patients responding well to dose reduction with subsequent recurrence on dose reescalation.^13,15

Historically, LDE resolves with discontinuation of the drug after a few weeks to months. When discontinuation of imatinib is unfavorable or patients report symptoms including severe pruritus or pain, treatment should be considered. Topical or oral corticosteroids can be used to treat imatinib-induced LDE, similar to lichen planus. When oral corticosteroids are contraindicated (eg, due to poor patient tolerance), oral acitretin at 25 to 35 mg once daily for 6 to 12 weeks has been reported as an alternative treatment.²⁵

In the majority of cases of imatinib-induced LDE, it was undesirable to stop imatinib (eTable). Notably, in half the reported cases, imatinib was able to be continued and patients were treated symptomatically with either oral and/or topical steroids and/or acitretin with complete remission or tolerable recurrences. Dalmau et al⁹ reported 3 patients who responded poorly to topical and oral steroids and were subsequently treated with acitretin 25 mg once daily; 2 of 3 patients responded favorably to treatment and imatinib was able to be continued. In the current case imatinib initially helped, but because his rash was relatively asymptomatic, imatinib was restarted with control of rash with topical steroids. He developed some pancytopenia, which required intermittent stoppage of the imatinib.

Conclusion

We present a case of imatinib-induced cutaneous and oral LDE in a patient with GIST. Topical corticosteroids, oral acitretin, and oral steroids all may be reasonable treatment options if discontinuing imatinib is not possible in a symptomatic patient. If these therapies fail and the eruption is extensive or intolerable, dosage adjustment is another option to consider before discontinuation of imatinib.

Imatinib mesylate is a tyrosine kinase inhibitor initially approved by the US Food and Drug Administration in 2001 for chronic myeloid leukemia (CML). The indications for imatinib have expanded since its initial approval. It is increasingly important that dermatologists recognize adverse cutaneous manifestations associated with imatinib and are aware of their management and outcomes to avoid unnecessarily discontinuing a potentially lifesaving medication.

Adverse cutaneous manifestations in response to imatinib are not infrequent, accounting for 7% to 21% of all side effects.¹ The most frequent cutaneous manifestations of imatinib are dry skin, alopecia, facial edema, and photosensitivity rash, respectively.¹ Other less common manifestations include exfoliative dermatitis, nail disorders, psoriasis, folliculitis, hypotrichosis, urticaria, petechiae, Stevens-Johnson syndrome, erythema multiforme, Sweet syndrome, and leukocytoclastic vasculitis.

We report a case of imatinib-induced lichenoid drug eruption (LDE), a rare cutaneous side effect of imatinib use, along with a review of the literature.

Case Report

An 86-year-old man with a history of gastrointestinal stromal tumors (GISTs) and myelodysplastic syndrome presented with diffuse hyperpigmented skin lesions on the trunk, arms, legs, and lower lip of 2 weeks’ duration. He had been taking imatinib 400 mg once daily for 5 months for GIST. Although the oncologist stopped the medication 2 weeks prior, the lesions were persistent and gradually expanded to involve the trunk, arms, legs, and lower lip. He denied any pain or pruritus. Physical examination revealed multiple ill-defined, brown to violaceous, slightly scaly macules and patches on the trunk (Figures 1A and 1B), arms, and legs (Figure 1C), as well as violaceous to erythematous patches on the mucosal aspect of the lower lip (Figure 2). Two 4-mm punch biopsies were performed from the chest and back, which revealed an atrophic epidermis, lichenoid infiltration, and multiple melanophages in the upper dermis consistent with LDE (Figure 3). Direct immunofluorescence was negative. Therefore, based on the clinicopathologic correlation, the diagnosis of imatinib-induced LDE was made. He was treated with clobetasol ointment twice daily for 3 weeks with some improvement. His GIST was stable on follow-up computed tomography 3 months after presentation, and imatinib was resumed 1 month later with continued rash that was stable with topical corticosteroid treatment.

Comment

In addition to CML, imatinib has been approved for acute lymphoblastic leukemia, myelodysplastic syndromes, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, and GIST. Moreover, off-label use of imatinib for various other tyrosine kinase–positive cancers and rheumatologic conditions have been documented.^2,3 With the expanding use of imatinib, there will be more occasions for dermatologists to encounter cutaneous manifestations associated with its use.

According to a PubMed search of articles indexed for MEDLINE using the terms imatinib mesylate lichenoid drug, there have been few case reports of LDE associated with imatinib in the literature (eTable).^4-24 Compared to classic LDE, imatinib-induced LDE has a few characteristic findings. Classic LDE frequently spares the oral mucosa and genitalia, but imatinib-induced LDE with manifestations on the oral mucosa and genitalia as well as cutaneous eruptions have been reported.^4-9 In fact, the first known case of imatinib-induced LDE was an oral eruption in a patient with CML.⁴ In patients with oral involvement, lesions have been described as lacy reticular macules and violaceous papules, erosions, and ulcers.^4,5,12 Interestingly, of those cases manifesting as concomitant oral and cutaneous LDE, the oral eruptions recurred more frequently, with 3 of 12 patients having recurrence of oral lesions after the cutaneous manifestations resolved.^8,16 Genital manifestations of imatinib-induced LDE were much less common.^9,11

To date, subsequent reports of imatinib-induced LDE have documented skin manifestations consistent with classic LDE occurring in a diffuse, bilateral, photodistributed pattern.^10,15,16 One case presented with diffuse hyperpigmentation associated with LDE in a Japanese patient.²⁰ The authors suggested this finding may be more prominent in patients with skin of color,²⁰ which is consistent with the current case. Nail findings such as subungual hyperkeratosis and longitudinal ridging also have been reported.^9,11

The latency period between initiation of imat-inib and onset of LDE generally ranges from 1 to 12 months, with onset most commonly occurring between 2 to 5 months or with dosage increase (eTable). Imatinib-induced LDE primarily has been documented with a 400-mg dose, with 1 case of a 600-mg dose and 1 case of an 800-mg dose, which suggests dose dependency. Furthermore, reports exist of several patients responding well to dose reduction with subsequent recurrence on dose reescalation.^13,15

