Cutis

Psoriasis affects 2% to 4% of the US population, with approximately one-third of cases beginning in childhood. The understanding of pediatric psoriasis has developed at a far slower pace than adult disease, with limitations in care including few medications that are approved by the US Food and Drug Administration for pediatric and adolescent use. Recently, a stable fixed-combination dose of calcipo-triene 0.005%–betamethasone dipropionate 0.064% topical suspension was approved for treatment of plaque psoriasis of the scalp in patients aged 12 to 17 years, which hopefully will lead a trend in psoriasis medication approval for children and teenagers.¹ Based on a PubMed search of articles indexed for MEDLINE using the search terms pediatric psoriasis, psoriasis, and strep that were published from April 2012 to April 2014, this article reviews newer data to address the issues that surround pediatric psoriasis and to provide an update on prior review articles on pediatric psoriasis.^2-5 This article reviews some of the newer literature on clinical presentation and comorbidities in pediatric psoriasis.⁵ Based on these recent findings, additional screenings including review of obesity parameters are recommended for pediatric patients with psoriasis (Table 1).

Update on Disease Manifestations, Associations, and Comorbidities

Disease Manifestations

A 2013 multicenter study delineated the clinical features of pediatric psoriasis.⁶ The study was conducted at 8 geographically diverse dermatology clinics in the United States to delineate the clinical manifestations of pediatric psoriasis. In an assessment of 181 participants aged 5 to 17 years, the investigators sought to determine the frequency of disease sites, severity, and guttate disease. Over a period of approximately 2 years, 43.1% of participants were determined to have mild disease and 56.9% had severe disease. Family history of psoriasis was present in 51.4% of participants, with first-degree relatives affected in 59.8% of cases. Scalp involvement at some time was noted in 79.0% of participants, and nail disease was noted in 55% of boys and 29% of girls. Guttate psoriasis was noted in 30% of participants, with more cases in the severe range (35.9%) versus the mild range (21.8%). Additionally, 22.1% of participants had a precipitating streptococcal infection, with the association being more common in pediatric patients with guttate psoriasis than plaque psoriasis.⁶ This study highlighted that pediatric psoriasis has a genetic basis, is frequently guttate in nature, commonly affects the nails, shows a trend toward being classified as severe, and may be triggered by streptococcal infections.

Streptococcal Infection

Pediatric psoriasis may be triggered or flared by Streptococcus pyogenes (group A β-hemolytic streptococci) infections, specifically β-hemolytic streptococci groups A, C, and G that have streptococcal M protein,^2,3,7 and this tendency can be associated with HLA-Cw6 or guttate psoriasis. Newer data have elucidated the role of streptococcal throat infections in psoriasis. Given that streptococcal throat infections are most common in school-aged children, these studies suggest a putative mechanism in pediatric psoriasis for triggering streptococcal infections, which would need to be confirmed in future studies, specifically in pediatric psoriasis patients.

It has been shown that T cells in psoriasis patients recognize common streptococcal M proteins and keratin determinants.⁷ Ferran et al⁸ recently demonstrated activation of circulating cutaneous lymphocyte–associated antigen (CLA)⁺ T cells but not CLA^- memory T cells in 27 psoriasis patients (ages not specified) when mixed with streptococcal throat extracts, causing production of IL-17, IP-10, IL-22, and IFN-γ; activation was not found in 6 healthy control patients. Antistreptolysin O levels were correlated with the messenger RNA up- regulation for IL-17, IP-10, IL-22, and IFN-γ, and also correlated with psoriasis area and severity index score in psoriasis patients. In this same study, injection of the activated culture supernatant into mouse skin caused epidermal hyperkeratosis and activation of nonlesional epidermal cells from psoriatic patients. This study thereby delineated some of the potential pathways of the streptococcal induction of psoriasis and psoriatic flares in childhood⁸; however, confirmation is needed through further study of pediatric psoriatic lymphocyte activity.

Differential Diagnosis

Additions to the extensive differential list have been cited in the recent literature. The differential diagnosis of pediatric psoriasis now includes sodium valproate–induced psoriasiform drug eruption⁹ and allergic contact dermatitis to methylchloroisothiazolinone and methylisothiazolinone, which are present in many sanitizing hand and diaper wipes and has been reported to cause psoriasiform dermatitis in a periorificial or perineal distribution.¹⁰ Clinicians should inquire about the use of these wipes, as caregivers rarely suspect this agent to be causative of the eruption.

Psoriatic Arthritis

Previously, psoriasis and psoriatic arthritis have been linked to autoimmune thyroid disease in adults.¹¹ A study of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry showed that family history of psoriasis, autoimmune thyroiditis, Crohn disease, and ankylosing spondylitis in a first-degree relative has been linked to juvenile idiopathic arthritis, highlighting that pediatric psoriasis can be genetically linked or associated with multiple autoimmune conditions and vice versa.¹²

Obesity, Metabolic Syndrome, and Cardiovascular Risks

Obesity is associated with pediatric psoriasis as highlighted in a growing body of recent literature.¹³ Excess adiposity as manifested by body mass index in the 85th percentile or greater (37.9% of 155 pediatric psoriasis patients vs 20.5% of 42 controls) and excess central adiposity as manifested by excess waist circumference and increased waist-to-height ratios are more common in pediatric patients with psoriasis than in controls.¹⁴

Obesity may be a trigger or associated with increased disease activity in pediatric psoriasis patients. Excess overall adiposity correlates with more severe disease. Obesity parameters may correlate with the onset of psoriasis and with disease severity. In fact, the odds of obesity may be higher in childhood than in adults.^14,15 A 2011 report of pediatric psoriasis patients aged 10 to 17 years (n=12) and wart controls (n=6)(mean age, 13.2 and 13.5 years, respectively) demonstrated that 4 of 12 patients with psoriasis and 0 of 6 patients with warts met criteria for metabolic syndrome as defined by 3 of the following: (1) triglycerides greater than or equal to 100 mg/dL; (2) high-density lipoprotein cholesterol less than 50 mg/dL in females and less than 5 mg/dL in males; (3) fasting blood glucose levels greater than or equal to 110 mg/dL, (4) waist circumference greater than the 75th percentile for age and sex; and (5) systolic or diastolic blood pressure greater than the 90th percentile for age, sex, and height.¹⁶ These studies highlight that obesity and metabolic syndrome are of concern in pediatric psoriasis patients; however, the best management approach using diet and weight interventions has yet to be identified.

Adiposity may precede the onset of psoriasis. A recent cohort of 27 pediatric psoriasis patients reported that the average age at onset of psoriasis was 8.7 years and the average age at onset of obesity was 4.1 years.¹⁵ In this study, 93% (25/27) of patients had adiposity preceding their psoriasis by 2 or more years. It is unclear if this is nature or nurture, as 48% (13/27) of patients had a family history of obesity, 41% (11/27) had a family history of psoriasis, and 48% (13/27) had a family history of hyperlipidemia.¹⁵ Therefore, obesity may be cultivated in some psoriatic families. The issue of household influences on diet and obesity needs to be addressed if successful weight management is to be achieved in future studies of pediatric psoriasis.

Cardiovascular risks in the pediatric psoriasis population are the subject of ongoing assessment but will likely mimic studies of adult psoriasis patients when reviewed longitudinally.¹⁶ Weight loss and healthy lifestyle interventions likely are beneficial to long-term health, but there is a lack of published data addressing dietary modification as a disease modifier for long-term care of pediatric psoriasis.

Anxiety and Depression

Anxiety and depression have been noted in adults with chronic skin diseases. A recent study assessed 118 patients and caregivers of pediatric patients with atopic dermatitis (n=50), psoriasis (n=25), or vitiligo (n=43) using the Children’s Dermatology Life Quality Index, the Hamilton Anxiety Scale, and the Beck Depression Inventory.¹⁷ Anxiety and depression were found in 36% of caregivers of pediatric psoriasis patients and depression was found in 36% of pediatric psoriasis patients, highlighting the need for interventions on a personal and family level to improve quality of life. As a comparator, anxiety was more prevalent in vitiligo caregivers (42%), but depression was only found in 26% of caregivers in the same group. Extent of disease (25%–75% body surface area affected) correlated with both depression and anxiety in the caregivers of pediatric patients with psoriasis as well as with anxiety in caregivers of pediatric patients with increased visible surface area of vitiligo.¹⁷ Parental anxiety has been reported at times to be linked to corticosteroid phobia, or corticophobia, which may interfere with disease therapy, as topical corticosteroids are considered the mainstay of therapy in childhood disease.¹⁸ Coordinating care with caregivers and addressing their concerns about the safety of medications should be integral to the pediatric psoriasis visit.

Pustular Psoriasis

Pustular psoriasis can be seen in any age group. Researchers recently have attempted to delineate the features and successful management of this severe subset of pediatric psoriasis patients. Twenty-four pediatric pustular psoriasis cases reviewed by Posso-De Los Rios et al¹⁹ revealed that 92% (22/24) had generalized and 8% (2/24) had limited acral disease. The mean (standard deviation) age at onset of pediatric pustular psoriasis was 6.3 (4.9) years. Half of the reported cases required more than one intervention. Treatment with acitretin, cyclosporine, and methotrexate was effective, but the investigators identified that there is a true dearth of evidence-based therapeutics in pediatric pustular psoriasis and much rebound with discontinuation.¹⁹ Although the subset of pediatric pustular psoriasis is rare, study of evidence-based intervention is needed.

Therapy

Recent reviews of pediatric and adolescent psoriasis highlight the paucity of therapeutic information for these patient populations. Investigators typically focus on topical therapies as the basis of treatment,²⁰ as well as the addition of phototherapy in mild to moderate plaque or guttate psoriasis and biologic or systemic agents in moderate to severe flares of plaque, erythrodermic, or pustular psoriasis.²¹ Further studies are needed to identify evidence-based therapeutic paradigms for pediatric psoriasis and to pinpoint therapies associated with the best quality of life in patients and their caregivers.

