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.

Kinetin (N6-furfuryladenine or 6-furfurylaminopurine) is a plant cytokinin or phytohormone that promotes cell division, delays senescence in plants, and is reputed to aid in the restoration of skin barrier function and, possibly, in reducing the signs and symptoms of rosacea (Clin. Exp. Dermatol. 2007;32:693-5; Plant Sci. 1999;148:37-45).

Kinetin is believed to develop in cellular DNA as a product of the oxidative, secondary modification of DNA (Plant Sci. 1999;148:37-45). In 1955, it became the first cytokinin isolated from DNA (from herring sperm) as an artifactual rearrangement product of the autoclaving process (J. Cosmet. Dermatol. 2007;6:243-9; Int. J. Biol. Macromol. 2007;40:182-92).

It has since been found to be present in human urine as well as DNA freshly extracted from human cells (Int. J. Biol. Macromol. 2007;40:182-92). The preponderance of amassed experimental evidence suggests that endogenous kinetin acts in vitro and in vivo as a potent antioxidant (Plant Sci. 1999;148:37-45). Currently, it is used as an anti-aging agent in various cosmetic products (J. Cosmet. Dermatol. 2007;6:243-9; J. Cosmet. Dermatol. 2010;9:218-25). Synthetic kinetin is thought to have the capacity to neutralize free radicals as well as limit the damage to DNA and fibroblasts (Photochem. Photobiol. 2012;88:748-52).

In vitro results

Olsen et al. demonstrated in vitro in 1999 that kinetin dose-dependently protected DNA against oxidative damage mediated by the Fenton reaction, and noted that kinetin had previously been linked to anti-aging activity in plants, fruit flies, and human cells in culture (Biochem. Biophys. Res. Commun. 1999;265:499-502). The following year, Verbeke et al. showed in vitro that kinetin potently inhibited damage caused by oxidation and glycoxidation (Biochem. Biophys. Res. Commun. 2000;276:1265-70).

In 2006, Vicanova et al. analyzed the effects of active ingredients from topical and systemic skin care formulations in vitro, finding that kinetin affected the upper dermis by enhancing deposits of fibrillin-1 and elastin fibers as well as their organization perpendicular to the dermal-epidermal junction. In the epidermis, kinetin stimulated keratinocyte production. Further, the investigators noted that the combination of topically applied kinetin with Imedeen Time Perfection ingredients (i.e., BioMarine Complex, grape seed extract, tomato extract, and vitamin C) supplemented systemically into culture medium yielded complementary benefits to dermal and epidermal development (Ann. N.Y. Acad. Sci. 2006;1067:337-42).

It is worth noting that in a study by Tournas et al. published the same month, investigators found that the topical application of a combination of vitamins C and E and ferulic acid yielded photoprotection to pig skin at 5 times the minimal erythema dose (MED) while individual antioxidants to which it was compared (i.e., coenzyme Q10, idebenone, and kinetin) delivered no photoprotective effects (J. Invest. Dermatol. 2006;126:1185-7). Nevertheless, Barciszewski et al. have observed that kinetin is the first stable secondary DNA damage product characterized by well defined cytokinin and anti-aging activity, with data showing that it has delayed human cellular aging in culture (Int. J. Biol. Macromol. 2007;40:182-92).

Rosacea

In 2007, Wu et al. performed a 12-week open-label study in 15 women and 3 men (aged 30-67 years) to ascertain the tolerability and efficacy of kinetin 0.1% lotion in the treatment of mild to moderate facial rosacea. Patients (17 of whom completed the study) applied the lotion twice daily, also daily applying an SPF 30 sunscreen. By week 4, significant improvements were observed in the reduction of skin roughness and mottled hyperpigmentation. Subject assessments at each 4-week interval after baseline and after 12 weeks revealed that kinetin 0.1% was well tolerated and effective for mild to moderate inflammatory rosacea (Clin. Exp. Dermatol. 2007;32:693-5).

Anti-aging

A 2002 study by J.L. McCullough and G.D. Weinstein represented the first evidence of the efficacy of topical kinetin in human beings, with twice-daily application for 24 weeks found to ameliorate skin texture, color, and blotchiness while diminishing rhytides and transepidermal water loss (J. Cosmet. Dermatol. 2002;15:29-32).

Two years later, T. Kimura and K. Doi showed that topical administration of kinetin improved the texture, wrinkling, and pigmentation of aged skin of hairless descendants of Mexican hairless dogs, resulting in notable depigmentation and rejuvenation after 100 days of treatment (Rejuvenation Res. 2004;7:32-9).In 2007, Chiu et al. conducted a randomized, double-blind, placebo-controlled, split-face comparative study in 52 Taiwanese subjects aged 30-60 years (90% of whom were female, all of whom had Fitzpatrick skin types II, III, or IV) to evaluate the clinical anti-aging effects and efficacy differences between kinetin plus niacinamide (kinetin 0.03%, niacinamide 4%) and niacinamide 4% alone versus vehicle placebo.

In the combination group, significant and sustained decreases were observed in counts of spots, pores, wrinkles, and evenness as well as persistent reductions in erythema index at weeks 8 and 12. At week 12, stratum corneum hydration status also was significantly enhanced in this group. In the niacinamide-only group, pore and evenness counts were significantly decreased at week 8, with declines in wrinkle counts emerging at week 12. The investigators concluded that kinetin and niacinamide display synergistic and dynamic anti-aging effects, showing substantial potential as topical anti-aging cosmeceutical agents (J. Cosmet. Dermatol. 2007;6:243-9).

However, Levin et al. noted in 2010 that while the effects of kinetin have been established in plants and its antioxidant properties have been displayed in vitro, the anti-aging effects and clinical efficacy ascribed to kinetin have been based on limited evidence, with no studies extant on the percutaneous absorption of kinetin. They added that research elucidating the mechanisms through which kinetin appears to improve skin barrier function, texture, and pigmentation also are lacking (J. Clin. Aesthet. Dermatol. 2010;3:22-41).

In 2012, Campos et al. assessed the effects on hydration, viscoelastic characteristics, and photoprotection of cosmetic preparations containing a dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid, and kinetin. They observed that the formulation protected hairless mouse skin barrier function against UV harm. After 4 weeks of application on human skin, the combination product was found to have improved moisturization of the stratum corneum, also delivering hydration effects to deeper skin layers. The researchers concluded that the cosmetic formulation containing kinetin shows promise as a cutaneous anti-aging product (Photochem. Photobiol. 2012;88:748-52).

Conclusion

While some experimental and clinical results appear to suggest an anti-aging effect exerted by topically applied kinetin, much more research – particularly randomized controlled and comparison studies – are needed to provide a clearer picture as to the mechanisms and appropriate role of kinetin in the dermatologic armamentarium.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.

Kinetin (N6-furfuryladenine or 6-furfurylaminopurine) is a plant cytokinin or phytohormone that promotes cell division, delays senescence in plants, and is reputed to aid in the restoration of skin barrier function and, possibly, in reducing the signs and symptoms of rosacea (Clin. Exp. Dermatol. 2007;32:693-5; Plant Sci. 1999;148:37-45).

Kinetin is believed to develop in cellular DNA as a product of the oxidative, secondary modification of DNA (Plant Sci. 1999;148:37-45). In 1955, it became the first cytokinin isolated from DNA (from herring sperm) as an artifactual rearrangement product of the autoclaving process (J. Cosmet. Dermatol. 2007;6:243-9; Int. J. Biol. Macromol. 2007;40:182-92).

It has since been found to be present in human urine as well as DNA freshly extracted from human cells (Int. J. Biol. Macromol. 2007;40:182-92). The preponderance of amassed experimental evidence suggests that endogenous kinetin acts in vitro and in vivo as a potent antioxidant (Plant Sci. 1999;148:37-45). Currently, it is used as an anti-aging agent in various cosmetic products (J. Cosmet. Dermatol. 2007;6:243-9; J. Cosmet. Dermatol. 2010;9:218-25). Synthetic kinetin is thought to have the capacity to neutralize free radicals as well as limit the damage to DNA and fibroblasts (Photochem. Photobiol. 2012;88:748-52).

In vitro results

Olsen et al. demonstrated in vitro in 1999 that kinetin dose-dependently protected DNA against oxidative damage mediated by the Fenton reaction, and noted that kinetin had previously been linked to anti-aging activity in plants, fruit flies, and human cells in culture (Biochem. Biophys. Res. Commun. 1999;265:499-502). The following year, Verbeke et al. showed in vitro that kinetin potently inhibited damage caused by oxidation and glycoxidation (Biochem. Biophys. Res. Commun. 2000;276:1265-70).

In 2006, Vicanova et al. analyzed the effects of active ingredients from topical and systemic skin care formulations in vitro, finding that kinetin affected the upper dermis by enhancing deposits of fibrillin-1 and elastin fibers as well as their organization perpendicular to the dermal-epidermal junction. In the epidermis, kinetin stimulated keratinocyte production. Further, the investigators noted that the combination of topically applied kinetin with Imedeen Time Perfection ingredients (i.e., BioMarine Complex, grape seed extract, tomato extract, and vitamin C) supplemented systemically into culture medium yielded complementary benefits to dermal and epidermal development (Ann. N.Y. Acad. Sci. 2006;1067:337-42).

It is worth noting that in a study by Tournas et al. published the same month, investigators found that the topical application of a combination of vitamins C and E and ferulic acid yielded photoprotection to pig skin at 5 times the minimal erythema dose (MED) while individual antioxidants to which it was compared (i.e., coenzyme Q10, idebenone, and kinetin) delivered no photoprotective effects (J. Invest. Dermatol. 2006;126:1185-7). Nevertheless, Barciszewski et al. have observed that kinetin is the first stable secondary DNA damage product characterized by well defined cytokinin and anti-aging activity, with data showing that it has delayed human cellular aging in culture (Int. J. Biol. Macromol. 2007;40:182-92).