Historically, LDE resolves with discontinuation of the drug after a few weeks to months. When discontinuation of imatinib is unfavorable or patients report symptoms including severe pruritus or pain, treatment should be considered. Topical or oral corticosteroids can be used to treat imatinib-induced LDE, similar to lichen planus. When oral corticosteroids are contraindicated (eg, due to poor patient tolerance), oral acitretin at 25 to 35 mg once daily for 6 to 12 weeks has been reported as an alternative treatment.²⁵

In the majority of cases of imatinib-induced LDE, it was undesirable to stop imatinib (eTable). Notably, in half the reported cases, imatinib was able to be continued and patients were treated symptomatically with either oral and/or topical steroids and/or acitretin with complete remission or tolerable recurrences. Dalmau et al⁹ reported 3 patients who responded poorly to topical and oral steroids and were subsequently treated with acitretin 25 mg once daily; 2 of 3 patients responded favorably to treatment and imatinib was able to be continued. In the current case imatinib initially helped, but because his rash was relatively asymptomatic, imatinib was restarted with control of rash with topical steroids. He developed some pancytopenia, which required intermittent stoppage of the imatinib.

Conclusion

We present a case of imatinib-induced cutaneous and oral LDE in a patient with GIST. Topical corticosteroids, oral acitretin, and oral steroids all may be reasonable treatment options if discontinuing imatinib is not possible in a symptomatic patient. If these therapies fail and the eruption is extensive or intolerable, dosage adjustment is another option to consider before discontinuation of imatinib.

To improve patient care and outcomes, leading dermatologists offered their recommendations on adult acne products. Consideration must be given to:

• Bioclear Face Lotion and Face Cream
  Jan Marini Skin Research, Inc
  “These products contain a powerful combination of glycolic, salicylic, and azelaic acids to smooth and brighten acne-prone skin.”—Larisa Ravitskiy, MD, Gahanna, Ohio

• Neutrogena Clear Pore Cleanser/Mask
  Johnson & Johnson Consumer Inc
  “This is a good daily product for acne-prone skin. It is formulated with benzoyl peroxide and can be used as a daily wash or mask.”—Anthony M. Rossi, MD, New York, New York

• Offects Sulfur Masque Acne Treatment
  ZO Skin Health Inc
  “This nonirritating mask reduces inflammation and oiliness and is safe to use in pregnancy.”—Larisa Ravitskiy, MD, Gahanna, Ohio

• PanOxyl Acne Foaming Wash and Acne Creamy Wash
  Stiefel, a GSK company
  Recommended by Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, as well as products for dry cuticles, hyperhidrosis, and sensitive skin will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

[polldaddy:9711250]

To improve patient care and outcomes, leading dermatologists offered their recommendations on adult acne products. Consideration must be given to:

• Bioclear Face Lotion and Face Cream
  Jan Marini Skin Research, Inc
  “These products contain a powerful combination of glycolic, salicylic, and azelaic acids to smooth and brighten acne-prone skin.”—Larisa Ravitskiy, MD, Gahanna, Ohio

• Neutrogena Clear Pore Cleanser/Mask
  Johnson & Johnson Consumer Inc
  “This is a good daily product for acne-prone skin. It is formulated with benzoyl peroxide and can be used as a daily wash or mask.”—Anthony M. Rossi, MD, New York, New York

• Offects Sulfur Masque Acne Treatment
  ZO Skin Health Inc
  “This nonirritating mask reduces inflammation and oiliness and is safe to use in pregnancy.”—Larisa Ravitskiy, MD, Gahanna, Ohio

• PanOxyl Acne Foaming Wash and Acne Creamy Wash
  Stiefel, a GSK company
  Recommended by Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, as well as products for dry cuticles, hyperhidrosis, and sensitive skin will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

[polldaddy:9711250]

To improve patient care and outcomes, leading dermatologists offered their recommendations on adult acne products. Consideration must be given to:

• Bioclear Face Lotion and Face Cream
  Jan Marini Skin Research, Inc
  “These products contain a powerful combination of glycolic, salicylic, and azelaic acids to smooth and brighten acne-prone skin.”—Larisa Ravitskiy, MD, Gahanna, Ohio

• Neutrogena Clear Pore Cleanser/Mask
  Johnson & Johnson Consumer Inc
  “This is a good daily product for acne-prone skin. It is formulated with benzoyl peroxide and can be used as a daily wash or mask.”—Anthony M. Rossi, MD, New York, New York

• Offects Sulfur Masque Acne Treatment
  ZO Skin Health Inc
  “This nonirritating mask reduces inflammation and oiliness and is safe to use in pregnancy.”—Larisa Ravitskiy, MD, Gahanna, Ohio

• PanOxyl Acne Foaming Wash and Acne Creamy Wash
  Stiefel, a GSK company
  Recommended by Gary Goldenberg, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, as well as products for dry cuticles, hyperhidrosis, and sensitive skin will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

[polldaddy:9711250]

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Mohs micrographic surgery (MMS) remains the gold standard for the removal of skin cancers in high-risk areas of the body while offering an excellent safety profile and sparing tissue.¹ In the current health care environment, online patient reviews have grown in popularity and influence. More than 60% of consumers consult social media before making health care decisions.² A recent analysis of online patient reviews of general dermatology practices demonstrated the perceived importance of physician empathy, thoroughness, and cognizance of cost in relation to patient-reported satisfaction.³ Because MMS is a well-recognized and unique outpatient-based surgical procedure, a review and analysis of online patient reviews specific to MMS can provide useful practice insights.

Materials and Methods

This study was conducted using an online platform (RealSelf [http://www.realself.com]) that connects patients and providers offering aesthetically oriented procedures; the site has 35 million unique visitors yearly.⁴ The community’s directory was used to identify and analyze all cumulative patient reviews from 2006 to December 20, 2015, using the search terms Mohs surgery or Mohs micrographic surgery. The study was exempt by the Northwestern University (Chicago, Illinois) institutional review board.