Tumor Necrosis Factor α Inhibitors

Safety and efficacy of etanercept for juvenile idiopathic arthritis including oligoarthritis, enthesitis-related arthritis, and psoriatic arthritis recently was reviewed by Windschall et al²² using data from the German pediatric Biologika in der Kinderrheumatologie registry. Juvenile Arthritis Disease Activity Score 10 improved from baseline for 127 pediatric patients with psoriatic arthritis in 3 to 24 months (mean [standard deviation], 14.7 [6.4], 5.0 [4.6], 5.3 [6.4] at baseline, 3 months, and 24 months, respectively). Overall side effects were relatively higher in the psoriatic arthritis group; the rate of serious (relative risk, 1.39 [0.95-2.03; P=.08]) and nonserious (relative risk, 1.18 [1.02-1.35; P=.03]) adverse events also was elevated. Uveitis risk was greatest in the psoriatic arthritis group and the number of associated cases of inflammatory bowel disease outnumbered those seen in other forms of arthritis. The investigators concluded that monitoring for extra-articular immunopathies should be conducted in pediatric patients with psoriatic arthritis who are undergoing etanercept therapy.²²

Tumor necrosis factor α (TNF-α) inhibitors have been associated with triggering psoriasiform dermatitis in pediatric patients treated for inflammatory bowel disease. A Finnish study of infliximab side effects in pediatric patients with inflammatory bowel disease (n=84; Crohn disease: n=64) demonstrated that almost half (47.6% [40/84]) of the participants presented with chronic skin reactions, 23% of which were severe in nature.²³ Psoriasiform lesions of the scalp and ears were most common, followed by the periorificial area, genitals, trunk, and extremities. Rare association with HLA-Cw*0602 genotype was noted. Skin manifestations did not correlate with gut inflammation (as determined by fecal calprotectin levels). Discontinuation of therapy rarely was required.²³ Other studies also have highlighted this side effect, suggesting an incidence of 2.7% in adults with colitis treated with TNF-α inhibitors²⁴ and 10.5% in pediatric patients with Crohn disease.²⁵ In a study by Sherlock et al,²⁵  pediatric patients with Crohn disease developing psoriasis following infliximab therapy were more likely to be homozygous for specific polymorphisms in the IL-23R gene (rs10489628, rs10789229, and rs1343151).

Methotrexate

For pediatric patients who are being treated with methotrexate, the polyglutamate assay recently has been reported to be helpful in identifying patients needing a dose escalation.²⁶ Higher numbers on the polyglutamate assay are associated with superior response to methotrexate therapy. Doses can be increased after 12 weeks in patients with low assays.²⁶

IL-23

The safety of IL-23 blockade in pediatric psoriasis patients has not yet been established, but data from adult cases have implicated the IL-17 and IL-23 pathways in psoriasis/psoriatic arthritis, including an association with IL-23R polymorphisms²⁷ and increases in soluble IL-20 and IL-22 associated with disease severity and an association of IL-17 levels with activity on the psoriasis area and severity index scores.²⁸ The data are more limited for pediatric cases. Pediatric patients with inflammatory bowel disease who have an IL-23R polymorphism appear to be susceptible to psoriatic flares while on TNF-α inhibitor therapy,²⁵ which suggests that the IL-23 blockade may be of benefit for some pediatric patients with psoriasis or psoriatic arthritis.

Conclusion

Pediatric psoriasis and psoriatic arthritis have now been identified as being part of the autoimmune spectrum and are associated with metabolic syndrome, including obesity and excess central adiposity, similar to their adult variants. An overview of potential unmet needs in pediatric psoriasis is included in Table 2. These unmet needs include further delineation of diet and weight modification in the care and prevention of psoriasis; expansion of therapeutic trials and US Food and Drug Administration–approved medications for children with psoriasis, especially severe variants such as extensive plaque and pustular disease; and development of guidelines for ongoing monitoring of children with psoriasis. The role of therapeutic interventions and weight management on long-term disease course remains to be shown in extended clinical trials. Despite the great advancements in psoriatic care, knowledge gaps remain in pediatric psoriasis that will need to be addressed in the future.

Psoriasis affects 2% to 4% of the US population, with approximately one-third of cases beginning in childhood. The understanding of pediatric psoriasis has developed at a far slower pace than adult disease, with limitations in care including few medications that are approved by the US Food and Drug Administration for pediatric and adolescent use. Recently, a stable fixed-combination dose of calcipo-triene 0.005%–betamethasone dipropionate 0.064% topical suspension was approved for treatment of plaque psoriasis of the scalp in patients aged 12 to 17 years, which hopefully will lead a trend in psoriasis medication approval for children and teenagers.¹ Based on a PubMed search of articles indexed for MEDLINE using the search terms pediatric psoriasis, psoriasis, and strep that were published from April 2012 to April 2014, this article reviews newer data to address the issues that surround pediatric psoriasis and to provide an update on prior review articles on pediatric psoriasis.^2-5 This article reviews some of the newer literature on clinical presentation and comorbidities in pediatric psoriasis.⁵ Based on these recent findings, additional screenings including review of obesity parameters are recommended for pediatric patients with psoriasis (Table 1).

Update on Disease Manifestations, Associations, and Comorbidities

Disease Manifestations

A 2013 multicenter study delineated the clinical features of pediatric psoriasis.⁶ The study was conducted at 8 geographically diverse dermatology clinics in the United States to delineate the clinical manifestations of pediatric psoriasis. In an assessment of 181 participants aged 5 to 17 years, the investigators sought to determine the frequency of disease sites, severity, and guttate disease. Over a period of approximately 2 years, 43.1% of participants were determined to have mild disease and 56.9% had severe disease. Family history of psoriasis was present in 51.4% of participants, with first-degree relatives affected in 59.8% of cases. Scalp involvement at some time was noted in 79.0% of participants, and nail disease was noted in 55% of boys and 29% of girls. Guttate psoriasis was noted in 30% of participants, with more cases in the severe range (35.9%) versus the mild range (21.8%). Additionally, 22.1% of participants had a precipitating streptococcal infection, with the association being more common in pediatric patients with guttate psoriasis than plaque psoriasis.⁶ This study highlighted that pediatric psoriasis has a genetic basis, is frequently guttate in nature, commonly affects the nails, shows a trend toward being classified as severe, and may be triggered by streptococcal infections.

Streptococcal Infection

Pediatric psoriasis may be triggered or flared by Streptococcus pyogenes (group A β-hemolytic streptococci) infections, specifically β-hemolytic streptococci groups A, C, and G that have streptococcal M protein,^2,3,7 and this tendency can be associated with HLA-Cw6 or guttate psoriasis. Newer data have elucidated the role of streptococcal throat infections in psoriasis. Given that streptococcal throat infections are most common in school-aged children, these studies suggest a putative mechanism in pediatric psoriasis for triggering streptococcal infections, which would need to be confirmed in future studies, specifically in pediatric psoriasis patients.

It has been shown that T cells in psoriasis patients recognize common streptococcal M proteins and keratin determinants.⁷ Ferran et al⁸ recently demonstrated activation of circulating cutaneous lymphocyte–associated antigen (CLA)⁺ T cells but not CLA^- memory T cells in 27 psoriasis patients (ages not specified) when mixed with streptococcal throat extracts, causing production of IL-17, IP-10, IL-22, and IFN-γ; activation was not found in 6 healthy control patients. Antistreptolysin O levels were correlated with the messenger RNA up- regulation for IL-17, IP-10, IL-22, and IFN-γ, and also correlated with psoriasis area and severity index score in psoriasis patients. In this same study, injection of the activated culture supernatant into mouse skin caused epidermal hyperkeratosis and activation of nonlesional epidermal cells from psoriatic patients. This study thereby delineated some of the potential pathways of the streptococcal induction of psoriasis and psoriatic flares in childhood⁸; however, confirmation is needed through further study of pediatric psoriatic lymphocyte activity.

Differential Diagnosis

Additions to the extensive differential list have been cited in the recent literature. The differential diagnosis of pediatric psoriasis now includes sodium valproate–induced psoriasiform drug eruption⁹ and allergic contact dermatitis to methylchloroisothiazolinone and methylisothiazolinone, which are present in many sanitizing hand and diaper wipes and has been reported to cause psoriasiform dermatitis in a periorificial or perineal distribution.¹⁰ Clinicians should inquire about the use of these wipes, as caregivers rarely suspect this agent to be causative of the eruption.

Psoriatic Arthritis

Previously, psoriasis and psoriatic arthritis have been linked to autoimmune thyroid disease in adults.¹¹ A study of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry showed that family history of psoriasis, autoimmune thyroiditis, Crohn disease, and ankylosing spondylitis in a first-degree relative has been linked to juvenile idiopathic arthritis, highlighting that pediatric psoriasis can be genetically linked or associated with multiple autoimmune conditions and vice versa.¹²

Obesity, Metabolic Syndrome, and Cardiovascular Risks

Obesity is associated with pediatric psoriasis as highlighted in a growing body of recent literature.¹³ Excess adiposity as manifested by body mass index in the 85th percentile or greater (37.9% of 155 pediatric psoriasis patients vs 20.5% of 42 controls) and excess central adiposity as manifested by excess waist circumference and increased waist-to-height ratios are more common in pediatric patients with psoriasis than in controls.¹⁴

Obesity may be a trigger or associated with increased disease activity in pediatric psoriasis patients. Excess overall adiposity correlates with more severe disease. Obesity parameters may correlate with the onset of psoriasis and with disease severity. In fact, the odds of obesity may be higher in childhood than in adults.^14,15 A 2011 report of pediatric psoriasis patients aged 10 to 17 years (n=12) and wart controls (n=6)(mean age, 13.2 and 13.5 years, respectively) demonstrated that 4 of 12 patients with psoriasis and 0 of 6 patients with warts met criteria for metabolic syndrome as defined by 3 of the following: (1) triglycerides greater than or equal to 100 mg/dL; (2) high-density lipoprotein cholesterol less than 50 mg/dL in females and less than 5 mg/dL in males; (3) fasting blood glucose levels greater than or equal to 110 mg/dL, (4) waist circumference greater than the 75th percentile for age and sex; and (5) systolic or diastolic blood pressure greater than the 90th percentile for age, sex, and height.¹⁶ These studies highlight that obesity and metabolic syndrome are of concern in pediatric psoriasis patients; however, the best management approach using diet and weight interventions has yet to be identified.

Adiposity may precede the onset of psoriasis. A recent cohort of 27 pediatric psoriasis patients reported that the average age at onset of psoriasis was 8.7 years and the average age at onset of obesity was 4.1 years.¹⁵ In this study, 93% (25/27) of patients had adiposity preceding their psoriasis by 2 or more years. It is unclear if this is nature or nurture, as 48% (13/27) of patients had a family history of obesity, 41% (11/27) had a family history of psoriasis, and 48% (13/27) had a family history of hyperlipidemia.¹⁵ Therefore, obesity may be cultivated in some psoriatic families. The issue of household influences on diet and obesity needs to be addressed if successful weight management is to be achieved in future studies of pediatric psoriasis.

Cardiovascular risks in the pediatric psoriasis population are the subject of ongoing assessment but will likely mimic studies of adult psoriasis patients when reviewed longitudinally.¹⁶ Weight loss and healthy lifestyle interventions likely are beneficial to long-term health, but there is a lack of published data addressing dietary modification as a disease modifier for long-term care of pediatric psoriasis.

