Atopic Dermatitis

SAN DIEGO — Parents of children newly diagnosed with atopic dermatitis can be riddled with angst.

Some gravitate to guilt and self-blame, figuring "we did something wrong to our child" or "it must be something we're giving him" that's causing the atopic dermatitis, Dr. Magdalene A. Dohil said at a meeting sponsored by Rady Children's Hospital.

Others believe that baths are bad for their child, and many are frightened to use topical steroids to treat the disease. "They may say things like, 'there are so many creams, we can't remember what goes on and where it goes,'" said Dr. Dohil, a pediatric dermatologist at Rady Children's Hospital, San Diego. "They want a simple and easy cure so they can control the disease."

Many parents find it hard to accept the fact that there is no treatment that completely cures atopic dermatitis. That is why she practices "extreme parent education" from the get-go.

"We have to battle myths and misperceptions," said Dr. Dohil, also of the University of California, San Diego. "We have some good safety data on atopic dermatitis treatments out there. It's just not common knowledge, and they are not that easy to explain."

Patient Resources

Web-based resources she points parents and patients to include The Eczema Center at Rady Children's Hospital (

www.eczemacenter.org

www.nationaleczema.org

www.undermyskin.com

Management of atopic dermatitis is currently based on the number, location, and intensity of lesions, persistence of disease, frequency of flares, patient age, and quality of life and emotional issues.

Dr. Dohil focused her discussion on topical corticosteroids and topical calcineurin inhibitors. "We have to stress for our patients that this is what it boils down to; this is our primary anti-inflammatory armamentarium right now," she said.

Topical Corticosteroids

Topical corticosteroids have been a mainstay of inflammatory atopic dermatitis treatment for decades. They are also used to manage acute flares and as maintenance therapy.

"We can start as low potency as needed or start high, control, and go back to low potency as needed," she said.

"This is my preference because I feel it gives you that initial trust and compliance if parents see their child getting better. It allows you to taper down and reassure parents that you are no longer at that very potent level of topical steroids," Dr. Dohil added.

The choice of topical corticosteroid is influenced by what prior agents have been used, the age of the patient, severity and localization of dermatitis, formularies, and parental steroid phobia. The anti-inflammatory effects of topical corticosteroids come at a price, Dr. Dohil said, including the potential for skin atrophy, telangiectasia, acne, perioral dermatitis, as well as hypothalamic-pituitary-adrenal axis suppression.

"This really scares parents. We need to take this parent fear factor into account at every step along the way because if you don't, you set yourself up for noncompliance. The eczema's not going to get better. The parents will get confused, and there is so much input from non-health professionals, such as 'this worked for my child. Why don't you try this?' and so on," she said.

Previous research has demonstrated that the anti-inflammatory effects of topical corticosteroids stem from a pathway of transrepression, while its side effects stem from a pathway of transactivation.

"Current research is focusing on trying to separate these two pathways," Dr. Dohil said.

"In the meantime we have great data down to 3 months of age that give us a sense of how safe they are, [and] how long we can use these agents. Most of these studies have run over a period of 4 weeks. I think it's important to share this information with parents, to help them feel comfortable about the treatment," she said.

Topical Calcineurin Inhibitors

The topical calcineurin inhibitors, tacrolimus ointment (Protopic) and pimecrolimus cream (Elidel), are popular second-line treatment options for treatment of moderate to severe disease.

According to labeling information, these agents are indicated in nonimmunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.

After a Food and Drug Administration black box warning was issued in January 2006 related to concerns about skin malignancies and lymphoma from the use of topical calcineurin inhibitors, several case-control studies, long-term registries, ongoing clinical studies, and data safety monitoring boards were launched to continue to assess their safety.

A 10-year study, A Prospective Pediatric Longitudinal Evaluation Study, will examine 8,000 pediatric subjects treated for at least 6 weeks.

Another 10-year trial, The Pediatric Eczema Elective Registry, is an observational parent-report registry designed to assess the risk of malignancies in 5,000 children aged 2–17 years who were treated with pimecrolimus for at least 6 weeks.

One recent study found that the patients with severe atopic dermatitis were 2.4 times more likely to develop lymphoma, compared with controls. However, use of pimecrolimus and tacrolimus conferred a protective effect, with odds ratios of 0.8 each (J. Invest. Dermatol. 2007;127:808–16).