A standardized qualitative coding methodology was created and applied to all available comments regarding MMS. A broad list of positive and negative patient experiences was first created and agreed upon by all 3 investigators. Each individual comment was then attributed to 1 or more of these positive or negative themes. Of these comments, 10% were coded by 2 investigators (S.X. and Z.A.) to ensure internal validity; 1 investigator coded the remaining statements by patients (Z.A.). Patient-reported satisfaction ratings categorized as “worth it” or “not worth it” (as used by RealSelf to describe the patient-perceived value and utility of a given procedure) as well as cost of MMS were gathered. Cumulative patient ratings were collected for the procedure overall, physician’s bedside manner, answered questions, aftercare follow-up, time spent with patients, telephone/email responsiveness, staff professionalism/courtesy, payment process, and wait times. Patient-reported characteristics of MMS also were evaluated including physician specialty, lesion location, type of skin cancer, and type of closure. For lesion location, we graded whether the location represented a high-risk area as defined by the American Academy of Dermatology, American College of Mohs Surgery, and American Society for Dermatologic Surgery.⁵

Results

A total of 219 reviews related to MMS were collected as of December 20, 2015. Overall, MMS was considered “worth it” by 89% of patients (Table 1). Only 2% of patients described MMS as “not worth it.” There was a wide range reported for the cost of the procedure ($1–$100,000 [median, $1800]). Of those patients who reported their sex, females were 2.5-times more likely to post a review compared to males (51% vs 20%); however, 30% of reviewers did not report their sex. The mean (standard deviation) overall satisfaction rating was 4.8 (0.8). With regard to category-specific ratings (eg, bedside manner, aftercare follow-up, time spent with patients), the mean scores were all 4.7 or greater (Table 2).

Regarding the surgical aspects of the procedure, the majority of patients reported that the excision of the lesion was performed by a dermatologist (62%). However, a notable portion of patients reported that the excision was performed by a plastic surgeon (21%). Physician specialty was not reported in 16% of the reviews. For the lesion closure, the patient-reported specialty of the physician was only slightly higher for dermatologists versus plastic surgeons (46% vs 44%)(Table 3).

The majority of patients who reported the location of the lesion treated with MMS identified a high-risk location (45%), a medium-risk location (18%), or an unspecified region of the face (15%), according to the appropriate-use criteria for MMS (Table 3).⁵ Patients did not specify the site of surgery 17% of the time. Only 5% of reported procedures were performed on low-risk areas.

Basal cell carcinomas were the most commonly reported lesions removed by MMS (38%), though 48% of reviews did not specify the type of tumor being treated (Table 3). A large majority (76%) did not specify the type of closure performed. When specified, secondary intention was used 10% of the time, followed by either a flap (6%) or skin graft (6%). Only 5% of patients reported an estimated size of the primary lesion in our study (data not shown).

The qualitative analysis demonstrated variance in themes for positive and negative characteristics (Table 4). Surgeon characteristics encompassed the 3 most commonly cited themes of positive remarks, including bedside manner (78%), communication skills (74%), and perceived expertise (58%). Specific to MMS, the tissue-sparing nature of the technique was cited by 14% of reviews as a positive theme. The most commonly cited themes of negative remarks were intraoperative and postoperative concerns, including postoperative disfigurement (16%), large scar (9%), healing time (9%), and procedural or postoperative pain (8%). A subtheme analysis of postoperative disfigurement revealed that eyelid or eyebrow distortion was the most common concern (29%), followed by redness and swelling (23%), an open wound (14%), and nostril/nose distortion (14%)(data not shown). Themes not commonly cited as either positive or negative included office environment, cost, and procedure time (data not shown).

Comment

The overall satisfaction with MMS (89%) was one of the highest for any procedure on this online patient review site, albeit based on fewer reviews compared to other common aesthetic surgical procedures. In comparison, 78% of 13,500 reviewers rated breast augmentation as “worth it,” while 60% of 6800 reviewers rated rhinoplasty as “worth it” (as of December 2015). Overall, the online patient reviews evaluated in this study were consistent with a previously published structured data report on patient satisfaction with MMS.⁶

The results show a greater than expected proportion of both the MMS excision and closure being performed by plastic surgeons compared to dermatologists. In reality, the majority of MMS excisions are performed by dermatologists. Based on a survey of American College of Mohs Surgery (ACMS) members, only 6% of procedures were sent to other specialties for closure.⁷ Our results may reflect reporting bias or patients misconstruing true MMS with an excision and standard frozen sections, techniques that have lower cure rates. If so, there may be a need to educate patients regarding the specifics of MMS. Other possible explanations for the discrepancy between the online patient reviews and ACMS data include misinterpretation by patients on the exact definition of MMS or that a higher than expected number of procedures were performed by non-ACMS Mohs surgeons.

Our qualitative analysis revealed that patients most frequently commented on the interpersonal skills of their surgeons (eg, bedside manner, communication) as positive themes during MMS, similar to prior analyses of general dermatology practices.³ In comparison to a recent study assessing patient satisfaction with rhinoplasty on RealSelf, the final appearance of the nose represented the most common positive- and negative-cited theme.⁸ Mohs micrographic surgery procedures typically are done under local anesthesia, which may explain the greater importance of bedside manner and communication intraoperatively in comparison to final surgical outcomes for patient satisfaction. For negative themes, 3 of 4 most common concerns were directly related to the intraoperative and postoperative periods. Providers may be able to improve patient satisfaction by explaining the postoperative course, such as healing time and temporary physical restrictions, as well as possible sequelae in greater detail, which may be particularly pertinent for MMS involving the nose or near the eyes.

The global ratings for MMS are high, as shown in our data set of patient reviews; however, patient reviews are highly susceptible to reporting bias, recall bias, and missing information. Prior work using this online patient review website to investigate laser and light procedures also demonstrated the risk for imperfect information associated with patient reviews.⁹ Even so, the data does provide a glimpse into what is considered important to patients. Surgeon interpersonal skills and communication were the most frequently cited positive themes for MMS. The best surgical aspects of MMS focused on the unique tissue-sparing nature of the procedure and the removal of a cancerous lesion. Potential areas for improvement include a more thorough explanation of the intraoperative and postoperative process, specifically potential asymmetry related to the nose or the eyes, healing time, and scarring. These patient reviews underscore the importance of setting appropriate patient expectations. As patients become more connected and utilize online platforms to report their experiences, Mohs surgeons can take insights derived from online patient reviews for their own practice or geographic area to improve satisfaction and manage expectations.