Rosacea

In 2007, Wu et al. performed a 12-week open-label study in 15 women and 3 men (aged 30-67 years) to ascertain the tolerability and efficacy of kinetin 0.1% lotion in the treatment of mild to moderate facial rosacea. Patients (17 of whom completed the study) applied the lotion twice daily, also daily applying an SPF 30 sunscreen. By week 4, significant improvements were observed in the reduction of skin roughness and mottled hyperpigmentation. Subject assessments at each 4-week interval after baseline and after 12 weeks revealed that kinetin 0.1% was well tolerated and effective for mild to moderate inflammatory rosacea (Clin. Exp. Dermatol. 2007;32:693-5).

Anti-aging

A 2002 study by J.L. McCullough and G.D. Weinstein represented the first evidence of the efficacy of topical kinetin in human beings, with twice-daily application for 24 weeks found to ameliorate skin texture, color, and blotchiness while diminishing rhytides and transepidermal water loss (J. Cosmet. Dermatol. 2002;15:29-32).

Two years later, T. Kimura and K. Doi showed that topical administration of kinetin improved the texture, wrinkling, and pigmentation of aged skin of hairless descendants of Mexican hairless dogs, resulting in notable depigmentation and rejuvenation after 100 days of treatment (Rejuvenation Res. 2004;7:32-9).In 2007, Chiu et al. conducted a randomized, double-blind, placebo-controlled, split-face comparative study in 52 Taiwanese subjects aged 30-60 years (90% of whom were female, all of whom had Fitzpatrick skin types II, III, or IV) to evaluate the clinical anti-aging effects and efficacy differences between kinetin plus niacinamide (kinetin 0.03%, niacinamide 4%) and niacinamide 4% alone versus vehicle placebo.

In the combination group, significant and sustained decreases were observed in counts of spots, pores, wrinkles, and evenness as well as persistent reductions in erythema index at weeks 8 and 12. At week 12, stratum corneum hydration status also was significantly enhanced in this group. In the niacinamide-only group, pore and evenness counts were significantly decreased at week 8, with declines in wrinkle counts emerging at week 12. The investigators concluded that kinetin and niacinamide display synergistic and dynamic anti-aging effects, showing substantial potential as topical anti-aging cosmeceutical agents (J. Cosmet. Dermatol. 2007;6:243-9).

However, Levin et al. noted in 2010 that while the effects of kinetin have been established in plants and its antioxidant properties have been displayed in vitro, the anti-aging effects and clinical efficacy ascribed to kinetin have been based on limited evidence, with no studies extant on the percutaneous absorption of kinetin. They added that research elucidating the mechanisms through which kinetin appears to improve skin barrier function, texture, and pigmentation also are lacking (J. Clin. Aesthet. Dermatol. 2010;3:22-41).

In 2012, Campos et al. assessed the effects on hydration, viscoelastic characteristics, and photoprotection of cosmetic preparations containing a dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid, and kinetin. They observed that the formulation protected hairless mouse skin barrier function against UV harm. After 4 weeks of application on human skin, the combination product was found to have improved moisturization of the stratum corneum, also delivering hydration effects to deeper skin layers. The researchers concluded that the cosmetic formulation containing kinetin shows promise as a cutaneous anti-aging product (Photochem. Photobiol. 2012;88:748-52).

Conclusion

While some experimental and clinical results appear to suggest an anti-aging effect exerted by topically applied kinetin, much more research – particularly randomized controlled and comparison studies – are needed to provide a clearer picture as to the mechanisms and appropriate role of kinetin in the dermatologic armamentarium.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.

Kinetin (N6-furfuryladenine or 6-furfurylaminopurine) is a plant cytokinin or phytohormone that promotes cell division, delays senescence in plants, and is reputed to aid in the restoration of skin barrier function and, possibly, in reducing the signs and symptoms of rosacea (Clin. Exp. Dermatol. 2007;32:693-5; Plant Sci. 1999;148:37-45).

Kinetin is believed to develop in cellular DNA as a product of the oxidative, secondary modification of DNA (Plant Sci. 1999;148:37-45). In 1955, it became the first cytokinin isolated from DNA (from herring sperm) as an artifactual rearrangement product of the autoclaving process (J. Cosmet. Dermatol. 2007;6:243-9; Int. J. Biol. Macromol. 2007;40:182-92).

It has since been found to be present in human urine as well as DNA freshly extracted from human cells (Int. J. Biol. Macromol. 2007;40:182-92). The preponderance of amassed experimental evidence suggests that endogenous kinetin acts in vitro and in vivo as a potent antioxidant (Plant Sci. 1999;148:37-45). Currently, it is used as an anti-aging agent in various cosmetic products (J. Cosmet. Dermatol. 2007;6:243-9; J. Cosmet. Dermatol. 2010;9:218-25). Synthetic kinetin is thought to have the capacity to neutralize free radicals as well as limit the damage to DNA and fibroblasts (Photochem. Photobiol. 2012;88:748-52).

In vitro results

Olsen et al. demonstrated in vitro in 1999 that kinetin dose-dependently protected DNA against oxidative damage mediated by the Fenton reaction, and noted that kinetin had previously been linked to anti-aging activity in plants, fruit flies, and human cells in culture (Biochem. Biophys. Res. Commun. 1999;265:499-502). The following year, Verbeke et al. showed in vitro that kinetin potently inhibited damage caused by oxidation and glycoxidation (Biochem. Biophys. Res. Commun. 2000;276:1265-70).

In 2006, Vicanova et al. analyzed the effects of active ingredients from topical and systemic skin care formulations in vitro, finding that kinetin affected the upper dermis by enhancing deposits of fibrillin-1 and elastin fibers as well as their organization perpendicular to the dermal-epidermal junction. In the epidermis, kinetin stimulated keratinocyte production. Further, the investigators noted that the combination of topically applied kinetin with Imedeen Time Perfection ingredients (i.e., BioMarine Complex, grape seed extract, tomato extract, and vitamin C) supplemented systemically into culture medium yielded complementary benefits to dermal and epidermal development (Ann. N.Y. Acad. Sci. 2006;1067:337-42).

It is worth noting that in a study by Tournas et al. published the same month, investigators found that the topical application of a combination of vitamins C and E and ferulic acid yielded photoprotection to pig skin at 5 times the minimal erythema dose (MED) while individual antioxidants to which it was compared (i.e., coenzyme Q10, idebenone, and kinetin) delivered no photoprotective effects (J. Invest. Dermatol. 2006;126:1185-7). Nevertheless, Barciszewski et al. have observed that kinetin is the first stable secondary DNA damage product characterized by well defined cytokinin and anti-aging activity, with data showing that it has delayed human cellular aging in culture (Int. J. Biol. Macromol. 2007;40:182-92).

Rosacea

In 2007, Wu et al. performed a 12-week open-label study in 15 women and 3 men (aged 30-67 years) to ascertain the tolerability and efficacy of kinetin 0.1% lotion in the treatment of mild to moderate facial rosacea. Patients (17 of whom completed the study) applied the lotion twice daily, also daily applying an SPF 30 sunscreen. By week 4, significant improvements were observed in the reduction of skin roughness and mottled hyperpigmentation. Subject assessments at each 4-week interval after baseline and after 12 weeks revealed that kinetin 0.1% was well tolerated and effective for mild to moderate inflammatory rosacea (Clin. Exp. Dermatol. 2007;32:693-5).

Anti-aging

A 2002 study by J.L. McCullough and G.D. Weinstein represented the first evidence of the efficacy of topical kinetin in human beings, with twice-daily application for 24 weeks found to ameliorate skin texture, color, and blotchiness while diminishing rhytides and transepidermal water loss (J. Cosmet. Dermatol. 2002;15:29-32).

Two years later, T. Kimura and K. Doi showed that topical administration of kinetin improved the texture, wrinkling, and pigmentation of aged skin of hairless descendants of Mexican hairless dogs, resulting in notable depigmentation and rejuvenation after 100 days of treatment (Rejuvenation Res. 2004;7:32-9).In 2007, Chiu et al. conducted a randomized, double-blind, placebo-controlled, split-face comparative study in 52 Taiwanese subjects aged 30-60 years (90% of whom were female, all of whom had Fitzpatrick skin types II, III, or IV) to evaluate the clinical anti-aging effects and efficacy differences between kinetin plus niacinamide (kinetin 0.03%, niacinamide 4%) and niacinamide 4% alone versus vehicle placebo.

In the combination group, significant and sustained decreases were observed in counts of spots, pores, wrinkles, and evenness as well as persistent reductions in erythema index at weeks 8 and 12. At week 12, stratum corneum hydration status also was significantly enhanced in this group. In the niacinamide-only group, pore and evenness counts were significantly decreased at week 8, with declines in wrinkle counts emerging at week 12. The investigators concluded that kinetin and niacinamide display synergistic and dynamic anti-aging effects, showing substantial potential as topical anti-aging cosmeceutical agents (J. Cosmet. Dermatol. 2007;6:243-9).

However, Levin et al. noted in 2010 that while the effects of kinetin have been established in plants and its antioxidant properties have been displayed in vitro, the anti-aging effects and clinical efficacy ascribed to kinetin have been based on limited evidence, with no studies extant on the percutaneous absorption of kinetin. They added that research elucidating the mechanisms through which kinetin appears to improve skin barrier function, texture, and pigmentation also are lacking (J. Clin. Aesthet. Dermatol. 2010;3:22-41).

In 2012, Campos et al. assessed the effects on hydration, viscoelastic characteristics, and photoprotection of cosmetic preparations containing a dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid, and kinetin. They observed that the formulation protected hairless mouse skin barrier function against UV harm. After 4 weeks of application on human skin, the combination product was found to have improved moisturization of the stratum corneum, also delivering hydration effects to deeper skin layers. The researchers concluded that the cosmetic formulation containing kinetin shows promise as a cutaneous anti-aging product (Photochem. Photobiol. 2012;88:748-52).