A separate case-control study of patients with inflammatory dermatitis found that those who used pimecrolimus and tacrolimus had almost a 50% reduction in the risk of developing nonmelanoma skin cancer (Dermatology 2007;214:289–95).

The odds ratio of association for nonmelanoma skin cancer decreased as the number of tubes used and the potency of the agent increased. "There was no clear explanation for this," Dr. Dohil said. "There's still a lot of discussion going on."

She added that studies of the blood levels of topical calcineurin inhibitors indicate that they "appear to be negligible when used appropriately."

In clinical practice these agents are commonly used for the face and genital area and for other so-called hot spots with high risk of atrophy.

They are often used in patients with concerns about steroids due to quantity of use in delicate locations, need for constant or near constant therapy, or in those with an adverse event history such as striae or systemic effects.

"Many people feel that topical calcineurin inhibitors can help patients experience a longer flare-free interval and then further transition from this maintenance treatment to maybe just a topical moisturizer if you give enough time for the skin to settle down," Dr. Dohil said.

Dr. Dohil disclosed that the department at Rady has received grant and research support from Hill Pharmaceuticals. She has also received honoraria from Medicis and Dermik.

Many parents find it hard to accept the fact that there is no treatment that completely cures atopic dermatitis. DR. DOHIL

SAN DIEGO — Parents of children newly diagnosed with atopic dermatitis can be riddled with angst.

Some gravitate to guilt and self-blame, figuring "we did something wrong to our child" or "it must be something we're giving him" that's causing the atopic dermatitis, Dr. Magdalene A. Dohil said at a meeting sponsored by Rady Children's Hospital.

Others believe that baths are bad for their child, and many are frightened to use topical steroids to treat the disease. "They may say things like, 'there are so many creams, we can't remember what goes on and where it goes,'" said Dr. Dohil, a pediatric dermatologist at Rady Children's Hospital, San Diego. "They want a simple and easy cure so they can control the disease."

Many parents find it hard to accept the fact that there is no treatment that completely cures atopic dermatitis. That is why she practices "extreme parent education" from the get-go.

"We have to battle myths and misperceptions," said Dr. Dohil, also of the University of California, San Diego. "We have some good safety data on atopic dermatitis treatments out there. It's just not common knowledge, and they are not that easy to explain."

Patient Resources

Web-based resources she points parents and patients to include The Eczema Center at Rady Children's Hospital (

www.eczemacenter.org

www.nationaleczema.org

www.undermyskin.com

Management of atopic dermatitis is currently based on the number, location, and intensity of lesions, persistence of disease, frequency of flares, patient age, and quality of life and emotional issues.

Dr. Dohil focused her discussion on topical corticosteroids and topical calcineurin inhibitors. "We have to stress for our patients that this is what it boils down to; this is our primary anti-inflammatory armamentarium right now," she said.

Topical Corticosteroids

Topical corticosteroids have been a mainstay of inflammatory atopic dermatitis treatment for decades. They are also used to manage acute flares and as maintenance therapy.

"We can start as low potency as needed or start high, control, and go back to low potency as needed," she said.

"This is my preference because I feel it gives you that initial trust and compliance if parents see their child getting better. It allows you to taper down and reassure parents that you are no longer at that very potent level of topical steroids," Dr. Dohil added.

The choice of topical corticosteroid is influenced by what prior agents have been used, the age of the patient, severity and localization of dermatitis, formularies, and parental steroid phobia. The anti-inflammatory effects of topical corticosteroids come at a price, Dr. Dohil said, including the potential for skin atrophy, telangiectasia, acne, perioral dermatitis, as well as hypothalamic-pituitary-adrenal axis suppression.

"This really scares parents. We need to take this parent fear factor into account at every step along the way because if you don't, you set yourself up for noncompliance. The eczema's not going to get better. The parents will get confused, and there is so much input from non-health professionals, such as 'this worked for my child. Why don't you try this?' and so on," she said.

Previous research has demonstrated that the anti-inflammatory effects of topical corticosteroids stem from a pathway of transrepression, while its side effects stem from a pathway of transactivation.

"Current research is focusing on trying to separate these two pathways," Dr. Dohil said.

"In the meantime we have great data down to 3 months of age that give us a sense of how safe they are, [and] how long we can use these agents. Most of these studies have run over a period of 4 weeks. I think it's important to share this information with parents, to help them feel comfortable about the treatment," she said.

Topical Calcineurin Inhibitors

The topical calcineurin inhibitors, tacrolimus ointment (Protopic) and pimecrolimus cream (Elidel), are popular second-line treatment options for treatment of moderate to severe disease.