Mohs micrographic surgery (MMS) remains the gold standard for the removal of skin cancers in high-risk areas of the body while offering an excellent safety profile and sparing tissue.¹ In the current health care environment, online patient reviews have grown in popularity and influence. More than 60% of consumers consult social media before making health care decisions.² A recent analysis of online patient reviews of general dermatology practices demonstrated the perceived importance of physician empathy, thoroughness, and cognizance of cost in relation to patient-reported satisfaction.³ Because MMS is a well-recognized and unique outpatient-based surgical procedure, a review and analysis of online patient reviews specific to MMS can provide useful practice insights.

Materials and Methods

This study was conducted using an online platform (RealSelf [http://www.realself.com]) that connects patients and providers offering aesthetically oriented procedures; the site has 35 million unique visitors yearly.⁴ The community’s directory was used to identify and analyze all cumulative patient reviews from 2006 to December 20, 2015, using the search terms Mohs surgery or Mohs micrographic surgery. The study was exempt by the Northwestern University (Chicago, Illinois) institutional review board.

A standardized qualitative coding methodology was created and applied to all available comments regarding MMS. A broad list of positive and negative patient experiences was first created and agreed upon by all 3 investigators. Each individual comment was then attributed to 1 or more of these positive or negative themes. Of these comments, 10% were coded by 2 investigators (S.X. and Z.A.) to ensure internal validity; 1 investigator coded the remaining statements by patients (Z.A.). Patient-reported satisfaction ratings categorized as “worth it” or “not worth it” (as used by RealSelf to describe the patient-perceived value and utility of a given procedure) as well as cost of MMS were gathered. Cumulative patient ratings were collected for the procedure overall, physician’s bedside manner, answered questions, aftercare follow-up, time spent with patients, telephone/email responsiveness, staff professionalism/courtesy, payment process, and wait times. Patient-reported characteristics of MMS also were evaluated including physician specialty, lesion location, type of skin cancer, and type of closure. For lesion location, we graded whether the location represented a high-risk area as defined by the American Academy of Dermatology, American College of Mohs Surgery, and American Society for Dermatologic Surgery.⁵

Results

A total of 219 reviews related to MMS were collected as of December 20, 2015. Overall, MMS was considered “worth it” by 89% of patients (Table 1). Only 2% of patients described MMS as “not worth it.” There was a wide range reported for the cost of the procedure ($1–$100,000 [median, $1800]). Of those patients who reported their sex, females were 2.5-times more likely to post a review compared to males (51% vs 20%); however, 30% of reviewers did not report their sex. The mean (standard deviation) overall satisfaction rating was 4.8 (0.8). With regard to category-specific ratings (eg, bedside manner, aftercare follow-up, time spent with patients), the mean scores were all 4.7 or greater (Table 2).

Regarding the surgical aspects of the procedure, the majority of patients reported that the excision of the lesion was performed by a dermatologist (62%). However, a notable portion of patients reported that the excision was performed by a plastic surgeon (21%). Physician specialty was not reported in 16% of the reviews. For the lesion closure, the patient-reported specialty of the physician was only slightly higher for dermatologists versus plastic surgeons (46% vs 44%)(Table 3).

The majority of patients who reported the location of the lesion treated with MMS identified a high-risk location (45%), a medium-risk location (18%), or an unspecified region of the face (15%), according to the appropriate-use criteria for MMS (Table 3).⁵ Patients did not specify the site of surgery 17% of the time. Only 5% of reported procedures were performed on low-risk areas.

Basal cell carcinomas were the most commonly reported lesions removed by MMS (38%), though 48% of reviews did not specify the type of tumor being treated (Table 3). A large majority (76%) did not specify the type of closure performed. When specified, secondary intention was used 10% of the time, followed by either a flap (6%) or skin graft (6%). Only 5% of patients reported an estimated size of the primary lesion in our study (data not shown).

The qualitative analysis demonstrated variance in themes for positive and negative characteristics (Table 4). Surgeon characteristics encompassed the 3 most commonly cited themes of positive remarks, including bedside manner (78%), communication skills (74%), and perceived expertise (58%). Specific to MMS, the tissue-sparing nature of the technique was cited by 14% of reviews as a positive theme. The most commonly cited themes of negative remarks were intraoperative and postoperative concerns, including postoperative disfigurement (16%), large scar (9%), healing time (9%), and procedural or postoperative pain (8%). A subtheme analysis of postoperative disfigurement revealed that eyelid or eyebrow distortion was the most common concern (29%), followed by redness and swelling (23%), an open wound (14%), and nostril/nose distortion (14%)(data not shown). Themes not commonly cited as either positive or negative included office environment, cost, and procedure time (data not shown).

Comment

The overall satisfaction with MMS (89%) was one of the highest for any procedure on this online patient review site, albeit based on fewer reviews compared to other common aesthetic surgical procedures. In comparison, 78% of 13,500 reviewers rated breast augmentation as “worth it,” while 60% of 6800 reviewers rated rhinoplasty as “worth it” (as of December 2015). Overall, the online patient reviews evaluated in this study were consistent with a previously published structured data report on patient satisfaction with MMS.⁶

The results show a greater than expected proportion of both the MMS excision and closure being performed by plastic surgeons compared to dermatologists. In reality, the majority of MMS excisions are performed by dermatologists. Based on a survey of American College of Mohs Surgery (ACMS) members, only 6% of procedures were sent to other specialties for closure.⁷ Our results may reflect reporting bias or patients misconstruing true MMS with an excision and standard frozen sections, techniques that have lower cure rates. If so, there may be a need to educate patients regarding the specifics of MMS. Other possible explanations for the discrepancy between the online patient reviews and ACMS data include misinterpretation by patients on the exact definition of MMS or that a higher than expected number of procedures were performed by non-ACMS Mohs surgeons.