Anxiety and Depression

Anxiety and depression have been noted in adults with chronic skin diseases. A recent study assessed 118 patients and caregivers of pediatric patients with atopic dermatitis (n=50), psoriasis (n=25), or vitiligo (n=43) using the Children’s Dermatology Life Quality Index, the Hamilton Anxiety Scale, and the Beck Depression Inventory.¹⁷ Anxiety and depression were found in 36% of caregivers of pediatric psoriasis patients and depression was found in 36% of pediatric psoriasis patients, highlighting the need for interventions on a personal and family level to improve quality of life. As a comparator, anxiety was more prevalent in vitiligo caregivers (42%), but depression was only found in 26% of caregivers in the same group. Extent of disease (25%–75% body surface area affected) correlated with both depression and anxiety in the caregivers of pediatric patients with psoriasis as well as with anxiety in caregivers of pediatric patients with increased visible surface area of vitiligo.¹⁷ Parental anxiety has been reported at times to be linked to corticosteroid phobia, or corticophobia, which may interfere with disease therapy, as topical corticosteroids are considered the mainstay of therapy in childhood disease.¹⁸ Coordinating care with caregivers and addressing their concerns about the safety of medications should be integral to the pediatric psoriasis visit.

Pustular Psoriasis

Pustular psoriasis can be seen in any age group. Researchers recently have attempted to delineate the features and successful management of this severe subset of pediatric psoriasis patients. Twenty-four pediatric pustular psoriasis cases reviewed by Posso-De Los Rios et al¹⁹ revealed that 92% (22/24) had generalized and 8% (2/24) had limited acral disease. The mean (standard deviation) age at onset of pediatric pustular psoriasis was 6.3 (4.9) years. Half of the reported cases required more than one intervention. Treatment with acitretin, cyclosporine, and methotrexate was effective, but the investigators identified that there is a true dearth of evidence-based therapeutics in pediatric pustular psoriasis and much rebound with discontinuation.¹⁹ Although the subset of pediatric pustular psoriasis is rare, study of evidence-based intervention is needed.

Therapy

Recent reviews of pediatric and adolescent psoriasis highlight the paucity of therapeutic information for these patient populations. Investigators typically focus on topical therapies as the basis of treatment,²⁰ as well as the addition of phototherapy in mild to moderate plaque or guttate psoriasis and biologic or systemic agents in moderate to severe flares of plaque, erythrodermic, or pustular psoriasis.²¹ Further studies are needed to identify evidence-based therapeutic paradigms for pediatric psoriasis and to pinpoint therapies associated with the best quality of life in patients and their caregivers.

Tumor Necrosis Factor α Inhibitors

Safety and efficacy of etanercept for juvenile idiopathic arthritis including oligoarthritis, enthesitis-related arthritis, and psoriatic arthritis recently was reviewed by Windschall et al²² using data from the German pediatric Biologika in der Kinderrheumatologie registry. Juvenile Arthritis Disease Activity Score 10 improved from baseline for 127 pediatric patients with psoriatic arthritis in 3 to 24 months (mean [standard deviation], 14.7 [6.4], 5.0 [4.6], 5.3 [6.4] at baseline, 3 months, and 24 months, respectively). Overall side effects were relatively higher in the psoriatic arthritis group; the rate of serious (relative risk, 1.39 [0.95-2.03; P=.08]) and nonserious (relative risk, 1.18 [1.02-1.35; P=.03]) adverse events also was elevated. Uveitis risk was greatest in the psoriatic arthritis group and the number of associated cases of inflammatory bowel disease outnumbered those seen in other forms of arthritis. The investigators concluded that monitoring for extra-articular immunopathies should be conducted in pediatric patients with psoriatic arthritis who are undergoing etanercept therapy.²²

Tumor necrosis factor α (TNF-α) inhibitors have been associated with triggering psoriasiform dermatitis in pediatric patients treated for inflammatory bowel disease. A Finnish study of infliximab side effects in pediatric patients with inflammatory bowel disease (n=84; Crohn disease: n=64) demonstrated that almost half (47.6% [40/84]) of the participants presented with chronic skin reactions, 23% of which were severe in nature.²³ Psoriasiform lesions of the scalp and ears were most common, followed by the periorificial area, genitals, trunk, and extremities. Rare association with HLA-Cw*0602 genotype was noted. Skin manifestations did not correlate with gut inflammation (as determined by fecal calprotectin levels). Discontinuation of therapy rarely was required.²³ Other studies also have highlighted this side effect, suggesting an incidence of 2.7% in adults with colitis treated with TNF-α inhibitors²⁴ and 10.5% in pediatric patients with Crohn disease.²⁵ In a study by Sherlock et al,²⁵  pediatric patients with Crohn disease developing psoriasis following infliximab therapy were more likely to be homozygous for specific polymorphisms in the IL-23R gene (rs10489628, rs10789229, and rs1343151).

Methotrexate

For pediatric patients who are being treated with methotrexate, the polyglutamate assay recently has been reported to be helpful in identifying patients needing a dose escalation.²⁶ Higher numbers on the polyglutamate assay are associated with superior response to methotrexate therapy. Doses can be increased after 12 weeks in patients with low assays.²⁶

IL-23

The safety of IL-23 blockade in pediatric psoriasis patients has not yet been established, but data from adult cases have implicated the IL-17 and IL-23 pathways in psoriasis/psoriatic arthritis, including an association with IL-23R polymorphisms²⁷ and increases in soluble IL-20 and IL-22 associated with disease severity and an association of IL-17 levels with activity on the psoriasis area and severity index scores.²⁸ The data are more limited for pediatric cases. Pediatric patients with inflammatory bowel disease who have an IL-23R polymorphism appear to be susceptible to psoriatic flares while on TNF-α inhibitor therapy,²⁵ which suggests that the IL-23 blockade may be of benefit for some pediatric patients with psoriasis or psoriatic arthritis.

Conclusion

Pediatric psoriasis and psoriatic arthritis have now been identified as being part of the autoimmune spectrum and are associated with metabolic syndrome, including obesity and excess central adiposity, similar to their adult variants. An overview of potential unmet needs in pediatric psoriasis is included in Table 2. These unmet needs include further delineation of diet and weight modification in the care and prevention of psoriasis; expansion of therapeutic trials and US Food and Drug Administration–approved medications for children with psoriasis, especially severe variants such as extensive plaque and pustular disease; and development of guidelines for ongoing monitoring of children with psoriasis. The role of therapeutic interventions and weight management on long-term disease course remains to be shown in extended clinical trials. Despite the great advancements in psoriatic care, knowledge gaps remain in pediatric psoriasis that will need to be addressed in the future.

Psoriasis affects 2% to 4% of the US population, with approximately one-third of cases beginning in childhood. The understanding of pediatric psoriasis has developed at a far slower pace than adult disease, with limitations in care including few medications that are approved by the US Food and Drug Administration for pediatric and adolescent use. Recently, a stable fixed-combination dose of calcipo-triene 0.005%–betamethasone dipropionate 0.064% topical suspension was approved for treatment of plaque psoriasis of the scalp in patients aged 12 to 17 years, which hopefully will lead a trend in psoriasis medication approval for children and teenagers.¹ Based on a PubMed search of articles indexed for MEDLINE using the search terms pediatric psoriasis, psoriasis, and strep that were published from April 2012 to April 2014, this article reviews newer data to address the issues that surround pediatric psoriasis and to provide an update on prior review articles on pediatric psoriasis.^2-5 This article reviews some of the newer literature on clinical presentation and comorbidities in pediatric psoriasis.⁵ Based on these recent findings, additional screenings including review of obesity parameters are recommended for pediatric patients with psoriasis (Table 1).

Update on Disease Manifestations, Associations, and Comorbidities

Disease Manifestations

A 2013 multicenter study delineated the clinical features of pediatric psoriasis.⁶ The study was conducted at 8 geographically diverse dermatology clinics in the United States to delineate the clinical manifestations of pediatric psoriasis. In an assessment of 181 participants aged 5 to 17 years, the investigators sought to determine the frequency of disease sites, severity, and guttate disease. Over a period of approximately 2 years, 43.1% of participants were determined to have mild disease and 56.9% had severe disease. Family history of psoriasis was present in 51.4% of participants, with first-degree relatives affected in 59.8% of cases. Scalp involvement at some time was noted in 79.0% of participants, and nail disease was noted in 55% of boys and 29% of girls. Guttate psoriasis was noted in 30% of participants, with more cases in the severe range (35.9%) versus the mild range (21.8%). Additionally, 22.1% of participants had a precipitating streptococcal infection, with the association being more common in pediatric patients with guttate psoriasis than plaque psoriasis.⁶ This study highlighted that pediatric psoriasis has a genetic basis, is frequently guttate in nature, commonly affects the nails, shows a trend toward being classified as severe, and may be triggered by streptococcal infections.

Streptococcal Infection

Pediatric psoriasis may be triggered or flared by Streptococcus pyogenes (group A β-hemolytic streptococci) infections, specifically β-hemolytic streptococci groups A, C, and G that have streptococcal M protein,^2,3,7 and this tendency can be associated with HLA-Cw6 or guttate psoriasis. Newer data have elucidated the role of streptococcal throat infections in psoriasis. Given that streptococcal throat infections are most common in school-aged children, these studies suggest a putative mechanism in pediatric psoriasis for triggering streptococcal infections, which would need to be confirmed in future studies, specifically in pediatric psoriasis patients.

It has been shown that T cells in psoriasis patients recognize common streptococcal M proteins and keratin determinants.⁷ Ferran et al⁸ recently demonstrated activation of circulating cutaneous lymphocyte–associated antigen (CLA)⁺ T cells but not CLA^- memory T cells in 27 psoriasis patients (ages not specified) when mixed with streptococcal throat extracts, causing production of IL-17, IP-10, IL-22, and IFN-γ; activation was not found in 6 healthy control patients. Antistreptolysin O levels were correlated with the messenger RNA up- regulation for IL-17, IP-10, IL-22, and IFN-γ, and also correlated with psoriasis area and severity index score in psoriasis patients. In this same study, injection of the activated culture supernatant into mouse skin caused epidermal hyperkeratosis and activation of nonlesional epidermal cells from psoriatic patients. This study thereby delineated some of the potential pathways of the streptococcal induction of psoriasis and psoriatic flares in childhood⁸; however, confirmation is needed through further study of pediatric psoriatic lymphocyte activity.

Differential Diagnosis

Additions to the extensive differential list have been cited in the recent literature. The differential diagnosis of pediatric psoriasis now includes sodium valproate–induced psoriasiform drug eruption⁹ and allergic contact dermatitis to methylchloroisothiazolinone and methylisothiazolinone, which are present in many sanitizing hand and diaper wipes and has been reported to cause psoriasiform dermatitis in a periorificial or perineal distribution.¹⁰ Clinicians should inquire about the use of these wipes, as caregivers rarely suspect this agent to be causative of the eruption.