According to labeling information, these agents are indicated in nonimmunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.

After a Food and Drug Administration black box warning was issued in January 2006 related to concerns about skin malignancies and lymphoma from the use of topical calcineurin inhibitors, several case-control studies, long-term registries, ongoing clinical studies, and data safety monitoring boards were launched to continue to assess their safety.

A 10-year study, A Prospective Pediatric Longitudinal Evaluation Study, will examine 8,000 pediatric subjects treated for at least 6 weeks.

Another 10-year trial, The Pediatric Eczema Elective Registry, is an observational parent-report registry designed to assess the risk of malignancies in 5,000 children aged 2–17 years who were treated with pimecrolimus for at least 6 weeks.

One recent study found that the patients with severe atopic dermatitis were 2.4 times more likely to develop lymphoma, compared with controls. However, use of pimecrolimus and tacrolimus conferred a protective effect, with odds ratios of 0.8 each (J. Invest. Dermatol. 2007;127:808–16).

A separate case-control study of patients with inflammatory dermatitis found that those who used pimecrolimus and tacrolimus had almost a 50% reduction in the risk of developing nonmelanoma skin cancer (Dermatology 2007;214:289–95).

The odds ratio of association for nonmelanoma skin cancer decreased as the number of tubes used and the potency of the agent increased. "There was no clear explanation for this," Dr. Dohil said. "There's still a lot of discussion going on."

She added that studies of the blood levels of topical calcineurin inhibitors indicate that they "appear to be negligible when used appropriately."

In clinical practice these agents are commonly used for the face and genital area and for other so-called hot spots with high risk of atrophy.

They are often used in patients with concerns about steroids due to quantity of use in delicate locations, need for constant or near constant therapy, or in those with an adverse event history such as striae or systemic effects.

"Many people feel that topical calcineurin inhibitors can help patients experience a longer flare-free interval and then further transition from this maintenance treatment to maybe just a topical moisturizer if you give enough time for the skin to settle down," Dr. Dohil said.

Dr. Dohil disclosed that the department at Rady has received grant and research support from Hill Pharmaceuticals. She has also received honoraria from Medicis and Dermik.

Many parents find it hard to accept the fact that there is no treatment that completely cures atopic dermatitis. DR. DOHIL

SAN DIEGO — Parents of children newly diagnosed with atopic dermatitis can be riddled with angst.

Some gravitate to guilt and self-blame, figuring "we did something wrong to our child" or "it must be something we're giving him" that's causing the atopic dermatitis, Dr. Magdalene A. Dohil said at a meeting sponsored by Rady Children's Hospital.

Others believe that baths are bad for their child, and many are frightened to use topical steroids to treat the disease. "They may say things like, 'there are so many creams, we can't remember what goes on and where it goes,'" said Dr. Dohil, a pediatric dermatologist at Rady Children's Hospital, San Diego. "They want a simple and easy cure so they can control the disease."

Many parents find it hard to accept the fact that there is no treatment that completely cures atopic dermatitis. That is why she practices "extreme parent education" from the get-go.

"We have to battle myths and misperceptions," said Dr. Dohil, also of the University of California, San Diego. "We have some good safety data on atopic dermatitis treatments out there. It's just not common knowledge, and they are not that easy to explain."

Patient Resources

Web-based resources she points parents and patients to include The Eczema Center at Rady Children's Hospital (

www.eczemacenter.org

www.nationaleczema.org

www.undermyskin.com

Management of atopic dermatitis is currently based on the number, location, and intensity of lesions, persistence of disease, frequency of flares, patient age, and quality of life and emotional issues.

Dr. Dohil focused her discussion on topical corticosteroids and topical calcineurin inhibitors. "We have to stress for our patients that this is what it boils down to; this is our primary anti-inflammatory armamentarium right now," she said.

Topical Corticosteroids

Topical corticosteroids have been a mainstay of inflammatory atopic dermatitis treatment for decades. They are also used to manage acute flares and as maintenance therapy.

"We can start as low potency as needed or start high, control, and go back to low potency as needed," she said.

"This is my preference because I feel it gives you that initial trust and compliance if parents see their child getting better. It allows you to taper down and reassure parents that you are no longer at that very potent level of topical steroids," Dr. Dohil added.