Conclusion

While some experimental and clinical results appear to suggest an anti-aging effect exerted by topically applied kinetin, much more research – particularly randomized controlled and comparison studies – are needed to provide a clearer picture as to the mechanisms and appropriate role of kinetin in the dermatologic armamentarium.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.

Patients with coronary heart disease who have both depression and stress are at increased risk of myocardial infarction and death, according to findings from a large, prospective, cohort study.

Of 4,487 adults with CHD who were part of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, 1,337 experienced MI or death during a median of nearly 6 years of follow-up. Those with both high depressive symptoms and high stress at baseline – about 6% of the study population – were at significantly increased risk of such events (adjusted hazard ratio, 1.48) during the first 2.5 years of follow-up, compared with those with low stress and low depressive symptoms. However, the association was not significant beyond the initial 2.5 years (HR, 0.89), Carmela Alcántara, Ph.D., of Columbia University, New York, and her colleagues reported.

Those with low stress and high depressive symptoms, and those with high stress and low depressive symptoms, were not at increased risk (HR, 0.92 and 0.86, respectively) at any point during follow-up (Circ. Cardiovasc. Qual. Outcomes 2015 March 10 [doi:10.1161/IRCOUTCOMES.114.001180]).

The findings provide initial empirical evidence to support a “psychosocial perfect storm conceptual model” based on the idea that it takes an underlying chronic psychosocial vulnerability such as depression along with a more transient state such as psychological stress to precipitate a clinical event. The confluence of these factors may be particularly destructive in the short term, the investigators concluded, noting that the findings could have implications for the development of preventive treatments that focus on depression and stress during this vulnerable period in CHD patients.

The National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute supported the study. Dr. Alcantara reported having no disclosures, but two other authors received salary support from Amgen for research, and one served as a consultant for DiaDexus.

Patients with coronary heart disease who have both depression and stress are at increased risk of myocardial infarction and death, according to findings from a large, prospective, cohort study.

Of 4,487 adults with CHD who were part of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, 1,337 experienced MI or death during a median of nearly 6 years of follow-up. Those with both high depressive symptoms and high stress at baseline – about 6% of the study population – were at significantly increased risk of such events (adjusted hazard ratio, 1.48) during the first 2.5 years of follow-up, compared with those with low stress and low depressive symptoms. However, the association was not significant beyond the initial 2.5 years (HR, 0.89), Carmela Alcántara, Ph.D., of Columbia University, New York, and her colleagues reported.

Those with low stress and high depressive symptoms, and those with high stress and low depressive symptoms, were not at increased risk (HR, 0.92 and 0.86, respectively) at any point during follow-up (Circ. Cardiovasc. Qual. Outcomes 2015 March 10 [doi:10.1161/IRCOUTCOMES.114.001180]).

The findings provide initial empirical evidence to support a “psychosocial perfect storm conceptual model” based on the idea that it takes an underlying chronic psychosocial vulnerability such as depression along with a more transient state such as psychological stress to precipitate a clinical event. The confluence of these factors may be particularly destructive in the short term, the investigators concluded, noting that the findings could have implications for the development of preventive treatments that focus on depression and stress during this vulnerable period in CHD patients.

The National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute supported the study. Dr. Alcantara reported having no disclosures, but two other authors received salary support from Amgen for research, and one served as a consultant for DiaDexus.

Patients with coronary heart disease who have both depression and stress are at increased risk of myocardial infarction and death, according to findings from a large, prospective, cohort study.

Of 4,487 adults with CHD who were part of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, 1,337 experienced MI or death during a median of nearly 6 years of follow-up. Those with both high depressive symptoms and high stress at baseline – about 6% of the study population – were at significantly increased risk of such events (adjusted hazard ratio, 1.48) during the first 2.5 years of follow-up, compared with those with low stress and low depressive symptoms. However, the association was not significant beyond the initial 2.5 years (HR, 0.89), Carmela Alcántara, Ph.D., of Columbia University, New York, and her colleagues reported.

Those with low stress and high depressive symptoms, and those with high stress and low depressive symptoms, were not at increased risk (HR, 0.92 and 0.86, respectively) at any point during follow-up (Circ. Cardiovasc. Qual. Outcomes 2015 March 10 [doi:10.1161/IRCOUTCOMES.114.001180]).

The findings provide initial empirical evidence to support a “psychosocial perfect storm conceptual model” based on the idea that it takes an underlying chronic psychosocial vulnerability such as depression along with a more transient state such as psychological stress to precipitate a clinical event. The confluence of these factors may be particularly destructive in the short term, the investigators concluded, noting that the findings could have implications for the development of preventive treatments that focus on depression and stress during this vulnerable period in CHD patients.

The National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute supported the study. Dr. Alcantara reported having no disclosures, but two other authors received salary support from Amgen for research, and one served as a consultant for DiaDexus.

For every 1,000 patients who underwent heart transplantation, about 45 had an episode of venous thromboembolism within a year after surgery, according to a retrospective study reported in the February issue of the Journal of Heart and Lung Transplantation.

Furthermore, patients who had a single VTE episode after transplant had a “high” risk of recurrent VTE, said Dr. Rolando Alvarez, a cardiologist at Complejo Hospitalario Universitario A Coruna in A Coruna, Spain, and his associates.

“Our opinion is that long-term oral anticoagulation should be maintained in these patients, especially if other risk factors are present and provided that the bleeding risk is not excessive,” said the researchers.

Venous thromboembolism is a common complication of lung, kidney, and liver transplantation, but less is known about VTE after heart transplant. The researchers found that “classic” risk factors for VTE, such as being older, obese, or having renal dysfunction, also increased the risk of VTE after heart transplant (J. Heart Lung Transplant. 2015;34:167-74).

The study included data from 635 consecutive patients who underwent heart transplantation at a single hospital between 1991 and 2013. During a median of 8.4 years of follow-up, the cumulative incidence of VTE was 8.5%, for an annual incidence rate of 12.7 episodes per year for every 1,000 patients, the researchers reported. The risk of VTE was far higher during the first year after transplant (45.1 episodes per 1,000 patients), but even after excluding these episodes, VTE was six times more common among heart transplant recipients than among the general population. Furthermore, VTE recurred an estimated 30.5 times/1,000 patient-years, and 50.8 times/1,000 patients-years among patients who had stopped anticoagulants.

The cumulative incidence rate of DVT and PE were 8.4 and 8.7 episodes per 1,000 patient-years.

In the multivariate analysis, significant risk factors for VTE at less than 1 year after transplantation included age, obesity, chronic kidney disease, and emergency transplantation, the investigators said. More than a year after transplantation, only use of the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus significantly increased VTE risk.

“The evidence that supports a potential association between mTOR inhibitors and an increased risk of VTE events is still weak, and might be confounded by a high prevalence of comorbid conditions such as chronic renal failure, dyslipidemia, or malignancy in patients taking these kinds of drugs,” the investigators cautioned.

The authors suggested that in view of the high recurrence rate, long-term anticoagulation should be considered in heart transplant patients after their first VTE episode.

The Fundacion BBVA-Carolina funded the study. Four coauthors reported receiving travel support from Novartis Pharma and Astellas Pharma. The other authors reported no relevant conflicts of interest.

For every 1,000 patients who underwent heart transplantation, about 45 had an episode of venous thromboembolism within a year after surgery, according to a retrospective study reported in the February issue of the Journal of Heart and Lung Transplantation.

Furthermore, patients who had a single VTE episode after transplant had a “high” risk of recurrent VTE, said Dr. Rolando Alvarez, a cardiologist at Complejo Hospitalario Universitario A Coruna in A Coruna, Spain, and his associates.

“Our opinion is that long-term oral anticoagulation should be maintained in these patients, especially if other risk factors are present and provided that the bleeding risk is not excessive,” said the researchers.

Venous thromboembolism is a common complication of lung, kidney, and liver transplantation, but less is known about VTE after heart transplant. The researchers found that “classic” risk factors for VTE, such as being older, obese, or having renal dysfunction, also increased the risk of VTE after heart transplant (J. Heart Lung Transplant. 2015;34:167-74).

The study included data from 635 consecutive patients who underwent heart transplantation at a single hospital between 1991 and 2013. During a median of 8.4 years of follow-up, the cumulative incidence of VTE was 8.5%, for an annual incidence rate of 12.7 episodes per year for every 1,000 patients, the researchers reported. The risk of VTE was far higher during the first year after transplant (45.1 episodes per 1,000 patients), but even after excluding these episodes, VTE was six times more common among heart transplant recipients than among the general population. Furthermore, VTE recurred an estimated 30.5 times/1,000 patient-years, and 50.8 times/1,000 patients-years among patients who had stopped anticoagulants.

The cumulative incidence rate of DVT and PE were 8.4 and 8.7 episodes per 1,000 patient-years.

In the multivariate analysis, significant risk factors for VTE at less than 1 year after transplantation included age, obesity, chronic kidney disease, and emergency transplantation, the investigators said. More than a year after transplantation, only use of the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus significantly increased VTE risk.

“The evidence that supports a potential association between mTOR inhibitors and an increased risk of VTE events is still weak, and might be confounded by a high prevalence of comorbid conditions such as chronic renal failure, dyslipidemia, or malignancy in patients taking these kinds of drugs,” the investigators cautioned.

The authors suggested that in view of the high recurrence rate, long-term anticoagulation should be considered in heart transplant patients after their first VTE episode.

The Fundacion BBVA-Carolina funded the study. Four coauthors reported receiving travel support from Novartis Pharma and Astellas Pharma. The other authors reported no relevant conflicts of interest.

For every 1,000 patients who underwent heart transplantation, about 45 had an episode of venous thromboembolism within a year after surgery, according to a retrospective study reported in the February issue of the Journal of Heart and Lung Transplantation.

Furthermore, patients who had a single VTE episode after transplant had a “high” risk of recurrent VTE, said Dr. Rolando Alvarez, a cardiologist at Complejo Hospitalario Universitario A Coruna in A Coruna, Spain, and his associates.