Psoriatic Arthritis

Previously, psoriasis and psoriatic arthritis have been linked to autoimmune thyroid disease in adults.¹¹ A study of the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry showed that family history of psoriasis, autoimmune thyroiditis, Crohn disease, and ankylosing spondylitis in a first-degree relative has been linked to juvenile idiopathic arthritis, highlighting that pediatric psoriasis can be genetically linked or associated with multiple autoimmune conditions and vice versa.¹²

Obesity, Metabolic Syndrome, and Cardiovascular Risks

Obesity is associated with pediatric psoriasis as highlighted in a growing body of recent literature.¹³ Excess adiposity as manifested by body mass index in the 85th percentile or greater (37.9% of 155 pediatric psoriasis patients vs 20.5% of 42 controls) and excess central adiposity as manifested by excess waist circumference and increased waist-to-height ratios are more common in pediatric patients with psoriasis than in controls.¹⁴

Obesity may be a trigger or associated with increased disease activity in pediatric psoriasis patients. Excess overall adiposity correlates with more severe disease. Obesity parameters may correlate with the onset of psoriasis and with disease severity. In fact, the odds of obesity may be higher in childhood than in adults.^14,15 A 2011 report of pediatric psoriasis patients aged 10 to 17 years (n=12) and wart controls (n=6)(mean age, 13.2 and 13.5 years, respectively) demonstrated that 4 of 12 patients with psoriasis and 0 of 6 patients with warts met criteria for metabolic syndrome as defined by 3 of the following: (1) triglycerides greater than or equal to 100 mg/dL; (2) high-density lipoprotein cholesterol less than 50 mg/dL in females and less than 5 mg/dL in males; (3) fasting blood glucose levels greater than or equal to 110 mg/dL, (4) waist circumference greater than the 75th percentile for age and sex; and (5) systolic or diastolic blood pressure greater than the 90th percentile for age, sex, and height.¹⁶ These studies highlight that obesity and metabolic syndrome are of concern in pediatric psoriasis patients; however, the best management approach using diet and weight interventions has yet to be identified.

Adiposity may precede the onset of psoriasis. A recent cohort of 27 pediatric psoriasis patients reported that the average age at onset of psoriasis was 8.7 years and the average age at onset of obesity was 4.1 years.¹⁵ In this study, 93% (25/27) of patients had adiposity preceding their psoriasis by 2 or more years. It is unclear if this is nature or nurture, as 48% (13/27) of patients had a family history of obesity, 41% (11/27) had a family history of psoriasis, and 48% (13/27) had a family history of hyperlipidemia.¹⁵ Therefore, obesity may be cultivated in some psoriatic families. The issue of household influences on diet and obesity needs to be addressed if successful weight management is to be achieved in future studies of pediatric psoriasis.

Cardiovascular risks in the pediatric psoriasis population are the subject of ongoing assessment but will likely mimic studies of adult psoriasis patients when reviewed longitudinally.¹⁶ Weight loss and healthy lifestyle interventions likely are beneficial to long-term health, but there is a lack of published data addressing dietary modification as a disease modifier for long-term care of pediatric psoriasis.

Anxiety and Depression

Anxiety and depression have been noted in adults with chronic skin diseases. A recent study assessed 118 patients and caregivers of pediatric patients with atopic dermatitis (n=50), psoriasis (n=25), or vitiligo (n=43) using the Children’s Dermatology Life Quality Index, the Hamilton Anxiety Scale, and the Beck Depression Inventory.¹⁷ Anxiety and depression were found in 36% of caregivers of pediatric psoriasis patients and depression was found in 36% of pediatric psoriasis patients, highlighting the need for interventions on a personal and family level to improve quality of life. As a comparator, anxiety was more prevalent in vitiligo caregivers (42%), but depression was only found in 26% of caregivers in the same group. Extent of disease (25%–75% body surface area affected) correlated with both depression and anxiety in the caregivers of pediatric patients with psoriasis as well as with anxiety in caregivers of pediatric patients with increased visible surface area of vitiligo.¹⁷ Parental anxiety has been reported at times to be linked to corticosteroid phobia, or corticophobia, which may interfere with disease therapy, as topical corticosteroids are considered the mainstay of therapy in childhood disease.¹⁸ Coordinating care with caregivers and addressing their concerns about the safety of medications should be integral to the pediatric psoriasis visit.

Pustular Psoriasis

Pustular psoriasis can be seen in any age group. Researchers recently have attempted to delineate the features and successful management of this severe subset of pediatric psoriasis patients. Twenty-four pediatric pustular psoriasis cases reviewed by Posso-De Los Rios et al¹⁹ revealed that 92% (22/24) had generalized and 8% (2/24) had limited acral disease. The mean (standard deviation) age at onset of pediatric pustular psoriasis was 6.3 (4.9) years. Half of the reported cases required more than one intervention. Treatment with acitretin, cyclosporine, and methotrexate was effective, but the investigators identified that there is a true dearth of evidence-based therapeutics in pediatric pustular psoriasis and much rebound with discontinuation.¹⁹ Although the subset of pediatric pustular psoriasis is rare, study of evidence-based intervention is needed.

Therapy

Recent reviews of pediatric and adolescent psoriasis highlight the paucity of therapeutic information for these patient populations. Investigators typically focus on topical therapies as the basis of treatment,²⁰ as well as the addition of phototherapy in mild to moderate plaque or guttate psoriasis and biologic or systemic agents in moderate to severe flares of plaque, erythrodermic, or pustular psoriasis.²¹ Further studies are needed to identify evidence-based therapeutic paradigms for pediatric psoriasis and to pinpoint therapies associated with the best quality of life in patients and their caregivers.

Tumor Necrosis Factor α Inhibitors

Safety and efficacy of etanercept for juvenile idiopathic arthritis including oligoarthritis, enthesitis-related arthritis, and psoriatic arthritis recently was reviewed by Windschall et al²² using data from the German pediatric Biologika in der Kinderrheumatologie registry. Juvenile Arthritis Disease Activity Score 10 improved from baseline for 127 pediatric patients with psoriatic arthritis in 3 to 24 months (mean [standard deviation], 14.7 [6.4], 5.0 [4.6], 5.3 [6.4] at baseline, 3 months, and 24 months, respectively). Overall side effects were relatively higher in the psoriatic arthritis group; the rate of serious (relative risk, 1.39 [0.95-2.03; P=.08]) and nonserious (relative risk, 1.18 [1.02-1.35; P=.03]) adverse events also was elevated. Uveitis risk was greatest in the psoriatic arthritis group and the number of associated cases of inflammatory bowel disease outnumbered those seen in other forms of arthritis. The investigators concluded that monitoring for extra-articular immunopathies should be conducted in pediatric patients with psoriatic arthritis who are undergoing etanercept therapy.²²

Tumor necrosis factor α (TNF-α) inhibitors have been associated with triggering psoriasiform dermatitis in pediatric patients treated for inflammatory bowel disease. A Finnish study of infliximab side effects in pediatric patients with inflammatory bowel disease (n=84; Crohn disease: n=64) demonstrated that almost half (47.6% [40/84]) of the participants presented with chronic skin reactions, 23% of which were severe in nature.²³ Psoriasiform lesions of the scalp and ears were most common, followed by the periorificial area, genitals, trunk, and extremities. Rare association with HLA-Cw*0602 genotype was noted. Skin manifestations did not correlate with gut inflammation (as determined by fecal calprotectin levels). Discontinuation of therapy rarely was required.²³ Other studies also have highlighted this side effect, suggesting an incidence of 2.7% in adults with colitis treated with TNF-α inhibitors²⁴ and 10.5% in pediatric patients with Crohn disease.²⁵ In a study by Sherlock et al,²⁵  pediatric patients with Crohn disease developing psoriasis following infliximab therapy were more likely to be homozygous for specific polymorphisms in the IL-23R gene (rs10489628, rs10789229, and rs1343151).

Methotrexate

For pediatric patients who are being treated with methotrexate, the polyglutamate assay recently has been reported to be helpful in identifying patients needing a dose escalation.²⁶ Higher numbers on the polyglutamate assay are associated with superior response to methotrexate therapy. Doses can be increased after 12 weeks in patients with low assays.²⁶

IL-23

The safety of IL-23 blockade in pediatric psoriasis patients has not yet been established, but data from adult cases have implicated the IL-17 and IL-23 pathways in psoriasis/psoriatic arthritis, including an association with IL-23R polymorphisms²⁷ and increases in soluble IL-20 and IL-22 associated with disease severity and an association of IL-17 levels with activity on the psoriasis area and severity index scores.²⁸ The data are more limited for pediatric cases. Pediatric patients with inflammatory bowel disease who have an IL-23R polymorphism appear to be susceptible to psoriatic flares while on TNF-α inhibitor therapy,²⁵ which suggests that the IL-23 blockade may be of benefit for some pediatric patients with psoriasis or psoriatic arthritis.

Conclusion

Pediatric psoriasis and psoriatic arthritis have now been identified as being part of the autoimmune spectrum and are associated with metabolic syndrome, including obesity and excess central adiposity, similar to their adult variants. An overview of potential unmet needs in pediatric psoriasis is included in Table 2. These unmet needs include further delineation of diet and weight modification in the care and prevention of psoriasis; expansion of therapeutic trials and US Food and Drug Administration–approved medications for children with psoriasis, especially severe variants such as extensive plaque and pustular disease; and development of guidelines for ongoing monitoring of children with psoriasis. The role of therapeutic interventions and weight management on long-term disease course remains to be shown in extended clinical trials. Despite the great advancements in psoriatic care, knowledge gaps remain in pediatric psoriasis that will need to be addressed in the future.

The larvae of Onchocerca volvulus, a nematode that is most commonly found in tropical Africa, Yemen, Central America, and South America, are transmitted by flies of the genus Simulium that breed near fast-flowing rivers.¹ The flies bite the host and transmit the larvae, and the larvae then mature into adults within the skin and subcutis, forming nodules that typically are not painful. The worms may reside within the skin for years and produce microfilariae, which can migrate and cause visual impairment, blindness, or a pruritic papular rash.¹

The nematode produces a nodule within the dermis or subcutis with surrounding fibrous tissue and a mixed inflammatory infiltrate with eosinophils (Figure 1). In some cases, microfilariae can be seen within the lymphatics or within the uteri of the worms.¹ Male and female worms typically are present and have a corrugated cuticle with a thin underlying layer of striated muscle. The females have paired uteri, which usually contain microfilariae² (Figure 2).

Figure 1. Cross-section of a nematode with surrounding inflammatory reaction, characteristic of onchocerciasis (H&E, original magnification ×20).

Figure 2. Onchocerca volvulus with a cuticle, underlying thin layer of muscle, and paired uteri containing microfilariae (H&E, original magnification ×100).

Dirofilaria repens also is a nematode that produces a subcutaneous nodule with an inflammatory reaction. This worm typically has a thick cuticle with longitudinal ridges, long thick muscle, and lateral cords.³ Additionally, because humans are not the usual host, Dirofilaria species do not complete their lifecycle and typically are not gravid, unlike Onchocerca species.