Our qualitative analysis revealed that patients most frequently commented on the interpersonal skills of their surgeons (eg, bedside manner, communication) as positive themes during MMS, similar to prior analyses of general dermatology practices.³ In comparison to a recent study assessing patient satisfaction with rhinoplasty on RealSelf, the final appearance of the nose represented the most common positive- and negative-cited theme.⁸ Mohs micrographic surgery procedures typically are done under local anesthesia, which may explain the greater importance of bedside manner and communication intraoperatively in comparison to final surgical outcomes for patient satisfaction. For negative themes, 3 of 4 most common concerns were directly related to the intraoperative and postoperative periods. Providers may be able to improve patient satisfaction by explaining the postoperative course, such as healing time and temporary physical restrictions, as well as possible sequelae in greater detail, which may be particularly pertinent for MMS involving the nose or near the eyes.

The global ratings for MMS are high, as shown in our data set of patient reviews; however, patient reviews are highly susceptible to reporting bias, recall bias, and missing information. Prior work using this online patient review website to investigate laser and light procedures also demonstrated the risk for imperfect information associated with patient reviews.⁹ Even so, the data does provide a glimpse into what is considered important to patients. Surgeon interpersonal skills and communication were the most frequently cited positive themes for MMS. The best surgical aspects of MMS focused on the unique tissue-sparing nature of the procedure and the removal of a cancerous lesion. Potential areas for improvement include a more thorough explanation of the intraoperative and postoperative process, specifically potential asymmetry related to the nose or the eyes, healing time, and scarring. These patient reviews underscore the importance of setting appropriate patient expectations. As patients become more connected and utilize online platforms to report their experiences, Mohs surgeons can take insights derived from online patient reviews for their own practice or geographic area to improve satisfaction and manage expectations.

Mohs micrographic surgery (MMS) remains the gold standard for the removal of skin cancers in high-risk areas of the body while offering an excellent safety profile and sparing tissue.¹ In the current health care environment, online patient reviews have grown in popularity and influence. More than 60% of consumers consult social media before making health care decisions.² A recent analysis of online patient reviews of general dermatology practices demonstrated the perceived importance of physician empathy, thoroughness, and cognizance of cost in relation to patient-reported satisfaction.³ Because MMS is a well-recognized and unique outpatient-based surgical procedure, a review and analysis of online patient reviews specific to MMS can provide useful practice insights.

Materials and Methods

This study was conducted using an online platform (RealSelf [http://www.realself.com]) that connects patients and providers offering aesthetically oriented procedures; the site has 35 million unique visitors yearly.⁴ The community’s directory was used to identify and analyze all cumulative patient reviews from 2006 to December 20, 2015, using the search terms Mohs surgery or Mohs micrographic surgery. The study was exempt by the Northwestern University (Chicago, Illinois) institutional review board.

A standardized qualitative coding methodology was created and applied to all available comments regarding MMS. A broad list of positive and negative patient experiences was first created and agreed upon by all 3 investigators. Each individual comment was then attributed to 1 or more of these positive or negative themes. Of these comments, 10% were coded by 2 investigators (S.X. and Z.A.) to ensure internal validity; 1 investigator coded the remaining statements by patients (Z.A.). Patient-reported satisfaction ratings categorized as “worth it” or “not worth it” (as used by RealSelf to describe the patient-perceived value and utility of a given procedure) as well as cost of MMS were gathered. Cumulative patient ratings were collected for the procedure overall, physician’s bedside manner, answered questions, aftercare follow-up, time spent with patients, telephone/email responsiveness, staff professionalism/courtesy, payment process, and wait times. Patient-reported characteristics of MMS also were evaluated including physician specialty, lesion location, type of skin cancer, and type of closure. For lesion location, we graded whether the location represented a high-risk area as defined by the American Academy of Dermatology, American College of Mohs Surgery, and American Society for Dermatologic Surgery.⁵

Results

A total of 219 reviews related to MMS were collected as of December 20, 2015. Overall, MMS was considered “worth it” by 89% of patients (Table 1). Only 2% of patients described MMS as “not worth it.” There was a wide range reported for the cost of the procedure ($1–$100,000 [median, $1800]). Of those patients who reported their sex, females were 2.5-times more likely to post a review compared to males (51% vs 20%); however, 30% of reviewers did not report their sex. The mean (standard deviation) overall satisfaction rating was 4.8 (0.8). With regard to category-specific ratings (eg, bedside manner, aftercare follow-up, time spent with patients), the mean scores were all 4.7 or greater (Table 2).

Regarding the surgical aspects of the procedure, the majority of patients reported that the excision of the lesion was performed by a dermatologist (62%). However, a notable portion of patients reported that the excision was performed by a plastic surgeon (21%). Physician specialty was not reported in 16% of the reviews. For the lesion closure, the patient-reported specialty of the physician was only slightly higher for dermatologists versus plastic surgeons (46% vs 44%)(Table 3).

The majority of patients who reported the location of the lesion treated with MMS identified a high-risk location (45%), a medium-risk location (18%), or an unspecified region of the face (15%), according to the appropriate-use criteria for MMS (Table 3).⁵ Patients did not specify the site of surgery 17% of the time. Only 5% of reported procedures were performed on low-risk areas.

Basal cell carcinomas were the most commonly reported lesions removed by MMS (38%), though 48% of reviews did not specify the type of tumor being treated (Table 3). A large majority (76%) did not specify the type of closure performed. When specified, secondary intention was used 10% of the time, followed by either a flap (6%) or skin graft (6%). Only 5% of patients reported an estimated size of the primary lesion in our study (data not shown).

The qualitative analysis demonstrated variance in themes for positive and negative characteristics (Table 4). Surgeon characteristics encompassed the 3 most commonly cited themes of positive remarks, including bedside manner (78%), communication skills (74%), and perceived expertise (58%). Specific to MMS, the tissue-sparing nature of the technique was cited by 14% of reviews as a positive theme. The most commonly cited themes of negative remarks were intraoperative and postoperative concerns, including postoperative disfigurement (16%), large scar (9%), healing time (9%), and procedural or postoperative pain (8%). A subtheme analysis of postoperative disfigurement revealed that eyelid or eyebrow distortion was the most common concern (29%), followed by redness and swelling (23%), an open wound (14%), and nostril/nose distortion (14%)(data not shown). Themes not commonly cited as either positive or negative included office environment, cost, and procedure time (data not shown).