“Our opinion is that long-term oral anticoagulation should be maintained in these patients, especially if other risk factors are present and provided that the bleeding risk is not excessive,” said the researchers.

Venous thromboembolism is a common complication of lung, kidney, and liver transplantation, but less is known about VTE after heart transplant. The researchers found that “classic” risk factors for VTE, such as being older, obese, or having renal dysfunction, also increased the risk of VTE after heart transplant (J. Heart Lung Transplant. 2015;34:167-74).

The study included data from 635 consecutive patients who underwent heart transplantation at a single hospital between 1991 and 2013. During a median of 8.4 years of follow-up, the cumulative incidence of VTE was 8.5%, for an annual incidence rate of 12.7 episodes per year for every 1,000 patients, the researchers reported. The risk of VTE was far higher during the first year after transplant (45.1 episodes per 1,000 patients), but even after excluding these episodes, VTE was six times more common among heart transplant recipients than among the general population. Furthermore, VTE recurred an estimated 30.5 times/1,000 patient-years, and 50.8 times/1,000 patients-years among patients who had stopped anticoagulants.

The cumulative incidence rate of DVT and PE were 8.4 and 8.7 episodes per 1,000 patient-years.

In the multivariate analysis, significant risk factors for VTE at less than 1 year after transplantation included age, obesity, chronic kidney disease, and emergency transplantation, the investigators said. More than a year after transplantation, only use of the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus significantly increased VTE risk.

“The evidence that supports a potential association between mTOR inhibitors and an increased risk of VTE events is still weak, and might be confounded by a high prevalence of comorbid conditions such as chronic renal failure, dyslipidemia, or malignancy in patients taking these kinds of drugs,” the investigators cautioned.

The authors suggested that in view of the high recurrence rate, long-term anticoagulation should be considered in heart transplant patients after their first VTE episode.

The Fundacion BBVA-Carolina funded the study. Four coauthors reported receiving travel support from Novartis Pharma and Astellas Pharma. The other authors reported no relevant conflicts of interest.

NASHVILLE, TENN. – Bringing a CT scanner and thrombolytic treatment directly to stroke patients in the field sped the time to thrombolysis, compared with waiting for the patient to arrive at the hospital.

Some U.S. stroke centers now send out a team that can immediately assess and start treating stroke patients in the community. In 2014, the first two U.S. mobile stroke-treatment units began operating, one in Houston and the second in Cleveland.

Mitchel L. Zoler/Frontline Medical News

Initial reports show both programs were successful in cutting the time to deliver thrombolytic treatment with intravenous tissue plasminogen activator (TPA) to appropriate patients.

In Houston, the active phase of the program started in May 2014, and by October 2014, 47 acute ischemic stroke patients had been treated with TPA. The mobile-unit crews started 43% of eligible patients on thrombolysis within 60 minutes of their symptom onset and another 31% were treated starting 61-80 minutes after symptom onset, said Stephanie A. Parker at the International Stroke Conference.

Courtesy American Heart Association

The unit also treats patients diagnosed with hemorrhagic stroke with intravenous nicardipine for rapid blood pressure reduction, said Ms. Parker, a critical care and emergency medicine–trained registered nurse who is project manager for the Houston mobile unit.

The Cleveland program began in July 2014; of the first 100 stroke patients seen by the mobile unit 16 of 19 eligible patients received tPA, with an average time of 56 minutes from symptom onset to treatment. This compared with an average 94 minutes to tPA onset in patients brought conventionally last year to a Cleveland-area hospital, Dr. M. Shazam Hussain said in a report at the meeting, sponsored by the American Heart Association.

Courtesy Amercian Heart Association

The clinical impact and cost effectiveness of the pilot programs using the mobile units have not yet been assessed from the data, Dr. Hussain and Ms. Parker emphasized. Funding for the Cleveland and Houston vehicles came from local donors; the Houston program also received equipment donations from manufacturers.

The two mobile units are standard 12-foot, box-shaped ambulances outfitted with a CT scanner, a point-of-care lab, and telemedicine components as well as more standard emergency-vehicle equipment. The Houston vehicle contains “all the diagnostic equipment that is in our emergency room,” Ms. Parker said.

The concept behind both the Cleveland unit, operated by the Cleveland Clinic, and the Houston unit, operated by the University of Texas, Houston, is that the mobile stroke unit arrives to a patient with a suspected stroke, the unit is stationary while a CT scan and other diagnostic tests are run, diagnosis occurs with telemedicine assistance. If the patient is cleared for TPA treatment, the infusion starts and the vehicle carries the patient to an appropriate stroke center.

Mitchel L. Zoler/Frontline Medical News

Currently, the Houston unit goes out with a vascular neurologist and a telemedicine physician on board, but plans are in place to test the feasibility of relying entirely on telemedicine when making diagnostic and treatment decisions. The Cleveland mobile unit already operates in this fashion, with no physician on board, and was the first mobile stroke unit in the world to depend completely on telemedicine, according to Dr. Hussain, a neurologist and head of the stroke program at the Cleveland Clinic.

The world’s first mobile stroke unit began operating in Saarland, Germany, in 2008 (Lancet Neurology 2012;11:397-404), and a second unit began running in Berlin after that, Dr. Hussain noted. Because of limited funding, the service he directs in Cleveland has been operating from 8 a.m.-8 p.m., 7 days a week. The program plans to expand to 24-hour coverage. The Houston mobile unit operates 24/7; it averages two runs per day and administers TPA on 1 of every 10 runs, Ms. Parker said. Both the Houston and Cleveland units tie into the local 911 emergency activation systems for their respective regions. 

[email protected]

On Twitter @mitchelzoler

NASHVILLE, TENN. – Bringing a CT scanner and thrombolytic treatment directly to stroke patients in the field sped the time to thrombolysis, compared with waiting for the patient to arrive at the hospital.

Some U.S. stroke centers now send out a team that can immediately assess and start treating stroke patients in the community. In 2014, the first two U.S. mobile stroke-treatment units began operating, one in Houston and the second in Cleveland.

Mitchel L. Zoler/Frontline Medical News

Initial reports show both programs were successful in cutting the time to deliver thrombolytic treatment with intravenous tissue plasminogen activator (TPA) to appropriate patients.

In Houston, the active phase of the program started in May 2014, and by October 2014, 47 acute ischemic stroke patients had been treated with TPA. The mobile-unit crews started 43% of eligible patients on thrombolysis within 60 minutes of their symptom onset and another 31% were treated starting 61-80 minutes after symptom onset, said Stephanie A. Parker at the International Stroke Conference.

Courtesy American Heart Association

The unit also treats patients diagnosed with hemorrhagic stroke with intravenous nicardipine for rapid blood pressure reduction, said Ms. Parker, a critical care and emergency medicine–trained registered nurse who is project manager for the Houston mobile unit.

The Cleveland program began in July 2014; of the first 100 stroke patients seen by the mobile unit 16 of 19 eligible patients received tPA, with an average time of 56 minutes from symptom onset to treatment. This compared with an average 94 minutes to tPA onset in patients brought conventionally last year to a Cleveland-area hospital, Dr. M. Shazam Hussain said in a report at the meeting, sponsored by the American Heart Association.

Courtesy Amercian Heart Association

The clinical impact and cost effectiveness of the pilot programs using the mobile units have not yet been assessed from the data, Dr. Hussain and Ms. Parker emphasized. Funding for the Cleveland and Houston vehicles came from local donors; the Houston program also received equipment donations from manufacturers.

The two mobile units are standard 12-foot, box-shaped ambulances outfitted with a CT scanner, a point-of-care lab, and telemedicine components as well as more standard emergency-vehicle equipment. The Houston vehicle contains “all the diagnostic equipment that is in our emergency room,” Ms. Parker said.

The concept behind both the Cleveland unit, operated by the Cleveland Clinic, and the Houston unit, operated by the University of Texas, Houston, is that the mobile stroke unit arrives to a patient with a suspected stroke, the unit is stationary while a CT scan and other diagnostic tests are run, diagnosis occurs with telemedicine assistance. If the patient is cleared for TPA treatment, the infusion starts and the vehicle carries the patient to an appropriate stroke center.

Mitchel L. Zoler/Frontline Medical News

Currently, the Houston unit goes out with a vascular neurologist and a telemedicine physician on board, but plans are in place to test the feasibility of relying entirely on telemedicine when making diagnostic and treatment decisions. The Cleveland mobile unit already operates in this fashion, with no physician on board, and was the first mobile stroke unit in the world to depend completely on telemedicine, according to Dr. Hussain, a neurologist and head of the stroke program at the Cleveland Clinic.

The world’s first mobile stroke unit began operating in Saarland, Germany, in 2008 (Lancet Neurology 2012;11:397-404), and a second unit began running in Berlin after that, Dr. Hussain noted. Because of limited funding, the service he directs in Cleveland has been operating from 8 a.m.-8 p.m., 7 days a week. The program plans to expand to 24-hour coverage. The Houston mobile unit operates 24/7; it averages two runs per day and administers TPA on 1 of every 10 runs, Ms. Parker said. Both the Houston and Cleveland units tie into the local 911 emergency activation systems for their respective regions. 

[email protected]

On Twitter @mitchelzoler

NASHVILLE, TENN. – Bringing a CT scanner and thrombolytic treatment directly to stroke patients in the field sped the time to thrombolysis, compared with waiting for the patient to arrive at the hospital.

Some U.S. stroke centers now send out a team that can immediately assess and start treating stroke patients in the community. In 2014, the first two U.S. mobile stroke-treatment units began operating, one in Houston and the second in Cleveland.

Mitchel L. Zoler/Frontline Medical News

Initial reports show both programs were successful in cutting the time to deliver thrombolytic treatment with intravenous tissue plasminogen activator (TPA) to appropriate patients.