Myiasis is the presence of fly larvae within the skin. The larvae demonstrate a thick hyaline cuticle with pigmented brown-yellow spikes (Figure 3). There is a thick muscular layer under the cuticle and a tubular tracheal system containing vertical striations. The digestive system has an epithelial lining with prominent vessels. Adipose tissue with granulated cytoplasm, prominent nuclei, and coarse chromatin also are present.⁴

Figure 3. A fly larva demonstrates a thick hyaline cuticle with yellow spikes, characteristic of myiasis (H&E, original magnification ×40).

Scabies mites (Figure 4), ova, and scybala are present within the stratum corneum. A mixed inflammatory infiltrate also can be present.¹ Tungiasis is caused by burrowing fleas and typically occurs on acral skin; therefore, it is more frequently found in the superficial portion of the skin. Erythrocytes usually are present in the gastrointestinal tract, and the females usually are gravid.² A surrounding mixed inflammatory infiltrate is present, and necrosis also can occur (Figure 5).¹

Figure 4. Scabies mites within the stratum corneum (H&E, original magnification ×100).

Figure 5. Tunga penetrans at the surface of acral skin. Erythrocytes can be noted within the gastrointestinal tract (H&E, original magnification ×40).

The larvae of Onchocerca volvulus, a nematode that is most commonly found in tropical Africa, Yemen, Central America, and South America, are transmitted by flies of the genus Simulium that breed near fast-flowing rivers.¹ The flies bite the host and transmit the larvae, and the larvae then mature into adults within the skin and subcutis, forming nodules that typically are not painful. The worms may reside within the skin for years and produce microfilariae, which can migrate and cause visual impairment, blindness, or a pruritic papular rash.¹

The nematode produces a nodule within the dermis or subcutis with surrounding fibrous tissue and a mixed inflammatory infiltrate with eosinophils (Figure 1). In some cases, microfilariae can be seen within the lymphatics or within the uteri of the worms.¹ Male and female worms typically are present and have a corrugated cuticle with a thin underlying layer of striated muscle. The females have paired uteri, which usually contain microfilariae² (Figure 2).

Figure 1. Cross-section of a nematode with surrounding inflammatory reaction, characteristic of onchocerciasis (H&E, original magnification ×20).

Figure 2. Onchocerca volvulus with a cuticle, underlying thin layer of muscle, and paired uteri containing microfilariae (H&E, original magnification ×100).

Dirofilaria repens also is a nematode that produces a subcutaneous nodule with an inflammatory reaction. This worm typically has a thick cuticle with longitudinal ridges, long thick muscle, and lateral cords.³ Additionally, because humans are not the usual host, Dirofilaria species do not complete their lifecycle and typically are not gravid, unlike Onchocerca species.

Myiasis is the presence of fly larvae within the skin. The larvae demonstrate a thick hyaline cuticle with pigmented brown-yellow spikes (Figure 3). There is a thick muscular layer under the cuticle and a tubular tracheal system containing vertical striations. The digestive system has an epithelial lining with prominent vessels. Adipose tissue with granulated cytoplasm, prominent nuclei, and coarse chromatin also are present.⁴

Figure 3. A fly larva demonstrates a thick hyaline cuticle with yellow spikes, characteristic of myiasis (H&E, original magnification ×40).

Scabies mites (Figure 4), ova, and scybala are present within the stratum corneum. A mixed inflammatory infiltrate also can be present.¹ Tungiasis is caused by burrowing fleas and typically occurs on acral skin; therefore, it is more frequently found in the superficial portion of the skin. Erythrocytes usually are present in the gastrointestinal tract, and the females usually are gravid.² A surrounding mixed inflammatory infiltrate is present, and necrosis also can occur (Figure 5).¹

Figure 4. Scabies mites within the stratum corneum (H&E, original magnification ×100).

Figure 5. Tunga penetrans at the surface of acral skin. Erythrocytes can be noted within the gastrointestinal tract (H&E, original magnification ×40).

The larvae of Onchocerca volvulus, a nematode that is most commonly found in tropical Africa, Yemen, Central America, and South America, are transmitted by flies of the genus Simulium that breed near fast-flowing rivers.¹ The flies bite the host and transmit the larvae, and the larvae then mature into adults within the skin and subcutis, forming nodules that typically are not painful. The worms may reside within the skin for years and produce microfilariae, which can migrate and cause visual impairment, blindness, or a pruritic papular rash.¹

The nematode produces a nodule within the dermis or subcutis with surrounding fibrous tissue and a mixed inflammatory infiltrate with eosinophils (Figure 1). In some cases, microfilariae can be seen within the lymphatics or within the uteri of the worms.¹ Male and female worms typically are present and have a corrugated cuticle with a thin underlying layer of striated muscle. The females have paired uteri, which usually contain microfilariae² (Figure 2).

Figure 1. Cross-section of a nematode with surrounding inflammatory reaction, characteristic of onchocerciasis (H&E, original magnification ×20).

Figure 2. Onchocerca volvulus with a cuticle, underlying thin layer of muscle, and paired uteri containing microfilariae (H&E, original magnification ×100).

Dirofilaria repens also is a nematode that produces a subcutaneous nodule with an inflammatory reaction. This worm typically has a thick cuticle with longitudinal ridges, long thick muscle, and lateral cords.³ Additionally, because humans are not the usual host, Dirofilaria species do not complete their lifecycle and typically are not gravid, unlike Onchocerca species.

Myiasis is the presence of fly larvae within the skin. The larvae demonstrate a thick hyaline cuticle with pigmented brown-yellow spikes (Figure 3). There is a thick muscular layer under the cuticle and a tubular tracheal system containing vertical striations. The digestive system has an epithelial lining with prominent vessels. Adipose tissue with granulated cytoplasm, prominent nuclei, and coarse chromatin also are present.⁴

Figure 3. A fly larva demonstrates a thick hyaline cuticle with yellow spikes, characteristic of myiasis (H&E, original magnification ×40).

Scabies mites (Figure 4), ova, and scybala are present within the stratum corneum. A mixed inflammatory infiltrate also can be present.¹ Tungiasis is caused by burrowing fleas and typically occurs on acral skin; therefore, it is more frequently found in the superficial portion of the skin. Erythrocytes usually are present in the gastrointestinal tract, and the females usually are gravid.² A surrounding mixed inflammatory infiltrate is present, and necrosis also can occur (Figure 5).¹

Figure 4. Scabies mites within the stratum corneum (H&E, original magnification ×100).

Figure 5. Tunga penetrans at the surface of acral skin. Erythrocytes can be noted within the gastrointestinal tract (H&E, original magnification ×40).

Cutaneous larva migrans (CLM), also known as creeping eruption, is a pruritic serpiginous eruption caused by the migration of animal hookworm larvae through the epidermis.^1,2 The most common parasites are Ancylostoma braziliense (common in dogs and cats) and Ancylostoma caninum (common in dogs).¹

Disease Transmission

The infection is typically acquired in warm climates and tropical areas after coming in direct contact with sand or soil that is contaminated with animal feces. Therefore, the eruption most commonly occurs as a single or unilateral erythematous, pruritic, serpiginous tract on the feet, hands, or buttocks (Figure).² The larval tract typically migrates at a rate of 1 to 2 cm per day,³ which is in contrast to the serpiginous urticarial rash of larva currens of strongyloidiasis that can travel up to 10 cm per hour.⁴

Serpiginous tract of cutaneous larva migrans on the palm (A) and dorsal aspect of the foot (B).

Clinical Presentation

Rarely, CLM can present with bilateral lesions⁵; in severe cases a single patient can have hundreds of lesions. It also may present as folliculitis and urticarial papules.⁶ Shih et al⁷ reported a patient with CLM that presented as a diffuse papular urticarialike eruption following a trip to Thailand. This case may represent an underdiagnosed presentation of CLM. Patients with a history of exposure to contaminated sand or soil diffusely on the body may exhibit lesions in less classic locations, such as the trunk and upper proximal extremities.³

Cutaneous larva migrans is a self-limited eruption, as the larvae cannot complete their lifecycles in the human body and typically die within 2 to 8 weeks.² However, rare cases lasting up to a year have been reported.³ Sarasombath and Young² reported a case of CLM that persisted for 4 months with intermittent symptoms characterized by several weeklong intervals with no symptoms or visible rash.

Cutaneous larva migrans typically presents with isolated dermatologic symptoms. Rare cases associated with Löffler syndrome characterized by migratory pulmonary infiltrates and peripheral eosinophilia have been reported.⁸ Two proposed mechanisms for pulmonary involvement include direct invasion of the lungs by the helminths and a systemic immunologic process triggered by the helminths, resulting in eosinophilic pulmonary infiltration.⁹

Diagnosis

Cutaneous larva migrans is a clinical diagnosis and skin biopsy usually is not obtained because the larvae often are located 1 to 2 cm beyond the visible erythematous border.^3,5 Rarely, the parasites are found on biopsy, revealing larvae that are 0.5-mm thick and up to 10-mm long.¹⁰ The larvae typically are confined to the deep epidermis because the parasite lacks the collagenase required to penetrate the basement membrane.²

Langley et al¹¹ showed that confocal scanning laser microscopy can be an effective method for identifying the highly refractile oval larva that disrupt the normal honeycomb pattern of the epidermis. Performing a 4-mm punch biopsy over the identified site can allow for precise excision and treatment of the intact hookworm larvae of CLM. There also are limited reports of dermoscopy being used to facilitate diagnosis of CLM.¹² Dermoscopic features of CLM include translucent, brown, structureless areas in a segmental arrangement corresponding to the larval bodies and red-dotted vessels corresponding to an empty burrow.¹³ However, Zalaudek et al¹³ concluded that the efficacy of dermoscopy in aiding in the diagnosis of CLM has not been fully established.

Treatment

Cutaneous larva migrans is a self-limited condition that often resolves within 2 to 8 weeks; however, pruritus can be intense and patients therefore are seldom willing to forego treatment. Treatment options include a single oral dose of albendazole 400 mg in adults, with increased efficacy if administered daily for 3 to 5 days (or 10–15 mg/kg, with a maximum dose of 800 mg daily in children), a single oral dose of ivermectin 12 mg in adults (or 150 µg/kg in children), or topical application of thiabendazole 10% to 15% three times daily for at least 15 days.¹⁴ Cases of CLM complicated by Löffler syndrome may require a longer treatment course, such as a 7-day course of albendazole 400 mg daily. Tan and Liu⁹ reported a case of CLM complicated by Löffler syndrome that was successfully treated with albendazole. In this patient, initial treatment with 2 courses of mebendazole (3 days each for a total of 6 days) resulted in improvement of cutaneous lesions but not the pulmonary infiltrate. A subsequent prolonged course of albendazole and intravenous hydrocortisone for 5 days resulted in complete resolution of the pulmonary infiltrate and peripheral eosinophilia. The authors concluded that inadequacy of treatment with mebendazole may be related to differences in the rate of absorption and efficacy when compared to albendazole.⁹

Conclusion

Cutaneous larva migrans is a self-limited and pruritic skin eruption that is acquired after direct inoculation with sand or soil that is contaminated with feces containing A braziliense or A caninum. Although the classic presentation is readily identifiable, there are a variety of atypical presentations that may go undiagnosed. Symptomatic relief usually can be achieved with short courses of oral or topical antihelminth medications.