The choice of topical corticosteroid is influenced by what prior agents have been used, the age of the patient, severity and localization of dermatitis, formularies, and parental steroid phobia. The anti-inflammatory effects of topical corticosteroids come at a price, Dr. Dohil said, including the potential for skin atrophy, telangiectasia, acne, perioral dermatitis, as well as hypothalamic-pituitary-adrenal axis suppression.

"This really scares parents. We need to take this parent fear factor into account at every step along the way because if you don't, you set yourself up for noncompliance. The eczema's not going to get better. The parents will get confused, and there is so much input from non-health professionals, such as 'this worked for my child. Why don't you try this?' and so on," she said.

Previous research has demonstrated that the anti-inflammatory effects of topical corticosteroids stem from a pathway of transrepression, while its side effects stem from a pathway of transactivation.

"Current research is focusing on trying to separate these two pathways," Dr. Dohil said.

"In the meantime we have great data down to 3 months of age that give us a sense of how safe they are, [and] how long we can use these agents. Most of these studies have run over a period of 4 weeks. I think it's important to share this information with parents, to help them feel comfortable about the treatment," she said.

Topical Calcineurin Inhibitors

The topical calcineurin inhibitors, tacrolimus ointment (Protopic) and pimecrolimus cream (Elidel), are popular second-line treatment options for treatment of moderate to severe disease.

According to labeling information, these agents are indicated in nonimmunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.

After a Food and Drug Administration black box warning was issued in January 2006 related to concerns about skin malignancies and lymphoma from the use of topical calcineurin inhibitors, several case-control studies, long-term registries, ongoing clinical studies, and data safety monitoring boards were launched to continue to assess their safety.

A 10-year study, A Prospective Pediatric Longitudinal Evaluation Study, will examine 8,000 pediatric subjects treated for at least 6 weeks.

Another 10-year trial, The Pediatric Eczema Elective Registry, is an observational parent-report registry designed to assess the risk of malignancies in 5,000 children aged 2–17 years who were treated with pimecrolimus for at least 6 weeks.

One recent study found that the patients with severe atopic dermatitis were 2.4 times more likely to develop lymphoma, compared with controls. However, use of pimecrolimus and tacrolimus conferred a protective effect, with odds ratios of 0.8 each (J. Invest. Dermatol. 2007;127:808–16).

A separate case-control study of patients with inflammatory dermatitis found that those who used pimecrolimus and tacrolimus had almost a 50% reduction in the risk of developing nonmelanoma skin cancer (Dermatology 2007;214:289–95).

The odds ratio of association for nonmelanoma skin cancer decreased as the number of tubes used and the potency of the agent increased. "There was no clear explanation for this," Dr. Dohil said. "There's still a lot of discussion going on."

She added that studies of the blood levels of topical calcineurin inhibitors indicate that they "appear to be negligible when used appropriately."

In clinical practice these agents are commonly used for the face and genital area and for other so-called hot spots with high risk of atrophy.

They are often used in patients with concerns about steroids due to quantity of use in delicate locations, need for constant or near constant therapy, or in those with an adverse event history such as striae or systemic effects.

"Many people feel that topical calcineurin inhibitors can help patients experience a longer flare-free interval and then further transition from this maintenance treatment to maybe just a topical moisturizer if you give enough time for the skin to settle down," Dr. Dohil said.

Dr. Dohil disclosed that the department at Rady has received grant and research support from Hill Pharmaceuticals. She has also received honoraria from Medicis and Dermik.

Many parents find it hard to accept the fact that there is no treatment that completely cures atopic dermatitis. DR. DOHIL

CHICAGO — The value of probiotics in atopic disease remains controversial, but clues are beginning to emerge in the literature about probiotics' role in treatment and prevention.

Dr. Sharon S. Raimer highlighted the conflicting trail of evidence surrounding probiotic supplementation for the prevention and treatment of pediatric atopic dermatitis (AD) at a meeting sponsored by the American Academy of Pediatrics.

"It looks like at the present time that probiotics are really not very good for treatment, but they might help in prevention; but you have to give the probiotic prenatally for it to really work," said Dr. Raimer, chair of dermatology, University of Texas at Galveston.

These considerations are largely based on a recent meta-analysis of six prevention and four treatment double-blind randomized controlled trials of probiotics and pediatric AD (J. Allergy Clin. Immunol. 2008;121: 116–21).

The analysis identified a significant risk reduction—by as much as 61%—associated with the use of prenatal and/or postnatal probiotics for primary pediatric AD prevention among 1,581 participants, but only a marginal effect of treatment among 299 participants.