In Houston, the active phase of the program started in May 2014, and by October 2014, 47 acute ischemic stroke patients had been treated with TPA. The mobile-unit crews started 43% of eligible patients on thrombolysis within 60 minutes of their symptom onset and another 31% were treated starting 61-80 minutes after symptom onset, said Stephanie A. Parker at the International Stroke Conference.

Courtesy American Heart Association

The unit also treats patients diagnosed with hemorrhagic stroke with intravenous nicardipine for rapid blood pressure reduction, said Ms. Parker, a critical care and emergency medicine–trained registered nurse who is project manager for the Houston mobile unit.

The Cleveland program began in July 2014; of the first 100 stroke patients seen by the mobile unit 16 of 19 eligible patients received tPA, with an average time of 56 minutes from symptom onset to treatment. This compared with an average 94 minutes to tPA onset in patients brought conventionally last year to a Cleveland-area hospital, Dr. M. Shazam Hussain said in a report at the meeting, sponsored by the American Heart Association.

Courtesy Amercian Heart Association

The clinical impact and cost effectiveness of the pilot programs using the mobile units have not yet been assessed from the data, Dr. Hussain and Ms. Parker emphasized. Funding for the Cleveland and Houston vehicles came from local donors; the Houston program also received equipment donations from manufacturers.

The two mobile units are standard 12-foot, box-shaped ambulances outfitted with a CT scanner, a point-of-care lab, and telemedicine components as well as more standard emergency-vehicle equipment. The Houston vehicle contains “all the diagnostic equipment that is in our emergency room,” Ms. Parker said.

The concept behind both the Cleveland unit, operated by the Cleveland Clinic, and the Houston unit, operated by the University of Texas, Houston, is that the mobile stroke unit arrives to a patient with a suspected stroke, the unit is stationary while a CT scan and other diagnostic tests are run, diagnosis occurs with telemedicine assistance. If the patient is cleared for TPA treatment, the infusion starts and the vehicle carries the patient to an appropriate stroke center.

Mitchel L. Zoler/Frontline Medical News

Currently, the Houston unit goes out with a vascular neurologist and a telemedicine physician on board, but plans are in place to test the feasibility of relying entirely on telemedicine when making diagnostic and treatment decisions. The Cleveland mobile unit already operates in this fashion, with no physician on board, and was the first mobile stroke unit in the world to depend completely on telemedicine, according to Dr. Hussain, a neurologist and head of the stroke program at the Cleveland Clinic.

The world’s first mobile stroke unit began operating in Saarland, Germany, in 2008 (Lancet Neurology 2012;11:397-404), and a second unit began running in Berlin after that, Dr. Hussain noted. Because of limited funding, the service he directs in Cleveland has been operating from 8 a.m.-8 p.m., 7 days a week. The program plans to expand to 24-hour coverage. The Houston mobile unit operates 24/7; it averages two runs per day and administers TPA on 1 of every 10 runs, Ms. Parker said. Both the Houston and Cleveland units tie into the local 911 emergency activation systems for their respective regions. 

[email protected]

On Twitter @mitchelzoler

When heart attack symptoms begin, women wait longer than do men to call for help, and it takes longer for them to arrive at a hospital that can care for them appropriately.

Further, statistical analysis suggests that this prehospital delay is a chief contributor to the higher in-hospital mortality rate for women who have sustained myocardial infarctions. Dr. Raffaele Bugiardini of the University of Bologna and his associates in the ISACS-TC study group examined data from a large international study to clarify gender disparities in heart attacks, and to identify more precisely where time is lost in caring for women.

They examined data from 2,282 women and 5,175 men who experienced ST-segment–elevation myocardial infarction (STEMI). Overall, female participants were older than males and were more likely to have diabetes, to be treated for hypertension, and to have experienced atypical chest pain – or no chest pain at all – during their heart attacks. The men were more likely to be smokers, to have chronic renal failure, and to have a prior history of angina.

The results were released in advance of the researchers’ presentation on March 14 at the annual meeting of the American College of Cardiology in San Diego.

Once symptoms began, women tended to wait significantly longer to call for help, a median 60.0 minutes, compared with 45.5 for men. Time to hospital admission was just a bit longer for women (60 minutes) compared to men (55 minutes). On admission, time to angioplasty or fibrinolysis did not vary significantly between the sexes. The likelihood of receiving appropriate medical treatment (aspirin, clopidogrel, heparin use) was also similar.

In outcome measures, 30% of women achieved hospital admission in 60 minutes or less from leaving home, compared with 70% of men. Dr. Bugiardini explained that the 60-minute admission marker is an important quality standard in the European framework. The odds ratio (OR) for a greater-than 60-minute time from home to hospital admission for women was 2.90 (95% CI, 1.52-5.82).

In-hospital mortality for women was nearly double that for men, at 11.8% compared to 6.3% for men (OR 1.34, 95% CI 1.01-1.77). However, after logistic regression analysis adjusted for the differences in time from home to hospital admission, the disparity in mortality disappeared (OR 0.90, 95% CI 0.31-2.56). Dr. Bugiardini emphasized that his analysis makes clear that delay in treatment is an important contributor to greater in-hospital mortality for women suffering heart attacks.

Though these finding were drawn from a large international study, American College of Cardiology Vice President Richard Chazal affirmed during a media briefing that the results are definitely applicable to the United States and other developed nations. “They are confirmatory,” said Dr. Chazal, “of other studies that have suggested this but have not shown this in such a complete and comprehensive way. This is very important information in this population.”

Heart disease kills more women than do all forms of cancer combined, but the varied presentation of heart attack symptoms in women is still underrecognized, noted Dr. Chazal of Lee Memorial Health System, Fort Myers, Fla. Raising awareness about heart disease risk and heart attack symptoms is critical to addressing the disparities identified in this study. “The delays in getting the patient to the hospital are really crucial in determining what the outcomes are,” he said.

“Time is still lost between contact with the system and arrival to the hospital” for women, he added. “There is less awareness not just by women, but in doctors in underestimating what’s going on with women. We are confused, so we stop and do one more EKG. We are losing time.”

Dr. Marija Vavlukis is on the speakers bureau for KRKA Macedonia. The other authors have no disclosures.

When heart attack symptoms begin, women wait longer than do men to call for help, and it takes longer for them to arrive at a hospital that can care for them appropriately.

Further, statistical analysis suggests that this prehospital delay is a chief contributor to the higher in-hospital mortality rate for women who have sustained myocardial infarctions. Dr. Raffaele Bugiardini of the University of Bologna and his associates in the ISACS-TC study group examined data from a large international study to clarify gender disparities in heart attacks, and to identify more precisely where time is lost in caring for women.

They examined data from 2,282 women and 5,175 men who experienced ST-segment–elevation myocardial infarction (STEMI). Overall, female participants were older than males and were more likely to have diabetes, to be treated for hypertension, and to have experienced atypical chest pain – or no chest pain at all – during their heart attacks. The men were more likely to be smokers, to have chronic renal failure, and to have a prior history of angina.

The results were released in advance of the researchers’ presentation on March 14 at the annual meeting of the American College of Cardiology in San Diego.

Once symptoms began, women tended to wait significantly longer to call for help, a median 60.0 minutes, compared with 45.5 for men. Time to hospital admission was just a bit longer for women (60 minutes) compared to men (55 minutes). On admission, time to angioplasty or fibrinolysis did not vary significantly between the sexes. The likelihood of receiving appropriate medical treatment (aspirin, clopidogrel, heparin use) was also similar.

In outcome measures, 30% of women achieved hospital admission in 60 minutes or less from leaving home, compared with 70% of men. Dr. Bugiardini explained that the 60-minute admission marker is an important quality standard in the European framework. The odds ratio (OR) for a greater-than 60-minute time from home to hospital admission for women was 2.90 (95% CI, 1.52-5.82).

In-hospital mortality for women was nearly double that for men, at 11.8% compared to 6.3% for men (OR 1.34, 95% CI 1.01-1.77). However, after logistic regression analysis adjusted for the differences in time from home to hospital admission, the disparity in mortality disappeared (OR 0.90, 95% CI 0.31-2.56). Dr. Bugiardini emphasized that his analysis makes clear that delay in treatment is an important contributor to greater in-hospital mortality for women suffering heart attacks.

Though these finding were drawn from a large international study, American College of Cardiology Vice President Richard Chazal affirmed during a media briefing that the results are definitely applicable to the United States and other developed nations. “They are confirmatory,” said Dr. Chazal, “of other studies that have suggested this but have not shown this in such a complete and comprehensive way. This is very important information in this population.”

Heart disease kills more women than do all forms of cancer combined, but the varied presentation of heart attack symptoms in women is still underrecognized, noted Dr. Chazal of Lee Memorial Health System, Fort Myers, Fla. Raising awareness about heart disease risk and heart attack symptoms is critical to addressing the disparities identified in this study. “The delays in getting the patient to the hospital are really crucial in determining what the outcomes are,” he said.

“Time is still lost between contact with the system and arrival to the hospital” for women, he added. “There is less awareness not just by women, but in doctors in underestimating what’s going on with women. We are confused, so we stop and do one more EKG. We are losing time.”

Dr. Marija Vavlukis is on the speakers bureau for KRKA Macedonia. The other authors have no disclosures.

When heart attack symptoms begin, women wait longer than do men to call for help, and it takes longer for them to arrive at a hospital that can care for them appropriately.

Further, statistical analysis suggests that this prehospital delay is a chief contributor to the higher in-hospital mortality rate for women who have sustained myocardial infarctions. Dr. Raffaele Bugiardini of the University of Bologna and his associates in the ISACS-TC study group examined data from a large international study to clarify gender disparities in heart attacks, and to identify more precisely where time is lost in caring for women.

They examined data from 2,282 women and 5,175 men who experienced ST-segment–elevation myocardial infarction (STEMI). Overall, female participants were older than males and were more likely to have diabetes, to be treated for hypertension, and to have experienced atypical chest pain – or no chest pain at all – during their heart attacks. The men were more likely to be smokers, to have chronic renal failure, and to have a prior history of angina.