Cutaneous larva migrans (CLM), also known as creeping eruption, is a pruritic serpiginous eruption caused by the migration of animal hookworm larvae through the epidermis.^1,2 The most common parasites are Ancylostoma braziliense (common in dogs and cats) and Ancylostoma caninum (common in dogs).¹

Disease Transmission

The infection is typically acquired in warm climates and tropical areas after coming in direct contact with sand or soil that is contaminated with animal feces. Therefore, the eruption most commonly occurs as a single or unilateral erythematous, pruritic, serpiginous tract on the feet, hands, or buttocks (Figure).² The larval tract typically migrates at a rate of 1 to 2 cm per day,³ which is in contrast to the serpiginous urticarial rash of larva currens of strongyloidiasis that can travel up to 10 cm per hour.⁴

Serpiginous tract of cutaneous larva migrans on the palm (A) and dorsal aspect of the foot (B).

Clinical Presentation

Rarely, CLM can present with bilateral lesions⁵; in severe cases a single patient can have hundreds of lesions. It also may present as folliculitis and urticarial papules.⁶ Shih et al⁷ reported a patient with CLM that presented as a diffuse papular urticarialike eruption following a trip to Thailand. This case may represent an underdiagnosed presentation of CLM. Patients with a history of exposure to contaminated sand or soil diffusely on the body may exhibit lesions in less classic locations, such as the trunk and upper proximal extremities.³

Cutaneous larva migrans is a self-limited eruption, as the larvae cannot complete their lifecycles in the human body and typically die within 2 to 8 weeks.² However, rare cases lasting up to a year have been reported.³ Sarasombath and Young² reported a case of CLM that persisted for 4 months with intermittent symptoms characterized by several weeklong intervals with no symptoms or visible rash.

Cutaneous larva migrans typically presents with isolated dermatologic symptoms. Rare cases associated with Löffler syndrome characterized by migratory pulmonary infiltrates and peripheral eosinophilia have been reported.⁸ Two proposed mechanisms for pulmonary involvement include direct invasion of the lungs by the helminths and a systemic immunologic process triggered by the helminths, resulting in eosinophilic pulmonary infiltration.⁹

Diagnosis

Cutaneous larva migrans is a clinical diagnosis and skin biopsy usually is not obtained because the larvae often are located 1 to 2 cm beyond the visible erythematous border.^3,5 Rarely, the parasites are found on biopsy, revealing larvae that are 0.5-mm thick and up to 10-mm long.¹⁰ The larvae typically are confined to the deep epidermis because the parasite lacks the collagenase required to penetrate the basement membrane.²

Langley et al¹¹ showed that confocal scanning laser microscopy can be an effective method for identifying the highly refractile oval larva that disrupt the normal honeycomb pattern of the epidermis. Performing a 4-mm punch biopsy over the identified site can allow for precise excision and treatment of the intact hookworm larvae of CLM. There also are limited reports of dermoscopy being used to facilitate diagnosis of CLM.¹² Dermoscopic features of CLM include translucent, brown, structureless areas in a segmental arrangement corresponding to the larval bodies and red-dotted vessels corresponding to an empty burrow.¹³ However, Zalaudek et al¹³ concluded that the efficacy of dermoscopy in aiding in the diagnosis of CLM has not been fully established.

Treatment

Cutaneous larva migrans is a self-limited condition that often resolves within 2 to 8 weeks; however, pruritus can be intense and patients therefore are seldom willing to forego treatment. Treatment options include a single oral dose of albendazole 400 mg in adults, with increased efficacy if administered daily for 3 to 5 days (or 10–15 mg/kg, with a maximum dose of 800 mg daily in children), a single oral dose of ivermectin 12 mg in adults (or 150 µg/kg in children), or topical application of thiabendazole 10% to 15% three times daily for at least 15 days.¹⁴ Cases of CLM complicated by Löffler syndrome may require a longer treatment course, such as a 7-day course of albendazole 400 mg daily. Tan and Liu⁹ reported a case of CLM complicated by Löffler syndrome that was successfully treated with albendazole. In this patient, initial treatment with 2 courses of mebendazole (3 days each for a total of 6 days) resulted in improvement of cutaneous lesions but not the pulmonary infiltrate. A subsequent prolonged course of albendazole and intravenous hydrocortisone for 5 days resulted in complete resolution of the pulmonary infiltrate and peripheral eosinophilia. The authors concluded that inadequacy of treatment with mebendazole may be related to differences in the rate of absorption and efficacy when compared to albendazole.⁹

Conclusion

Cutaneous larva migrans is a self-limited and pruritic skin eruption that is acquired after direct inoculation with sand or soil that is contaminated with feces containing A braziliense or A caninum. Although the classic presentation is readily identifiable, there are a variety of atypical presentations that may go undiagnosed. Symptomatic relief usually can be achieved with short courses of oral or topical antihelminth medications.

Cutaneous larva migrans (CLM), also known as creeping eruption, is a pruritic serpiginous eruption caused by the migration of animal hookworm larvae through the epidermis.^1,2 The most common parasites are Ancylostoma braziliense (common in dogs and cats) and Ancylostoma caninum (common in dogs).¹

Disease Transmission

The infection is typically acquired in warm climates and tropical areas after coming in direct contact with sand or soil that is contaminated with animal feces. Therefore, the eruption most commonly occurs as a single or unilateral erythematous, pruritic, serpiginous tract on the feet, hands, or buttocks (Figure).² The larval tract typically migrates at a rate of 1 to 2 cm per day,³ which is in contrast to the serpiginous urticarial rash of larva currens of strongyloidiasis that can travel up to 10 cm per hour.⁴

Serpiginous tract of cutaneous larva migrans on the palm (A) and dorsal aspect of the foot (B).

Clinical Presentation

Rarely, CLM can present with bilateral lesions⁵; in severe cases a single patient can have hundreds of lesions. It also may present as folliculitis and urticarial papules.⁶ Shih et al⁷ reported a patient with CLM that presented as a diffuse papular urticarialike eruption following a trip to Thailand. This case may represent an underdiagnosed presentation of CLM. Patients with a history of exposure to contaminated sand or soil diffusely on the body may exhibit lesions in less classic locations, such as the trunk and upper proximal extremities.³

Cutaneous larva migrans is a self-limited eruption, as the larvae cannot complete their lifecycles in the human body and typically die within 2 to 8 weeks.² However, rare cases lasting up to a year have been reported.³ Sarasombath and Young² reported a case of CLM that persisted for 4 months with intermittent symptoms characterized by several weeklong intervals with no symptoms or visible rash.

Cutaneous larva migrans typically presents with isolated dermatologic symptoms. Rare cases associated with Löffler syndrome characterized by migratory pulmonary infiltrates and peripheral eosinophilia have been reported.⁸ Two proposed mechanisms for pulmonary involvement include direct invasion of the lungs by the helminths and a systemic immunologic process triggered by the helminths, resulting in eosinophilic pulmonary infiltration.⁹

Diagnosis

Cutaneous larva migrans is a clinical diagnosis and skin biopsy usually is not obtained because the larvae often are located 1 to 2 cm beyond the visible erythematous border.^3,5 Rarely, the parasites are found on biopsy, revealing larvae that are 0.5-mm thick and up to 10-mm long.¹⁰ The larvae typically are confined to the deep epidermis because the parasite lacks the collagenase required to penetrate the basement membrane.²

Langley et al¹¹ showed that confocal scanning laser microscopy can be an effective method for identifying the highly refractile oval larva that disrupt the normal honeycomb pattern of the epidermis. Performing a 4-mm punch biopsy over the identified site can allow for precise excision and treatment of the intact hookworm larvae of CLM. There also are limited reports of dermoscopy being used to facilitate diagnosis of CLM.¹² Dermoscopic features of CLM include translucent, brown, structureless areas in a segmental arrangement corresponding to the larval bodies and red-dotted vessels corresponding to an empty burrow.¹³ However, Zalaudek et al¹³ concluded that the efficacy of dermoscopy in aiding in the diagnosis of CLM has not been fully established.

Treatment

Cutaneous larva migrans is a self-limited condition that often resolves within 2 to 8 weeks; however, pruritus can be intense and patients therefore are seldom willing to forego treatment. Treatment options include a single oral dose of albendazole 400 mg in adults, with increased efficacy if administered daily for 3 to 5 days (or 10–15 mg/kg, with a maximum dose of 800 mg daily in children), a single oral dose of ivermectin 12 mg in adults (or 150 µg/kg in children), or topical application of thiabendazole 10% to 15% three times daily for at least 15 days.¹⁴ Cases of CLM complicated by Löffler syndrome may require a longer treatment course, such as a 7-day course of albendazole 400 mg daily. Tan and Liu⁹ reported a case of CLM complicated by Löffler syndrome that was successfully treated with albendazole. In this patient, initial treatment with 2 courses of mebendazole (3 days each for a total of 6 days) resulted in improvement of cutaneous lesions but not the pulmonary infiltrate. A subsequent prolonged course of albendazole and intravenous hydrocortisone for 5 days resulted in complete resolution of the pulmonary infiltrate and peripheral eosinophilia. The authors concluded that inadequacy of treatment with mebendazole may be related to differences in the rate of absorption and efficacy when compared to albendazole.⁹

Conclusion

Cutaneous larva migrans is a self-limited and pruritic skin eruption that is acquired after direct inoculation with sand or soil that is contaminated with feces containing A braziliense or A caninum. Although the classic presentation is readily identifiable, there are a variety of atypical presentations that may go undiagnosed. Symptomatic relief usually can be achieved with short courses of oral or topical antihelminth medications.

To the Editor:

Pemphigus vulgaris is an uncommon autoimmune blistering dermatosis characterized by painful mucocutaneous erosions. It can be a life-threatening condition if left untreated. The autoimmune process is mediated by autoantibodies against the keratinocyte surface antigens desmoglein 1 and 3.¹ Therapy is directed at lowering autoantibody levels with systemic corticosteroids and immunosuppressive agents. Use of these agents often is limited by collateral adverse effects.² Refractory disease may occur despite the use of high-dose corticosteroids or a combination of other immunosuppressants. The level of these pathogenic autoantibodies generally parallels the extent of disease activity, and removing them with plasmapheresis followed by immunosuppression should result in therapeutic response.³ We report a case of refractory pemphigus vulgaris that was controlled with plasmapheresis used in synchrony with pulse cyclophosphamide.