Such meta-analyses are complicated by the variety of bacteria strains and strengths studied, Dr. Raimer said.

Probiotic trials also typically have small sample sizes and heterogeneity of protocols, and might not assess for use of potential confounders such as concomitant antibiotics, topical corticosteroids, and antigen- eliminating diets.

An early trial supporting the role of probiotics in allergy prevention randomized mothers with a family history of atopic eczema, allergic rhinitis, or asthma to two capsules containing placebo or 1 × 1010 colony-forming units of Lactobacillus rhamnosus GG daily for 2–4 weeks before date of delivery.

After delivery, breastfeeding mothers were given the capsules, while infants who were not breastfed were given the capsule contents mixed with water, for 6 months.

Atopic eczema was diagnosed in 46 of 132 (35%) children at 2 years of age, with the frequency of eczema in the probiotic group half that of the placebo group (23% vs. 46%) (Lancet 2001;357:1076–9).

A follow-up study of these at-risk children revealed that 14 of 53 (26%) receiving Lactobacillus had developed atopic eczema at 4 years, compared with 25 of 54 (46%) receiving placebo (Lancet 2003;361:1869–71), suggesting that the preventive effect of Lactobacillus extends beyond infancy. Skin-prick test reactivity was found to be the same in both groups.

Early probiotic supplementation alone appears not to be beneficial in reducing the risk of AD and might actually increase the risk of allergen sensitization in high-risk children, said Dr. Raimer, also a professor of dermatology and pediatrics.

She cited an Australian study that found no difference in AD rates at 6 and 12 months between 177 infants who received Lactobacillus acidophilus or placebo for the first 6 months of life, and a significantly higher rate of sensitization to common allergens in the probiotic group at 12 months (Allergy Clin. Immunol. 2007;119:184–91).

Finally, a prospective randomized trial of supplementation during pregnancy and early infancy adds even more intrigue to the probiotic controversy.

Supplementation with 5 × 109 colony-forming units of Lactobacillus GG twice daily for 4–6 weeks before delivery and 6 months postnatally neither reduced the incidence of atopic eczema nor altered disease severity in AD affected children, but was associated with an increased rate of recurrent episodes of wheezing bronchitis in the study children (Pediatrics 2008;121:e850–6).

The German researchers concluded that Lactobacillus GG cannot be generally recommended for primary prevention of atopic eczema.

CHICAGO — The value of probiotics in atopic disease remains controversial, but clues are beginning to emerge in the literature about probiotics' role in treatment and prevention.

Dr. Sharon S. Raimer highlighted the conflicting trail of evidence surrounding probiotic supplementation for the prevention and treatment of pediatric atopic dermatitis (AD) at a meeting sponsored by the American Academy of Pediatrics.

"It looks like at the present time that probiotics are really not very good for treatment, but they might help in prevention; but you have to give the probiotic prenatally for it to really work," said Dr. Raimer, chair of dermatology, University of Texas at Galveston.

These considerations are largely based on a recent meta-analysis of six prevention and four treatment double-blind randomized controlled trials of probiotics and pediatric AD (J. Allergy Clin. Immunol. 2008;121: 116–21).

The analysis identified a significant risk reduction—by as much as 61%—associated with the use of prenatal and/or postnatal probiotics for primary pediatric AD prevention among 1,581 participants, but only a marginal effect of treatment among 299 participants.

Such meta-analyses are complicated by the variety of bacteria strains and strengths studied, Dr. Raimer said.

Probiotic trials also typically have small sample sizes and heterogeneity of protocols, and might not assess for use of potential confounders such as concomitant antibiotics, topical corticosteroids, and antigen- eliminating diets.

An early trial supporting the role of probiotics in allergy prevention randomized mothers with a family history of atopic eczema, allergic rhinitis, or asthma to two capsules containing placebo or 1 × 1010 colony-forming units of Lactobacillus rhamnosus GG daily for 2–4 weeks before date of delivery.

After delivery, breastfeeding mothers were given the capsules, while infants who were not breastfed were given the capsule contents mixed with water, for 6 months.

Atopic eczema was diagnosed in 46 of 132 (35%) children at 2 years of age, with the frequency of eczema in the probiotic group half that of the placebo group (23% vs. 46%) (Lancet 2001;357:1076–9).