The results were released in advance of the researchers’ presentation on March 14 at the annual meeting of the American College of Cardiology in San Diego.

Once symptoms began, women tended to wait significantly longer to call for help, a median 60.0 minutes, compared with 45.5 for men. Time to hospital admission was just a bit longer for women (60 minutes) compared to men (55 minutes). On admission, time to angioplasty or fibrinolysis did not vary significantly between the sexes. The likelihood of receiving appropriate medical treatment (aspirin, clopidogrel, heparin use) was also similar.

In outcome measures, 30% of women achieved hospital admission in 60 minutes or less from leaving home, compared with 70% of men. Dr. Bugiardini explained that the 60-minute admission marker is an important quality standard in the European framework. The odds ratio (OR) for a greater-than 60-minute time from home to hospital admission for women was 2.90 (95% CI, 1.52-5.82).

In-hospital mortality for women was nearly double that for men, at 11.8% compared to 6.3% for men (OR 1.34, 95% CI 1.01-1.77). However, after logistic regression analysis adjusted for the differences in time from home to hospital admission, the disparity in mortality disappeared (OR 0.90, 95% CI 0.31-2.56). Dr. Bugiardini emphasized that his analysis makes clear that delay in treatment is an important contributor to greater in-hospital mortality for women suffering heart attacks.

Though these finding were drawn from a large international study, American College of Cardiology Vice President Richard Chazal affirmed during a media briefing that the results are definitely applicable to the United States and other developed nations. “They are confirmatory,” said Dr. Chazal, “of other studies that have suggested this but have not shown this in such a complete and comprehensive way. This is very important information in this population.”

Heart disease kills more women than do all forms of cancer combined, but the varied presentation of heart attack symptoms in women is still underrecognized, noted Dr. Chazal of Lee Memorial Health System, Fort Myers, Fla. Raising awareness about heart disease risk and heart attack symptoms is critical to addressing the disparities identified in this study. “The delays in getting the patient to the hospital are really crucial in determining what the outcomes are,” he said.

“Time is still lost between contact with the system and arrival to the hospital” for women, he added. “There is less awareness not just by women, but in doctors in underestimating what’s going on with women. We are confused, so we stop and do one more EKG. We are losing time.”

Dr. Marija Vavlukis is on the speakers bureau for KRKA Macedonia. The other authors have no disclosures.

The Food and Drug Administration has approved dinutuximab as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy, for pediatric patients with high-risk neuroblastoma.

The drug “marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the March 10 FDA announcement.

Dinutuximab is a chimeric monoclonal antibody that targets GD2, a glycolipid on the surface of tumor cells, according to the manufacturer, United Therapeutics.

The FDA granted approval based on a clinical trial of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Three years after being randomly assigned to receive either isotretinoin or dinutuximab in combination with interleukin-2 and granulocyte macrophage colony-stimulating factor, 63% of participants receiving the combination were alive and free of tumor growth or recurrence, compared with 46% of participants treated with isotretinoin alone.

In an updated analysis, 73% of participants who received the combination were alive, compared with 58% of those receiving isotretinoin alone, the FDA said in the announcement.

The most common side effects were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, hyponatremia, elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels in the blood, capillary leak syndrome, neutropenia and lymphopenia, hives, and low blood calcium levels, the statement said.

The drug carries a boxed warning that the drug can irritate nerve cells, causing severe pain that requires treatment with intravenous narcotics, and can cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Dinutuximab may also cause other serious side effects, including infections, eye problems, electrolyte abnormalities, and bone marrow suppression.

The FDA granted approval of dinutuximab, to be marketed as Unituxin, following a priority review and orphan product designation.

[email protected]
On Twitter @nikolaideslaura

The Food and Drug Administration has approved dinutuximab as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy, for pediatric patients with high-risk neuroblastoma.

The drug “marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the March 10 FDA announcement.

Dinutuximab is a chimeric monoclonal antibody that targets GD2, a glycolipid on the surface of tumor cells, according to the manufacturer, United Therapeutics.

The FDA granted approval based on a clinical trial of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Three years after being randomly assigned to receive either isotretinoin or dinutuximab in combination with interleukin-2 and granulocyte macrophage colony-stimulating factor, 63% of participants receiving the combination were alive and free of tumor growth or recurrence, compared with 46% of participants treated with isotretinoin alone.

In an updated analysis, 73% of participants who received the combination were alive, compared with 58% of those receiving isotretinoin alone, the FDA said in the announcement.

The most common side effects were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, hyponatremia, elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels in the blood, capillary leak syndrome, neutropenia and lymphopenia, hives, and low blood calcium levels, the statement said.

The drug carries a boxed warning that the drug can irritate nerve cells, causing severe pain that requires treatment with intravenous narcotics, and can cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Dinutuximab may also cause other serious side effects, including infections, eye problems, electrolyte abnormalities, and bone marrow suppression.

The FDA granted approval of dinutuximab, to be marketed as Unituxin, following a priority review and orphan product designation.

[email protected]
On Twitter @nikolaideslaura

The Food and Drug Administration has approved dinutuximab as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy, for pediatric patients with high-risk neuroblastoma.

The drug “marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in the March 10 FDA announcement.

Dinutuximab is a chimeric monoclonal antibody that targets GD2, a glycolipid on the surface of tumor cells, according to the manufacturer, United Therapeutics.

The FDA granted approval based on a clinical trial of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Three years after being randomly assigned to receive either isotretinoin or dinutuximab in combination with interleukin-2 and granulocyte macrophage colony-stimulating factor, 63% of participants receiving the combination were alive and free of tumor growth or recurrence, compared with 46% of participants treated with isotretinoin alone.

In an updated analysis, 73% of participants who received the combination were alive, compared with 58% of those receiving isotretinoin alone, the FDA said in the announcement.

The most common side effects were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, hyponatremia, elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels in the blood, capillary leak syndrome, neutropenia and lymphopenia, hives, and low blood calcium levels, the statement said.

The drug carries a boxed warning that the drug can irritate nerve cells, causing severe pain that requires treatment with intravenous narcotics, and can cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Dinutuximab may also cause other serious side effects, including infections, eye problems, electrolyte abnormalities, and bone marrow suppression.

The FDA granted approval of dinutuximab, to be marketed as Unituxin, following a priority review and orphan product designation.

[email protected]
On Twitter @nikolaideslaura

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).

SNOWMASS, COLO. – The 2014 American Heart Association/American College of Cardiology guidelines for the management of valvular heart disease break new ground in numerous ways, Dr. Rick A. Nishimura said at the Annual Cardiovascular Conference at Snowmass.

“We needed to do things differently. These guidelines were created in a different format from prior valvular heart disease guidelines. We wanted these guidelines to promote access to concise, relevant bytes of information at the point of care,” explained Dr. Nishimura, professor of medicine at the Mayo Clinic in Rochester, Minn., and cochair of the guidelines writing committee.

These guidelines – the first major revision in 8 years – introduce a new taxonomy and the first staging system for valvular heart disease. The guidelines also lower the threshold for intervention in asymptomatic patients, recommending surgical or catheter-based treatment at an earlier point in the disease process than ever before. And the guidelines introduce the concept of heart valve centers of excellence, offering a strong recommendation that patients be referred to those centers for procedures to be performed in the asymptomatic phase of disease (J. Am. Coll. Cardiol. 2014;63:2438-88).

These valvular heart disease guidelines place greater emphasis than before on the quality of the scientific evidence underlying recommendations. Since valvular heart disease is a field with a paucity of randomized trials, that meant cutting back.

“Our goal was, if there’s little evidence, don’t write a recommendation. So the number of recommendations went down, but at least the ones that were made were based on evidence,” the cardiologist noted.

Indeed, in the 2006 guidelines, more than 70% of the recommendations were Level of Evidence C and based solely upon expert opinion; in the new guidelines, that’s true for less than 50%. And the proportion of recommendations that are Level of Evidence B increased from 30% to 45%.

The 2014 update was prompted by huge changes in the field of valvular heart disease since 2006. For example, better data became available on the natural history of valvular heart disease. The old concept was not to operate on the asymptomatic patient with severe aortic stenosis and normal left ventricular function, but more recent natural history studies have shown that, left untreated, 72% of such patients will die or develop symptoms within 5 years.

So there has been a push to intervene earlier. Fortunately, that became doable, as recent years also brought improved noninvasive imaging, new catheter-based interventions, and refined surgical methods, enabling operators to safely lower the threshold for intervention in asymptomatic patients while at the same time extending procedural therapies to older, sicker populations.

Dr. Nishimura predicted that cardiologists and surgeons will find the new staging system clinically useful. The four stages, A-D, define the categories “at risk,” “progressive,” “asymptomatic severe,” and “symptomatic severe,” respectively. These categories are particularly helpful in determining how often to schedule patient follow-up and when to time intervention.

The guidelines recommend observation for patients who are Stage A or B and intervention when reasonable in patients who are Stage C2 or D. What bumps a patient with hemodynamically severe yet asymptomatic mitral regurgitation from Stage C1 to C2 is an left ventricular ejection fraction below 60% or a left ventricular end systolic dimension of 40 mm or more. In the setting of asymptomatic aortic stenosis, it’s a peak aortic valve velocity of 4.0 m/sec on Doppler echocardiography plus an LVEF of less than 50%.

The latest guidelines introduced the concept of heart valve centers of excellence in response to evidence of large variability across the country in terms of experience with valve operations. For example, the majority of centers perform fewer than 40 mitral valve repairs per year, and surgeons who perform mitral operations do a median of just five per year. The guideline committee, which included general and interventional cardiologists, surgeons, anesthesiologists, and imaging experts, was persuaded that those numbers are not sufficient to achieve optimal results in complex valve operations for asymptomatic patients.