Comment

The overall satisfaction with MMS (89%) was one of the highest for any procedure on this online patient review site, albeit based on fewer reviews compared to other common aesthetic surgical procedures. In comparison, 78% of 13,500 reviewers rated breast augmentation as “worth it,” while 60% of 6800 reviewers rated rhinoplasty as “worth it” (as of December 2015). Overall, the online patient reviews evaluated in this study were consistent with a previously published structured data report on patient satisfaction with MMS.⁶

The results show a greater than expected proportion of both the MMS excision and closure being performed by plastic surgeons compared to dermatologists. In reality, the majority of MMS excisions are performed by dermatologists. Based on a survey of American College of Mohs Surgery (ACMS) members, only 6% of procedures were sent to other specialties for closure.⁷ Our results may reflect reporting bias or patients misconstruing true MMS with an excision and standard frozen sections, techniques that have lower cure rates. If so, there may be a need to educate patients regarding the specifics of MMS. Other possible explanations for the discrepancy between the online patient reviews and ACMS data include misinterpretation by patients on the exact definition of MMS or that a higher than expected number of procedures were performed by non-ACMS Mohs surgeons.

Our qualitative analysis revealed that patients most frequently commented on the interpersonal skills of their surgeons (eg, bedside manner, communication) as positive themes during MMS, similar to prior analyses of general dermatology practices.³ In comparison to a recent study assessing patient satisfaction with rhinoplasty on RealSelf, the final appearance of the nose represented the most common positive- and negative-cited theme.⁸ Mohs micrographic surgery procedures typically are done under local anesthesia, which may explain the greater importance of bedside manner and communication intraoperatively in comparison to final surgical outcomes for patient satisfaction. For negative themes, 3 of 4 most common concerns were directly related to the intraoperative and postoperative periods. Providers may be able to improve patient satisfaction by explaining the postoperative course, such as healing time and temporary physical restrictions, as well as possible sequelae in greater detail, which may be particularly pertinent for MMS involving the nose or near the eyes.

The global ratings for MMS are high, as shown in our data set of patient reviews; however, patient reviews are highly susceptible to reporting bias, recall bias, and missing information. Prior work using this online patient review website to investigate laser and light procedures also demonstrated the risk for imperfect information associated with patient reviews.⁹ Even so, the data does provide a glimpse into what is considered important to patients. Surgeon interpersonal skills and communication were the most frequently cited positive themes for MMS. The best surgical aspects of MMS focused on the unique tissue-sparing nature of the procedure and the removal of a cancerous lesion. Potential areas for improvement include a more thorough explanation of the intraoperative and postoperative process, specifically potential asymmetry related to the nose or the eyes, healing time, and scarring. These patient reviews underscore the importance of setting appropriate patient expectations. As patients become more connected and utilize online platforms to report their experiences, Mohs surgeons can take insights derived from online patient reviews for their own practice or geographic area to improve satisfaction and manage expectations.

Lupus erythematosus tumidus (LET) is a relatively rare condition but may simply be underdiagnosed in the literature. It presents as urticarialike papules and plaques in sun-exposed areas, characterized by induration and erythema. Lesions occur on the face, neck, upper extremities, and trunk and heal without scarring.^1,2 Rarely, lesions can show fine scaling and associated pruritus, but most often the lesions are asymptomatic.³

Case Report

A 45-year-old woman presented with 2 asymptomatic self-described bald spots on the top of the head of 2 months’ duration. The patient denied prior treatment of the lesions and noted one patch was resolving. She reported no involvement of the eyebrows, eyelashes, and axillary and pubic hair. A review of systems was negative. The patient denied personal or family history of lupus, thyroid disease, or vitiligo.

Clinical examination revealed a 1.1-cm round patch of nonscarring alopecia on the right vertex scalp and a 0.9-cm round patch of nonscarring alopecia with moderate hair regrowth on the left vertex scalp. There was no erythema, scaling, or induration. The rest of the scalp was normal in appearance and the eyebrows and eyelashes were uninvolved. The patient was diagnosed with alopecia areata and was treated with 10 mg/mL of intralesional triamcinolone once monthly for 4 months.

The patient initially showed improvement with moderate hair regrowth. After 4 months of treatment, she developed 3 new 1- to 1.5-cm erythematous alopecic patches on the vertex scalp and had worsening in the initial patches (Figure 1). Given the resistance to standard therapy and the onset of multiple new areas with evidence of inflammatory involvement, a punch biopsy was performed. Histopathologic examination revealed a fairly unremarkable epidermis and a dense dermal inflammatory infiltrate that was present both in the superficial and deep dermis (Figure 2). The inflammatory cells, which appeared to be predominantly comprised of lymphocytes, had a predilection for the vasculature but also were observed within the interstitial dermis. Additionally, mucin appeared to be slightly increased in the deep dermis. The lymphocytic phenotype was confirmed by immunohistochemical studies for CD20 and CD3. The most likely possibilities for this reaction pattern were LET, Jessner lymphocytic infiltrate of the skin (JLIS), gyrate erythema, and lymphoma; however, the immunohistochemical studies effectively ruled out lymphoma. Additionally, there was pronounced dermal mucin noted in the specimen. The patient was diagnosed with LET of the scalp based on the constellation of findings.

Comment

The classification of LET as a single unique entity or disease process sui generis has been in flux in the last decade. Its similarities to JLIS and other forms of chronic cutaneous lupus erythematosus (CCLE) have brought debate.^4-6 In 1930, Gougerot and Burnier⁷ documented the first case of LET in the literature, describing smooth, infiltrated, erythematous lesions with no desquamation or other superficial changes seen in 5 patients.