A 48-year-old Chinese man first presented with mucocutaneous erosions 2 years ago, and a diagnosis of pemphigus vulgaris was confirmed based on typical histologic and immunofluorescence features. Histologic features included suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (Figure 1). Direct immunofluorescence demonstrated intercellular deposits of IgG and complements in the lower epidermis, and indirect immunofluorescence showed the presence of the pathogenic pemphigus autoantibodies. The patient was initially treated with prednisolone (up to 1 mg/kg daily) and mycophenolate mofetil (1 g twice daily) for 6 months with moderate disease response. Two months later he experienced a disease flare that was triggered by sun exposure and concomitant herpes simplex virus infection. He achieved moderate disease control with acyclovir, 3 days of intravenous immunoglobulin, and combination prednisolone and azathioprine. There was no other relevant medical history. For the last year, the patient received continuous prednisolone (varying doses 0.5–1 mg/kg daily), concomitant azathioprine (up to 3 mg/kg daily), and long-term prophylactic acyclovir, but he continued to have residual crusted erosions over the scalp and face (best score of 25 points based on the autoimmune bullous skin disorder intensity score [ABSIS] ranging from 0–150 points⁴). He was admitted at the current presentation with another, more severe disease flare with extensive painful erosions over the trunk, arms, legs, face, and scalp (80% body surface area involvement and ABSIS score of 120 points)(Figure 2)⁴ that occurred after azathioprine was temporarily ceased for 1 week due to transaminitis, and despite a temporary increment in prednisolone dose. There was, however, no significant oral mucosal involvement. The desmoglein 1 and 3 antibody levels were elevated at more than 300 U/mL and 186 U/mL, respectively (>20 U/mL indicates positivity). A 3-day course of pulse intravenous methylprednisolone (10 mg/kg) failed to achieve clinical improvement or reduction of antibody titers. The use of various immunosuppressive agents was limited by persistent transaminitis and transient leukopenia.

Figure 1. Histologic features of pemphigus vulgaris including suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (H&E, original magnification ×40). Figure 2. Acute flare of pemphigus vulgaris with extensive erosions of the trunk and arms (80% body surface area involvement). Figure 3. Clinical improvement of pemphigus vulgaris after 9 sessions of plasmapheresis synchronized with pulse intravenous cyclophosphamide over a 3-week period. The erosions were almost completely reepithelialized.

Because of remarkable morbidity, the patient underwent interim plasmapheresis for rapid disease control. Plasmapheresis was carried out through a pheresible central venous catheter. One plasma volume exchange was done each session, which was 5 L for the patient’s body weight and hematocrit. Equal volume of colloid comprising 2.5 L of fresh frozen plasma and 2.5 L of 5% albumin was used for replacement. Plasma exchange was performed with a cell separator by discontinuous flow centrifugation with 4% acid citrate dextrose as an anticoagulant. For each session of plasmapheresis, 16 cycles of exchange (each processing approximately 300 mL of blood) was carried out, the entire process lasting for 4 hours. The coagulation and biochemical profile was checked after each session of plasmapheresis and corrected when necessary. The patient underwent 9 sessions of plasmapheresis over a 3-week period, synchronized with pulse intravenous cyclophosphamide (15 mg/kg) immediately after completion of the plasmapheresis sessions, resulting in a remarkable decrease in pathogenic antibody titers to near undetectable levels and clinical improvement (Figure 3). The extensive erosions gradually healed with good reepithelialization, and there was a notable reduction in the ABSIS score to 12 points. He received 3 more monthly treatments with pulse intravenous cyclophosphamide (15 mg/kg) and is currently maintained on oral cyclophosphamide (2 mg/kg daily) and low-dose prednisolone (0.3 mg/kg daily). There was no subsequent disease relapse at 6-month follow-up, with the ABSIS score maintained at 5 points, and no increase in pathogenic autoantibody titers. The patient subsequently was lost to follow-up.

Patients with severe disease or refractory cases of pemphigus vulgaris that have been maintained on unacceptably high doses of corticosteroids or immunosuppressants that cannot be tapered without a disease flare may develop remarkable adverse effects, both from medications and from long-term immunosuppression.² Our case illustrates the short-term benefit of plasmapheresis combined with immunosuppressants resulting in rapid disease control.

Plasmapheresis involves the selective removal of pathogenic materials from the circulation to achieve therapeutic effect, followed by appropriate replacement fluids. Treating pemphigus vulgaris with plasmapheresis was introduced in 1978 based on the rationale of removing pathogenic autoantibodies from the circulation.^3,5 Using desmoglein enzyme-linked immunosorbent assay, it has been shown that one centrifugal plasmapheresis procedure eliminates approximately 15% of the IgG autoantibodies from the whole body.⁶ An average of 5 plasmapheresis sessions on alternate days usually is required to deplete the levels of pathogenic autoantibodies to near undetectable levels.⁷ Our case required 9 plasmapheresis sessions over 3 weeks to achieve good therapeutic response.

It seems that using plasmapheresis to treat pemphigus vulgaris has fallen out of favor due to its inability to prevent the antibody rebound occurring during weeks 1 and 2 posttreatment. Because of a feedback mechanism, a massive antibody depletion by plasmapheresis triggers a rebound synthesis of more autoantibodies by pathogenic B cells to titers comparable to or higher than those before plasmapheresis.⁸ The use of plasmapheresis should be supported by immunosuppressive therapy to prevent antibody feedback rebound. Due to the advent of available immunosuppressive agents in recent years, there is a resurgence in the successful use of this old treatment modality combined with immunosuppressive therapy in managing refractory pemphigus vulgaris.^7,8 At present there is no clear data to support the use of one immunosuppressant versus another, but our case supports the use of pulse intravenous cyclophosphamide, as documented in other reports.^7,9 The success of immunosuppressive agents at reducing antibody levels depends on the timing (immediately after plasmapheresis) as well as individual responsiveness to the immunosuppressant.⁷

Our armamentarium of therapies for refractory pemphigus vulgaris continues to evolve. A more selective method of removing antibodies by extracorporeal immunoadsorption has the benefit of higher removal rates and reduced inadvertent loss of other plasma components.¹⁰ The combination of protein A immunoadsorption with rituximab, a monoclonal anti-CD20 antibody that induces B-cell depletion, also has been shown to induce rapid and durable remission in refractory cases.¹¹

Our case shows that plasmapheresis can be a useful alternative or adjunctive intervention in pemphigus vulgaris that is not responding to conventional therapy or in cases when steroids or immunosuppressants are contraindicated. There is a definite role for such therapeutic plasma exchanges in the rapid control of potentially life-threatening disease. Its benefits are optimized when used in synchrony with immunosuppressants immediately following plasmapheresis to prevent rebound effect of antibody depletion.

To the Editor:

Pemphigus vulgaris is an uncommon autoimmune blistering dermatosis characterized by painful mucocutaneous erosions. It can be a life-threatening condition if left untreated. The autoimmune process is mediated by autoantibodies against the keratinocyte surface antigens desmoglein 1 and 3.¹ Therapy is directed at lowering autoantibody levels with systemic corticosteroids and immunosuppressive agents. Use of these agents often is limited by collateral adverse effects.² Refractory disease may occur despite the use of high-dose corticosteroids or a combination of other immunosuppressants. The level of these pathogenic autoantibodies generally parallels the extent of disease activity, and removing them with plasmapheresis followed by immunosuppression should result in therapeutic response.³ We report a case of refractory pemphigus vulgaris that was controlled with plasmapheresis used in synchrony with pulse cyclophosphamide.

A 48-year-old Chinese man first presented with mucocutaneous erosions 2 years ago, and a diagnosis of pemphigus vulgaris was confirmed based on typical histologic and immunofluorescence features. Histologic features included suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (Figure 1). Direct immunofluorescence demonstrated intercellular deposits of IgG and complements in the lower epidermis, and indirect immunofluorescence showed the presence of the pathogenic pemphigus autoantibodies. The patient was initially treated with prednisolone (up to 1 mg/kg daily) and mycophenolate mofetil (1 g twice daily) for 6 months with moderate disease response. Two months later he experienced a disease flare that was triggered by sun exposure and concomitant herpes simplex virus infection. He achieved moderate disease control with acyclovir, 3 days of intravenous immunoglobulin, and combination prednisolone and azathioprine. There was no other relevant medical history. For the last year, the patient received continuous prednisolone (varying doses 0.5–1 mg/kg daily), concomitant azathioprine (up to 3 mg/kg daily), and long-term prophylactic acyclovir, but he continued to have residual crusted erosions over the scalp and face (best score of 25 points based on the autoimmune bullous skin disorder intensity score [ABSIS] ranging from 0–150 points⁴). He was admitted at the current presentation with another, more severe disease flare with extensive painful erosions over the trunk, arms, legs, face, and scalp (80% body surface area involvement and ABSIS score of 120 points)(Figure 2)⁴ that occurred after azathioprine was temporarily ceased for 1 week due to transaminitis, and despite a temporary increment in prednisolone dose. There was, however, no significant oral mucosal involvement. The desmoglein 1 and 3 antibody levels were elevated at more than 300 U/mL and 186 U/mL, respectively (>20 U/mL indicates positivity). A 3-day course of pulse intravenous methylprednisolone (10 mg/kg) failed to achieve clinical improvement or reduction of antibody titers. The use of various immunosuppressive agents was limited by persistent transaminitis and transient leukopenia.

Figure 1. Histologic features of pemphigus vulgaris including suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (H&E, original magnification ×40). Figure 2. Acute flare of pemphigus vulgaris with extensive erosions of the trunk and arms (80% body surface area involvement). Figure 3. Clinical improvement of pemphigus vulgaris after 9 sessions of plasmapheresis synchronized with pulse intravenous cyclophosphamide over a 3-week period. The erosions were almost completely reepithelialized.

Because of remarkable morbidity, the patient underwent interim plasmapheresis for rapid disease control. Plasmapheresis was carried out through a pheresible central venous catheter. One plasma volume exchange was done each session, which was 5 L for the patient’s body weight and hematocrit. Equal volume of colloid comprising 2.5 L of fresh frozen plasma and 2.5 L of 5% albumin was used for replacement. Plasma exchange was performed with a cell separator by discontinuous flow centrifugation with 4% acid citrate dextrose as an anticoagulant. For each session of plasmapheresis, 16 cycles of exchange (each processing approximately 300 mL of blood) was carried out, the entire process lasting for 4 hours. The coagulation and biochemical profile was checked after each session of plasmapheresis and corrected when necessary. The patient underwent 9 sessions of plasmapheresis over a 3-week period, synchronized with pulse intravenous cyclophosphamide (15 mg/kg) immediately after completion of the plasmapheresis sessions, resulting in a remarkable decrease in pathogenic antibody titers to near undetectable levels and clinical improvement (Figure 3). The extensive erosions gradually healed with good reepithelialization, and there was a notable reduction in the ABSIS score to 12 points. He received 3 more monthly treatments with pulse intravenous cyclophosphamide (15 mg/kg) and is currently maintained on oral cyclophosphamide (2 mg/kg daily) and low-dose prednisolone (0.3 mg/kg daily). There was no subsequent disease relapse at 6-month follow-up, with the ABSIS score maintained at 5 points, and no increase in pathogenic autoantibody titers. The patient subsequently was lost to follow-up.