The criteria for qualifying as a heart valve center of excellence, as defined in the guidelines, include having a multidisciplinary heart valve team, high patient volume, high-level surgical experience and expertise in complex valve procedures, and active participation in multicenter data registries and continuous quality improvement processes.

“The most important thing is you have to be very transparent with your data,” according to the cardiologist.

Ultimately, the most far-reaching change introduced in the current valvular heart disease guidelines is the switch from textbook format to what Dr. Nishimura calls structured data knowledge management.

“The AHA/ACC clinical practice guidelines are generally recognized as the flagship of U.S. cardiovascular medicine, but they’re like a library of old books. Clinically valuable knowledge is buried within documents that can be 200 pages long. What we need at the point of care is the gist: concise, relevant bytes of information that answer a specific clinical question, synthesized by experts,” Dr. Nishimura said.

The new approach is designed to counter the information overload that plagues contemporary medical practice. Each recommendation in the current valvular heart disease guidelines addresses a specific clinical question via a brief summary statement followed by a short explanatory paragraph, with accompanying references for those who seek additional details. This new format is designed to lead AHA/ACC clinical practice guidelines into the electronic information management future.

“In the future, you’ll go to your iPad or iPhone or whatever, type in search terms such as ‘anticoagulation for mechanical valves during pregnancy,’ and it will take you straight to the relevant knowledge byte. You can then click on ‘more’ and find out more and get to the supporting evidence tables. The knowledge chunks will be stored in a centralized knowledge management system. The nice thing about this is that it will be a living document that can easily be updated, instead of having to wait 8 years for a new version,” Dr. Nishimura explained.

He reported having no financial conflicts of interest.

[email protected]

SNOWMASS, COLO. – The 2014 American Heart Association/American College of Cardiology guidelines for the management of valvular heart disease break new ground in numerous ways, Dr. Rick A. Nishimura said at the Annual Cardiovascular Conference at Snowmass.

“We needed to do things differently. These guidelines were created in a different format from prior valvular heart disease guidelines. We wanted these guidelines to promote access to concise, relevant bytes of information at the point of care,” explained Dr. Nishimura, professor of medicine at the Mayo Clinic in Rochester, Minn., and cochair of the guidelines writing committee.

These guidelines – the first major revision in 8 years – introduce a new taxonomy and the first staging system for valvular heart disease. The guidelines also lower the threshold for intervention in asymptomatic patients, recommending surgical or catheter-based treatment at an earlier point in the disease process than ever before. And the guidelines introduce the concept of heart valve centers of excellence, offering a strong recommendation that patients be referred to those centers for procedures to be performed in the asymptomatic phase of disease (J. Am. Coll. Cardiol. 2014;63:2438-88).

These valvular heart disease guidelines place greater emphasis than before on the quality of the scientific evidence underlying recommendations. Since valvular heart disease is a field with a paucity of randomized trials, that meant cutting back.

“Our goal was, if there’s little evidence, don’t write a recommendation. So the number of recommendations went down, but at least the ones that were made were based on evidence,” the cardiologist noted.

Indeed, in the 2006 guidelines, more than 70% of the recommendations were Level of Evidence C and based solely upon expert opinion; in the new guidelines, that’s true for less than 50%. And the proportion of recommendations that are Level of Evidence B increased from 30% to 45%.

The 2014 update was prompted by huge changes in the field of valvular heart disease since 2006. For example, better data became available on the natural history of valvular heart disease. The old concept was not to operate on the asymptomatic patient with severe aortic stenosis and normal left ventricular function, but more recent natural history studies have shown that, left untreated, 72% of such patients will die or develop symptoms within 5 years.

So there has been a push to intervene earlier. Fortunately, that became doable, as recent years also brought improved noninvasive imaging, new catheter-based interventions, and refined surgical methods, enabling operators to safely lower the threshold for intervention in asymptomatic patients while at the same time extending procedural therapies to older, sicker populations.

Dr. Nishimura predicted that cardiologists and surgeons will find the new staging system clinically useful. The four stages, A-D, define the categories “at risk,” “progressive,” “asymptomatic severe,” and “symptomatic severe,” respectively. These categories are particularly helpful in determining how often to schedule patient follow-up and when to time intervention.

The guidelines recommend observation for patients who are Stage A or B and intervention when reasonable in patients who are Stage C2 or D. What bumps a patient with hemodynamically severe yet asymptomatic mitral regurgitation from Stage C1 to C2 is an left ventricular ejection fraction below 60% or a left ventricular end systolic dimension of 40 mm or more. In the setting of asymptomatic aortic stenosis, it’s a peak aortic valve velocity of 4.0 m/sec on Doppler echocardiography plus an LVEF of less than 50%.

The latest guidelines introduced the concept of heart valve centers of excellence in response to evidence of large variability across the country in terms of experience with valve operations. For example, the majority of centers perform fewer than 40 mitral valve repairs per year, and surgeons who perform mitral operations do a median of just five per year. The guideline committee, which included general and interventional cardiologists, surgeons, anesthesiologists, and imaging experts, was persuaded that those numbers are not sufficient to achieve optimal results in complex valve operations for asymptomatic patients.

The criteria for qualifying as a heart valve center of excellence, as defined in the guidelines, include having a multidisciplinary heart valve team, high patient volume, high-level surgical experience and expertise in complex valve procedures, and active participation in multicenter data registries and continuous quality improvement processes.

“The most important thing is you have to be very transparent with your data,” according to the cardiologist.

Ultimately, the most far-reaching change introduced in the current valvular heart disease guidelines is the switch from textbook format to what Dr. Nishimura calls structured data knowledge management.

“The AHA/ACC clinical practice guidelines are generally recognized as the flagship of U.S. cardiovascular medicine, but they’re like a library of old books. Clinically valuable knowledge is buried within documents that can be 200 pages long. What we need at the point of care is the gist: concise, relevant bytes of information that answer a specific clinical question, synthesized by experts,” Dr. Nishimura said.

The new approach is designed to counter the information overload that plagues contemporary medical practice. Each recommendation in the current valvular heart disease guidelines addresses a specific clinical question via a brief summary statement followed by a short explanatory paragraph, with accompanying references for those who seek additional details. This new format is designed to lead AHA/ACC clinical practice guidelines into the electronic information management future.

“In the future, you’ll go to your iPad or iPhone or whatever, type in search terms such as ‘anticoagulation for mechanical valves during pregnancy,’ and it will take you straight to the relevant knowledge byte. You can then click on ‘more’ and find out more and get to the supporting evidence tables. The knowledge chunks will be stored in a centralized knowledge management system. The nice thing about this is that it will be a living document that can easily be updated, instead of having to wait 8 years for a new version,” Dr. Nishimura explained.

He reported having no financial conflicts of interest.

[email protected]

SNOWMASS, COLO. – The 2014 American Heart Association/American College of Cardiology guidelines for the management of valvular heart disease break new ground in numerous ways, Dr. Rick A. Nishimura said at the Annual Cardiovascular Conference at Snowmass.

“We needed to do things differently. These guidelines were created in a different format from prior valvular heart disease guidelines. We wanted these guidelines to promote access to concise, relevant bytes of information at the point of care,” explained Dr. Nishimura, professor of medicine at the Mayo Clinic in Rochester, Minn., and cochair of the guidelines writing committee.

These guidelines – the first major revision in 8 years – introduce a new taxonomy and the first staging system for valvular heart disease. The guidelines also lower the threshold for intervention in asymptomatic patients, recommending surgical or catheter-based treatment at an earlier point in the disease process than ever before. And the guidelines introduce the concept of heart valve centers of excellence, offering a strong recommendation that patients be referred to those centers for procedures to be performed in the asymptomatic phase of disease (J. Am. Coll. Cardiol. 2014;63:2438-88).

These valvular heart disease guidelines place greater emphasis than before on the quality of the scientific evidence underlying recommendations. Since valvular heart disease is a field with a paucity of randomized trials, that meant cutting back.

“Our goal was, if there’s little evidence, don’t write a recommendation. So the number of recommendations went down, but at least the ones that were made were based on evidence,” the cardiologist noted.

Indeed, in the 2006 guidelines, more than 70% of the recommendations were Level of Evidence C and based solely upon expert opinion; in the new guidelines, that’s true for less than 50%. And the proportion of recommendations that are Level of Evidence B increased from 30% to 45%.

The 2014 update was prompted by huge changes in the field of valvular heart disease since 2006. For example, better data became available on the natural history of valvular heart disease. The old concept was not to operate on the asymptomatic patient with severe aortic stenosis and normal left ventricular function, but more recent natural history studies have shown that, left untreated, 72% of such patients will die or develop symptoms within 5 years.

So there has been a push to intervene earlier. Fortunately, that became doable, as recent years also brought improved noninvasive imaging, new catheter-based interventions, and refined surgical methods, enabling operators to safely lower the threshold for intervention in asymptomatic patients while at the same time extending procedural therapies to older, sicker populations.

Dr. Nishimura predicted that cardiologists and surgeons will find the new staging system clinically useful. The four stages, A-D, define the categories “at risk,” “progressive,” “asymptomatic severe,” and “symptomatic severe,” respectively. These categories are particularly helpful in determining how often to schedule patient follow-up and when to time intervention.

The guidelines recommend observation for patients who are Stage A or B and intervention when reasonable in patients who are Stage C2 or D. What bumps a patient with hemodynamically severe yet asymptomatic mitral regurgitation from Stage C1 to C2 is an left ventricular ejection fraction below 60% or a left ventricular end systolic dimension of 40 mm or more. In the setting of asymptomatic aortic stenosis, it’s a peak aortic valve velocity of 4.0 m/sec on Doppler echocardiography plus an LVEF of less than 50%.

The latest guidelines introduced the concept of heart valve centers of excellence in response to evidence of large variability across the country in terms of experience with valve operations. For example, the majority of centers perform fewer than 40 mitral valve repairs per year, and surgeons who perform mitral operations do a median of just five per year. The guideline committee, which included general and interventional cardiologists, surgeons, anesthesiologists, and imaging experts, was persuaded that those numbers are not sufficient to achieve optimal results in complex valve operations for asymptomatic patients.