In 2000, interest in LET and other forms of CCLE was increasing, and reports in the literature paralleled. That year, Kuhn et al⁴ reported 40 cases of LET, characterizing the clinical and histological features of each case to demonstrate that LET should be separate from other forms of CCLE. Until then, it is likely that many lesions that should have been classified as LET were instead classified as various forms of CCLE. The investigators maintained that LET also should be distinct from JLIS because it is associated with UV exposure.⁴ Kuhn et al⁸ reviewed phototesting in 60 patients with LET in 2001 and confirmed this subset was the most photosensitive type of lupus erythematosus.

In general, the histopathologic and immunohistochemical studies in LET and JLIS can be quite similar. Relatively distinguishing histopathologic findings in JLIS include no evidence of epidermal atrophy, basal vacuolar change, or follicular plugging, as well as negative immunofluorescence studies. Both entities show a predominantly T-cell population with a smaller component of B cells and thus a distinction cannot be made based on relative proportions of T and B cells in lesions.²

In 2003, Alexiades-Armenakas et al⁶ determined immunohistochemical criteria for LET, finding a predominance of T cells and more CD4 lymphocytes than CD8 lymphocytes with a mean ratio of roughly 3 to 1. Their study results maintained LET should be classified as a form of CCLE due to the chronicity of the lesions, the serologic profile with negative anti–double-stranded DNA, anticentromere, anti-Smith, anti-Ro/Sjögren syndrome antigen A, anti-La/Sjögren syndrome antigen B, and anti-nuclear ribonucleoprotein antibodies and the rare association with systemic disease.⁶ This conclusion was further solidified by a review published that same year citing unique histopathological features when compared to subacute cutaneous LE and discoid lupus erythematosus.⁵

This case illustrates the importance of histologic evaluation in determining the correct diagnosis in a patient with alopecia areata recalcitrant to treatment. Including LET in the differential of alopecic patches on the scalp could prove beneficial for patients, as LET responds well to antimalarial drugs and photoprotection.⁹ This patient had a normal antinuclear antibody panel and no signs or symptoms of systemic lupus. It was recommended that she avoid sun exposure and begin treatment with hydroxychloroquine but she declined. At a follow-up visit 6 months later she reported the lesions had improved, but a permanent wig had been sewn over the area, so it could not be examined.

Lupus erythematosus tumidus (LET) is a relatively rare condition but may simply be underdiagnosed in the literature. It presents as urticarialike papules and plaques in sun-exposed areas, characterized by induration and erythema. Lesions occur on the face, neck, upper extremities, and trunk and heal without scarring.^1,2 Rarely, lesions can show fine scaling and associated pruritus, but most often the lesions are asymptomatic.³

Case Report

A 45-year-old woman presented with 2 asymptomatic self-described bald spots on the top of the head of 2 months’ duration. The patient denied prior treatment of the lesions and noted one patch was resolving. She reported no involvement of the eyebrows, eyelashes, and axillary and pubic hair. A review of systems was negative. The patient denied personal or family history of lupus, thyroid disease, or vitiligo.

Clinical examination revealed a 1.1-cm round patch of nonscarring alopecia on the right vertex scalp and a 0.9-cm round patch of nonscarring alopecia with moderate hair regrowth on the left vertex scalp. There was no erythema, scaling, or induration. The rest of the scalp was normal in appearance and the eyebrows and eyelashes were uninvolved. The patient was diagnosed with alopecia areata and was treated with 10 mg/mL of intralesional triamcinolone once monthly for 4 months.

The patient initially showed improvement with moderate hair regrowth. After 4 months of treatment, she developed 3 new 1- to 1.5-cm erythematous alopecic patches on the vertex scalp and had worsening in the initial patches (Figure 1). Given the resistance to standard therapy and the onset of multiple new areas with evidence of inflammatory involvement, a punch biopsy was performed. Histopathologic examination revealed a fairly unremarkable epidermis and a dense dermal inflammatory infiltrate that was present both in the superficial and deep dermis (Figure 2). The inflammatory cells, which appeared to be predominantly comprised of lymphocytes, had a predilection for the vasculature but also were observed within the interstitial dermis. Additionally, mucin appeared to be slightly increased in the deep dermis. The lymphocytic phenotype was confirmed by immunohistochemical studies for CD20 and CD3. The most likely possibilities for this reaction pattern were LET, Jessner lymphocytic infiltrate of the skin (JLIS), gyrate erythema, and lymphoma; however, the immunohistochemical studies effectively ruled out lymphoma. Additionally, there was pronounced dermal mucin noted in the specimen. The patient was diagnosed with LET of the scalp based on the constellation of findings.

Comment

The classification of LET as a single unique entity or disease process sui generis has been in flux in the last decade. Its similarities to JLIS and other forms of chronic cutaneous lupus erythematosus (CCLE) have brought debate.^4-6 In 1930, Gougerot and Burnier⁷ documented the first case of LET in the literature, describing smooth, infiltrated, erythematous lesions with no desquamation or other superficial changes seen in 5 patients.

In 2000, interest in LET and other forms of CCLE was increasing, and reports in the literature paralleled. That year, Kuhn et al⁴ reported 40 cases of LET, characterizing the clinical and histological features of each case to demonstrate that LET should be separate from other forms of CCLE. Until then, it is likely that many lesions that should have been classified as LET were instead classified as various forms of CCLE. The investigators maintained that LET also should be distinct from JLIS because it is associated with UV exposure.⁴ Kuhn et al⁸ reviewed phototesting in 60 patients with LET in 2001 and confirmed this subset was the most photosensitive type of lupus erythematosus.