Patients with severe disease or refractory cases of pemphigus vulgaris that have been maintained on unacceptably high doses of corticosteroids or immunosuppressants that cannot be tapered without a disease flare may develop remarkable adverse effects, both from medications and from long-term immunosuppression.² Our case illustrates the short-term benefit of plasmapheresis combined with immunosuppressants resulting in rapid disease control.

Plasmapheresis involves the selective removal of pathogenic materials from the circulation to achieve therapeutic effect, followed by appropriate replacement fluids. Treating pemphigus vulgaris with plasmapheresis was introduced in 1978 based on the rationale of removing pathogenic autoantibodies from the circulation.^3,5 Using desmoglein enzyme-linked immunosorbent assay, it has been shown that one centrifugal plasmapheresis procedure eliminates approximately 15% of the IgG autoantibodies from the whole body.⁶ An average of 5 plasmapheresis sessions on alternate days usually is required to deplete the levels of pathogenic autoantibodies to near undetectable levels.⁷ Our case required 9 plasmapheresis sessions over 3 weeks to achieve good therapeutic response.

It seems that using plasmapheresis to treat pemphigus vulgaris has fallen out of favor due to its inability to prevent the antibody rebound occurring during weeks 1 and 2 posttreatment. Because of a feedback mechanism, a massive antibody depletion by plasmapheresis triggers a rebound synthesis of more autoantibodies by pathogenic B cells to titers comparable to or higher than those before plasmapheresis.⁸ The use of plasmapheresis should be supported by immunosuppressive therapy to prevent antibody feedback rebound. Due to the advent of available immunosuppressive agents in recent years, there is a resurgence in the successful use of this old treatment modality combined with immunosuppressive therapy in managing refractory pemphigus vulgaris.^7,8 At present there is no clear data to support the use of one immunosuppressant versus another, but our case supports the use of pulse intravenous cyclophosphamide, as documented in other reports.^7,9 The success of immunosuppressive agents at reducing antibody levels depends on the timing (immediately after plasmapheresis) as well as individual responsiveness to the immunosuppressant.⁷

Our armamentarium of therapies for refractory pemphigus vulgaris continues to evolve. A more selective method of removing antibodies by extracorporeal immunoadsorption has the benefit of higher removal rates and reduced inadvertent loss of other plasma components.¹⁰ The combination of protein A immunoadsorption with rituximab, a monoclonal anti-CD20 antibody that induces B-cell depletion, also has been shown to induce rapid and durable remission in refractory cases.¹¹

Our case shows that plasmapheresis can be a useful alternative or adjunctive intervention in pemphigus vulgaris that is not responding to conventional therapy or in cases when steroids or immunosuppressants are contraindicated. There is a definite role for such therapeutic plasma exchanges in the rapid control of potentially life-threatening disease. Its benefits are optimized when used in synchrony with immunosuppressants immediately following plasmapheresis to prevent rebound effect of antibody depletion.

To the Editor:

Pemphigus vulgaris is an uncommon autoimmune blistering dermatosis characterized by painful mucocutaneous erosions. It can be a life-threatening condition if left untreated. The autoimmune process is mediated by autoantibodies against the keratinocyte surface antigens desmoglein 1 and 3.¹ Therapy is directed at lowering autoantibody levels with systemic corticosteroids and immunosuppressive agents. Use of these agents often is limited by collateral adverse effects.² Refractory disease may occur despite the use of high-dose corticosteroids or a combination of other immunosuppressants. The level of these pathogenic autoantibodies generally parallels the extent of disease activity, and removing them with plasmapheresis followed by immunosuppression should result in therapeutic response.³ We report a case of refractory pemphigus vulgaris that was controlled with plasmapheresis used in synchrony with pulse cyclophosphamide.

A 48-year-old Chinese man first presented with mucocutaneous erosions 2 years ago, and a diagnosis of pemphigus vulgaris was confirmed based on typical histologic and immunofluorescence features. Histologic features included suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (Figure 1). Direct immunofluorescence demonstrated intercellular deposits of IgG and complements in the lower epidermis, and indirect immunofluorescence showed the presence of the pathogenic pemphigus autoantibodies. The patient was initially treated with prednisolone (up to 1 mg/kg daily) and mycophenolate mofetil (1 g twice daily) for 6 months with moderate disease response. Two months later he experienced a disease flare that was triggered by sun exposure and concomitant herpes simplex virus infection. He achieved moderate disease control with acyclovir, 3 days of intravenous immunoglobulin, and combination prednisolone and azathioprine. There was no other relevant medical history. For the last year, the patient received continuous prednisolone (varying doses 0.5–1 mg/kg daily), concomitant azathioprine (up to 3 mg/kg daily), and long-term prophylactic acyclovir, but he continued to have residual crusted erosions over the scalp and face (best score of 25 points based on the autoimmune bullous skin disorder intensity score [ABSIS] ranging from 0–150 points⁴). He was admitted at the current presentation with another, more severe disease flare with extensive painful erosions over the trunk, arms, legs, face, and scalp (80% body surface area involvement and ABSIS score of 120 points)(Figure 2)⁴ that occurred after azathioprine was temporarily ceased for 1 week due to transaminitis, and despite a temporary increment in prednisolone dose. There was, however, no significant oral mucosal involvement. The desmoglein 1 and 3 antibody levels were elevated at more than 300 U/mL and 186 U/mL, respectively (>20 U/mL indicates positivity). A 3-day course of pulse intravenous methylprednisolone (10 mg/kg) failed to achieve clinical improvement or reduction of antibody titers. The use of various immunosuppressive agents was limited by persistent transaminitis and transient leukopenia.

Figure 1. Histologic features of pemphigus vulgaris including suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (H&E, original magnification ×40). Figure 2. Acute flare of pemphigus vulgaris with extensive erosions of the trunk and arms (80% body surface area involvement). Figure 3. Clinical improvement of pemphigus vulgaris after 9 sessions of plasmapheresis synchronized with pulse intravenous cyclophosphamide over a 3-week period. The erosions were almost completely reepithelialized.

Because of remarkable morbidity, the patient underwent interim plasmapheresis for rapid disease control. Plasmapheresis was carried out through a pheresible central venous catheter. One plasma volume exchange was done each session, which was 5 L for the patient’s body weight and hematocrit. Equal volume of colloid comprising 2.5 L of fresh frozen plasma and 2.5 L of 5% albumin was used for replacement. Plasma exchange was performed with a cell separator by discontinuous flow centrifugation with 4% acid citrate dextrose as an anticoagulant. For each session of plasmapheresis, 16 cycles of exchange (each processing approximately 300 mL of blood) was carried out, the entire process lasting for 4 hours. The coagulation and biochemical profile was checked after each session of plasmapheresis and corrected when necessary. The patient underwent 9 sessions of plasmapheresis over a 3-week period, synchronized with pulse intravenous cyclophosphamide (15 mg/kg) immediately after completion of the plasmapheresis sessions, resulting in a remarkable decrease in pathogenic antibody titers to near undetectable levels and clinical improvement (Figure 3). The extensive erosions gradually healed with good reepithelialization, and there was a notable reduction in the ABSIS score to 12 points. He received 3 more monthly treatments with pulse intravenous cyclophosphamide (15 mg/kg) and is currently maintained on oral cyclophosphamide (2 mg/kg daily) and low-dose prednisolone (0.3 mg/kg daily). There was no subsequent disease relapse at 6-month follow-up, with the ABSIS score maintained at 5 points, and no increase in pathogenic autoantibody titers. The patient subsequently was lost to follow-up.

Patients with severe disease or refractory cases of pemphigus vulgaris that have been maintained on unacceptably high doses of corticosteroids or immunosuppressants that cannot be tapered without a disease flare may develop remarkable adverse effects, both from medications and from long-term immunosuppression.² Our case illustrates the short-term benefit of plasmapheresis combined with immunosuppressants resulting in rapid disease control.

Plasmapheresis involves the selective removal of pathogenic materials from the circulation to achieve therapeutic effect, followed by appropriate replacement fluids. Treating pemphigus vulgaris with plasmapheresis was introduced in 1978 based on the rationale of removing pathogenic autoantibodies from the circulation.^3,5 Using desmoglein enzyme-linked immunosorbent assay, it has been shown that one centrifugal plasmapheresis procedure eliminates approximately 15% of the IgG autoantibodies from the whole body.⁶ An average of 5 plasmapheresis sessions on alternate days usually is required to deplete the levels of pathogenic autoantibodies to near undetectable levels.⁷ Our case required 9 plasmapheresis sessions over 3 weeks to achieve good therapeutic response.

It seems that using plasmapheresis to treat pemphigus vulgaris has fallen out of favor due to its inability to prevent the antibody rebound occurring during weeks 1 and 2 posttreatment. Because of a feedback mechanism, a massive antibody depletion by plasmapheresis triggers a rebound synthesis of more autoantibodies by pathogenic B cells to titers comparable to or higher than those before plasmapheresis.⁸ The use of plasmapheresis should be supported by immunosuppressive therapy to prevent antibody feedback rebound. Due to the advent of available immunosuppressive agents in recent years, there is a resurgence in the successful use of this old treatment modality combined with immunosuppressive therapy in managing refractory pemphigus vulgaris.^7,8 At present there is no clear data to support the use of one immunosuppressant versus another, but our case supports the use of pulse intravenous cyclophosphamide, as documented in other reports.^7,9 The success of immunosuppressive agents at reducing antibody levels depends on the timing (immediately after plasmapheresis) as well as individual responsiveness to the immunosuppressant.⁷

Our armamentarium of therapies for refractory pemphigus vulgaris continues to evolve. A more selective method of removing antibodies by extracorporeal immunoadsorption has the benefit of higher removal rates and reduced inadvertent loss of other plasma components.¹⁰ The combination of protein A immunoadsorption with rituximab, a monoclonal anti-CD20 antibody that induces B-cell depletion, also has been shown to induce rapid and durable remission in refractory cases.¹¹

Our case shows that plasmapheresis can be a useful alternative or adjunctive intervention in pemphigus vulgaris that is not responding to conventional therapy or in cases when steroids or immunosuppressants are contraindicated. There is a definite role for such therapeutic plasma exchanges in the rapid control of potentially life-threatening disease. Its benefits are optimized when used in synchrony with immunosuppressants immediately following plasmapheresis to prevent rebound effect of antibody depletion.