The criteria for qualifying as a heart valve center of excellence, as defined in the guidelines, include having a multidisciplinary heart valve team, high patient volume, high-level surgical experience and expertise in complex valve procedures, and active participation in multicenter data registries and continuous quality improvement processes.

“The most important thing is you have to be very transparent with your data,” according to the cardiologist.

Ultimately, the most far-reaching change introduced in the current valvular heart disease guidelines is the switch from textbook format to what Dr. Nishimura calls structured data knowledge management.

“The AHA/ACC clinical practice guidelines are generally recognized as the flagship of U.S. cardiovascular medicine, but they’re like a library of old books. Clinically valuable knowledge is buried within documents that can be 200 pages long. What we need at the point of care is the gist: concise, relevant bytes of information that answer a specific clinical question, synthesized by experts,” Dr. Nishimura said.

The new approach is designed to counter the information overload that plagues contemporary medical practice. Each recommendation in the current valvular heart disease guidelines addresses a specific clinical question via a brief summary statement followed by a short explanatory paragraph, with accompanying references for those who seek additional details. This new format is designed to lead AHA/ACC clinical practice guidelines into the electronic information management future.

“In the future, you’ll go to your iPad or iPhone or whatever, type in search terms such as ‘anticoagulation for mechanical valves during pregnancy,’ and it will take you straight to the relevant knowledge byte. You can then click on ‘more’ and find out more and get to the supporting evidence tables. The knowledge chunks will be stored in a centralized knowledge management system. The nice thing about this is that it will be a living document that can easily be updated, instead of having to wait 8 years for a new version,” Dr. Nishimura explained.

He reported having no financial conflicts of interest.

[email protected]

One year after transcatheter aortic valve replacement in the United States, the overall mortality was 23.7%, the stroke rate was 4.1%, and the composite outcome of death and stroke was 26.0%, according to a report published online March 10 in JAMA.

Long-term outcomes for TAVR haven’t been well studied until now, yet the procedure is being performed with increasing frequency for aortic stenosis in patients who are too high risk to undergo conventional surgical aortic valve replacement, said Dr. David R. Holmes Jr. of the Mayo Clinic, Rochester, Minn., and his associates.

They assessed 1-year outcomes by analyzing administrative data from the Centers for Medicare & Medicaid Services and clinical data from the Transcatheter Valve Therapies Registry, an initiative of the Society of Thoracic Surgeons and the American College of Cardiology. The study involved 12,182 patients who underwent TAVR at 299 medical centers across the country during a 19-month period. The patients’ median age was 84 years; 95% were white and 52% were women. The transfemoral approach was used in most patients, but alternative approaches were used in roughly 44%. As expected for an elderly, high-risk study population, baseline functional status was poor and comorbidities were common. They included reduced left ventricular ejection fraction (26% of patients), prior stroke (12%), moderate or severe lung disease (28%), renal failure (16%), peripheral vascular disease (32%), and atrial fibrillation (42%), Dr. Holmes and his associates reported (JAMA 2015 March 10 [doi:10.1001/jama.2015.1474]).

In addition to the mortality and stroke rates listed above, the 1-year rate of one rehospitalization was 24.4%, that of two rehospitalizations was 12.5%, and that of three or more rehospitalizations was 11.6%. The 1-year readmission rate specifically for stroke, heart failure, or repeat aortic valve intervention was 18.6%. These are important considerations for elderly, fragile patients because rehospitalizations indicate “an unacceptable quality-of-life outcome” and are very costly, the investigators noted.

Several baseline characteristics, including male sex, severe chronic obstructive pulmonary disease, dialysis-dependent end-stage renal disease, older age, higher STS Predicted Risk of Operative Mortality (PROM) score, a history of atrial fibrillation/flutter, and use of an access route (other than transfemoral), were found to be independently associated with higher 1-year mortality. Thus, “It may be possible to identify patients who may not benefit from this procedure and who should be counseled accordingly.” For example, in this study there was a small (77 patients) very high-risk subset of patients – aged 85-94 years, dependent on dialysis, and having an STS PROM score greater than 15% – whose 1-year mortality was 53.5%.

The STS and the ACC supported this study, and support the Transcatheter Valve Therapies Registry. Dr. Holmes reported having no relevant financial disclosures; his associates reported ties to Boston Scientific, Edwards Lifesciences, Janssen, Eli Lilly, Boehringer Ingelheim, Bayer, and AstraZeneca.

One year after transcatheter aortic valve replacement in the United States, the overall mortality was 23.7%, the stroke rate was 4.1%, and the composite outcome of death and stroke was 26.0%, according to a report published online March 10 in JAMA.

Long-term outcomes for TAVR haven’t been well studied until now, yet the procedure is being performed with increasing frequency for aortic stenosis in patients who are too high risk to undergo conventional surgical aortic valve replacement, said Dr. David R. Holmes Jr. of the Mayo Clinic, Rochester, Minn., and his associates.

They assessed 1-year outcomes by analyzing administrative data from the Centers for Medicare & Medicaid Services and clinical data from the Transcatheter Valve Therapies Registry, an initiative of the Society of Thoracic Surgeons and the American College of Cardiology. The study involved 12,182 patients who underwent TAVR at 299 medical centers across the country during a 19-month period. The patients’ median age was 84 years; 95% were white and 52% were women. The transfemoral approach was used in most patients, but alternative approaches were used in roughly 44%. As expected for an elderly, high-risk study population, baseline functional status was poor and comorbidities were common. They included reduced left ventricular ejection fraction (26% of patients), prior stroke (12%), moderate or severe lung disease (28%), renal failure (16%), peripheral vascular disease (32%), and atrial fibrillation (42%), Dr. Holmes and his associates reported (JAMA 2015 March 10 [doi:10.1001/jama.2015.1474]).

In addition to the mortality and stroke rates listed above, the 1-year rate of one rehospitalization was 24.4%, that of two rehospitalizations was 12.5%, and that of three or more rehospitalizations was 11.6%. The 1-year readmission rate specifically for stroke, heart failure, or repeat aortic valve intervention was 18.6%. These are important considerations for elderly, fragile patients because rehospitalizations indicate “an unacceptable quality-of-life outcome” and are very costly, the investigators noted.

Several baseline characteristics, including male sex, severe chronic obstructive pulmonary disease, dialysis-dependent end-stage renal disease, older age, higher STS Predicted Risk of Operative Mortality (PROM) score, a history of atrial fibrillation/flutter, and use of an access route (other than transfemoral), were found to be independently associated with higher 1-year mortality. Thus, “It may be possible to identify patients who may not benefit from this procedure and who should be counseled accordingly.” For example, in this study there was a small (77 patients) very high-risk subset of patients – aged 85-94 years, dependent on dialysis, and having an STS PROM score greater than 15% – whose 1-year mortality was 53.5%.

The STS and the ACC supported this study, and support the Transcatheter Valve Therapies Registry. Dr. Holmes reported having no relevant financial disclosures; his associates reported ties to Boston Scientific, Edwards Lifesciences, Janssen, Eli Lilly, Boehringer Ingelheim, Bayer, and AstraZeneca.

One year after transcatheter aortic valve replacement in the United States, the overall mortality was 23.7%, the stroke rate was 4.1%, and the composite outcome of death and stroke was 26.0%, according to a report published online March 10 in JAMA.

Long-term outcomes for TAVR haven’t been well studied until now, yet the procedure is being performed with increasing frequency for aortic stenosis in patients who are too high risk to undergo conventional surgical aortic valve replacement, said Dr. David R. Holmes Jr. of the Mayo Clinic, Rochester, Minn., and his associates.

They assessed 1-year outcomes by analyzing administrative data from the Centers for Medicare & Medicaid Services and clinical data from the Transcatheter Valve Therapies Registry, an initiative of the Society of Thoracic Surgeons and the American College of Cardiology. The study involved 12,182 patients who underwent TAVR at 299 medical centers across the country during a 19-month period. The patients’ median age was 84 years; 95% were white and 52% were women. The transfemoral approach was used in most patients, but alternative approaches were used in roughly 44%. As expected for an elderly, high-risk study population, baseline functional status was poor and comorbidities were common. They included reduced left ventricular ejection fraction (26% of patients), prior stroke (12%), moderate or severe lung disease (28%), renal failure (16%), peripheral vascular disease (32%), and atrial fibrillation (42%), Dr. Holmes and his associates reported (JAMA 2015 March 10 [doi:10.1001/jama.2015.1474]).

In addition to the mortality and stroke rates listed above, the 1-year rate of one rehospitalization was 24.4%, that of two rehospitalizations was 12.5%, and that of three or more rehospitalizations was 11.6%. The 1-year readmission rate specifically for stroke, heart failure, or repeat aortic valve intervention was 18.6%. These are important considerations for elderly, fragile patients because rehospitalizations indicate “an unacceptable quality-of-life outcome” and are very costly, the investigators noted.

Several baseline characteristics, including male sex, severe chronic obstructive pulmonary disease, dialysis-dependent end-stage renal disease, older age, higher STS Predicted Risk of Operative Mortality (PROM) score, a history of atrial fibrillation/flutter, and use of an access route (other than transfemoral), were found to be independently associated with higher 1-year mortality. Thus, “It may be possible to identify patients who may not benefit from this procedure and who should be counseled accordingly.” For example, in this study there was a small (77 patients) very high-risk subset of patients – aged 85-94 years, dependent on dialysis, and having an STS PROM score greater than 15% – whose 1-year mortality was 53.5%.

The STS and the ACC supported this study, and support the Transcatheter Valve Therapies Registry. Dr. Holmes reported having no relevant financial disclosures; his associates reported ties to Boston Scientific, Edwards Lifesciences, Janssen, Eli Lilly, Boehringer Ingelheim, Bayer, and AstraZeneca.