In general, the histopathologic and immunohistochemical studies in LET and JLIS can be quite similar. Relatively distinguishing histopathologic findings in JLIS include no evidence of epidermal atrophy, basal vacuolar change, or follicular plugging, as well as negative immunofluorescence studies. Both entities show a predominantly T-cell population with a smaller component of B cells and thus a distinction cannot be made based on relative proportions of T and B cells in lesions.²

In 2003, Alexiades-Armenakas et al⁶ determined immunohistochemical criteria for LET, finding a predominance of T cells and more CD4 lymphocytes than CD8 lymphocytes with a mean ratio of roughly 3 to 1. Their study results maintained LET should be classified as a form of CCLE due to the chronicity of the lesions, the serologic profile with negative anti–double-stranded DNA, anticentromere, anti-Smith, anti-Ro/Sjögren syndrome antigen A, anti-La/Sjögren syndrome antigen B, and anti-nuclear ribonucleoprotein antibodies and the rare association with systemic disease.⁶ This conclusion was further solidified by a review published that same year citing unique histopathological features when compared to subacute cutaneous LE and discoid lupus erythematosus.⁵

This case illustrates the importance of histologic evaluation in determining the correct diagnosis in a patient with alopecia areata recalcitrant to treatment. Including LET in the differential of alopecic patches on the scalp could prove beneficial for patients, as LET responds well to antimalarial drugs and photoprotection.⁹ This patient had a normal antinuclear antibody panel and no signs or symptoms of systemic lupus. It was recommended that she avoid sun exposure and begin treatment with hydroxychloroquine but she declined. At a follow-up visit 6 months later she reported the lesions had improved, but a permanent wig had been sewn over the area, so it could not be examined.

Lupus erythematosus tumidus (LET) is a relatively rare condition but may simply be underdiagnosed in the literature. It presents as urticarialike papules and plaques in sun-exposed areas, characterized by induration and erythema. Lesions occur on the face, neck, upper extremities, and trunk and heal without scarring.^1,2 Rarely, lesions can show fine scaling and associated pruritus, but most often the lesions are asymptomatic.³

Case Report

A 45-year-old woman presented with 2 asymptomatic self-described bald spots on the top of the head of 2 months’ duration. The patient denied prior treatment of the lesions and noted one patch was resolving. She reported no involvement of the eyebrows, eyelashes, and axillary and pubic hair. A review of systems was negative. The patient denied personal or family history of lupus, thyroid disease, or vitiligo.

Clinical examination revealed a 1.1-cm round patch of nonscarring alopecia on the right vertex scalp and a 0.9-cm round patch of nonscarring alopecia with moderate hair regrowth on the left vertex scalp. There was no erythema, scaling, or induration. The rest of the scalp was normal in appearance and the eyebrows and eyelashes were uninvolved. The patient was diagnosed with alopecia areata and was treated with 10 mg/mL of intralesional triamcinolone once monthly for 4 months.

The patient initially showed improvement with moderate hair regrowth. After 4 months of treatment, she developed 3 new 1- to 1.5-cm erythematous alopecic patches on the vertex scalp and had worsening in the initial patches (Figure 1). Given the resistance to standard therapy and the onset of multiple new areas with evidence of inflammatory involvement, a punch biopsy was performed. Histopathologic examination revealed a fairly unremarkable epidermis and a dense dermal inflammatory infiltrate that was present both in the superficial and deep dermis (Figure 2). The inflammatory cells, which appeared to be predominantly comprised of lymphocytes, had a predilection for the vasculature but also were observed within the interstitial dermis. Additionally, mucin appeared to be slightly increased in the deep dermis. The lymphocytic phenotype was confirmed by immunohistochemical studies for CD20 and CD3. The most likely possibilities for this reaction pattern were LET, Jessner lymphocytic infiltrate of the skin (JLIS), gyrate erythema, and lymphoma; however, the immunohistochemical studies effectively ruled out lymphoma. Additionally, there was pronounced dermal mucin noted in the specimen. The patient was diagnosed with LET of the scalp based on the constellation of findings.

Comment

The classification of LET as a single unique entity or disease process sui generis has been in flux in the last decade. Its similarities to JLIS and other forms of chronic cutaneous lupus erythematosus (CCLE) have brought debate.^4-6 In 1930, Gougerot and Burnier⁷ documented the first case of LET in the literature, describing smooth, infiltrated, erythematous lesions with no desquamation or other superficial changes seen in 5 patients.

In 2000, interest in LET and other forms of CCLE was increasing, and reports in the literature paralleled. That year, Kuhn et al⁴ reported 40 cases of LET, characterizing the clinical and histological features of each case to demonstrate that LET should be separate from other forms of CCLE. Until then, it is likely that many lesions that should have been classified as LET were instead classified as various forms of CCLE. The investigators maintained that LET also should be distinct from JLIS because it is associated with UV exposure.⁴ Kuhn et al⁸ reviewed phototesting in 60 patients with LET in 2001 and confirmed this subset was the most photosensitive type of lupus erythematosus.

In general, the histopathologic and immunohistochemical studies in LET and JLIS can be quite similar. Relatively distinguishing histopathologic findings in JLIS include no evidence of epidermal atrophy, basal vacuolar change, or follicular plugging, as well as negative immunofluorescence studies. Both entities show a predominantly T-cell population with a smaller component of B cells and thus a distinction cannot be made based on relative proportions of T and B cells in lesions.²

In 2003, Alexiades-Armenakas et al⁶ determined immunohistochemical criteria for LET, finding a predominance of T cells and more CD4 lymphocytes than CD8 lymphocytes with a mean ratio of roughly 3 to 1. Their study results maintained LET should be classified as a form of CCLE due to the chronicity of the lesions, the serologic profile with negative anti–double-stranded DNA, anticentromere, anti-Smith, anti-Ro/Sjögren syndrome antigen A, anti-La/Sjögren syndrome antigen B, and anti-nuclear ribonucleoprotein antibodies and the rare association with systemic disease.⁶ This conclusion was further solidified by a review published that same year citing unique histopathological features when compared to subacute cutaneous LE and discoid lupus erythematosus.⁵

This case illustrates the importance of histologic evaluation in determining the correct diagnosis in a patient with alopecia areata recalcitrant to treatment. Including LET in the differential of alopecic patches on the scalp could prove beneficial for patients, as LET responds well to antimalarial drugs and photoprotection.⁹ This patient had a normal antinuclear antibody panel and no signs or symptoms of systemic lupus. It was recommended that she avoid sun exposure and begin treatment with hydroxychloroquine but she declined. At a follow-up visit 6 months later she reported the lesions had improved, but a permanent wig had been sewn over the area, so it could not be examined.