A follow-up study of these at-risk children revealed that 14 of 53 (26%) receiving Lactobacillus had developed atopic eczema at 4 years, compared with 25 of 54 (46%) receiving placebo (Lancet 2003;361:1869–71), suggesting that the preventive effect of Lactobacillus extends beyond infancy. Skin-prick test reactivity was found to be the same in both groups.

Early probiotic supplementation alone appears not to be beneficial in reducing the risk of AD and might actually increase the risk of allergen sensitization in high-risk children, said Dr. Raimer, also a professor of dermatology and pediatrics.

She cited an Australian study that found no difference in AD rates at 6 and 12 months between 177 infants who received Lactobacillus acidophilus or placebo for the first 6 months of life, and a significantly higher rate of sensitization to common allergens in the probiotic group at 12 months (Allergy Clin. Immunol. 2007;119:184–91).

Finally, a prospective randomized trial of supplementation during pregnancy and early infancy adds even more intrigue to the probiotic controversy.

Supplementation with 5 × 109 colony-forming units of Lactobacillus GG twice daily for 4–6 weeks before delivery and 6 months postnatally neither reduced the incidence of atopic eczema nor altered disease severity in AD affected children, but was associated with an increased rate of recurrent episodes of wheezing bronchitis in the study children (Pediatrics 2008;121:e850–6).

The German researchers concluded that Lactobacillus GG cannot be generally recommended for primary prevention of atopic eczema.

CHICAGO — The value of probiotics in atopic disease remains controversial, but clues are beginning to emerge in the literature about probiotics' role in treatment and prevention.

Dr. Sharon S. Raimer highlighted the conflicting trail of evidence surrounding probiotic supplementation for the prevention and treatment of pediatric atopic dermatitis (AD) at a meeting sponsored by the American Academy of Pediatrics.

"It looks like at the present time that probiotics are really not very good for treatment, but they might help in prevention; but you have to give the probiotic prenatally for it to really work," said Dr. Raimer, chair of dermatology, University of Texas at Galveston.

These considerations are largely based on a recent meta-analysis of six prevention and four treatment double-blind randomized controlled trials of probiotics and pediatric AD (J. Allergy Clin. Immunol. 2008;121: 116–21).

The analysis identified a significant risk reduction—by as much as 61%—associated with the use of prenatal and/or postnatal probiotics for primary pediatric AD prevention among 1,581 participants, but only a marginal effect of treatment among 299 participants.

Such meta-analyses are complicated by the variety of bacteria strains and strengths studied, Dr. Raimer said.

Probiotic trials also typically have small sample sizes and heterogeneity of protocols, and might not assess for use of potential confounders such as concomitant antibiotics, topical corticosteroids, and antigen- eliminating diets.

An early trial supporting the role of probiotics in allergy prevention randomized mothers with a family history of atopic eczema, allergic rhinitis, or asthma to two capsules containing placebo or 1 × 1010 colony-forming units of Lactobacillus rhamnosus GG daily for 2–4 weeks before date of delivery.

After delivery, breastfeeding mothers were given the capsules, while infants who were not breastfed were given the capsule contents mixed with water, for 6 months.

Atopic eczema was diagnosed in 46 of 132 (35%) children at 2 years of age, with the frequency of eczema in the probiotic group half that of the placebo group (23% vs. 46%) (Lancet 2001;357:1076–9).

A follow-up study of these at-risk children revealed that 14 of 53 (26%) receiving Lactobacillus had developed atopic eczema at 4 years, compared with 25 of 54 (46%) receiving placebo (Lancet 2003;361:1869–71), suggesting that the preventive effect of Lactobacillus extends beyond infancy. Skin-prick test reactivity was found to be the same in both groups.

Early probiotic supplementation alone appears not to be beneficial in reducing the risk of AD and might actually increase the risk of allergen sensitization in high-risk children, said Dr. Raimer, also a professor of dermatology and pediatrics.

She cited an Australian study that found no difference in AD rates at 6 and 12 months between 177 infants who received Lactobacillus acidophilus or placebo for the first 6 months of life, and a significantly higher rate of sensitization to common allergens in the probiotic group at 12 months (Allergy Clin. Immunol. 2007;119:184–91).

Finally, a prospective randomized trial of supplementation during pregnancy and early infancy adds even more intrigue to the probiotic controversy.

Supplementation with 5 × 109 colony-forming units of Lactobacillus GG twice daily for 4–6 weeks before delivery and 6 months postnatally neither reduced the incidence of atopic eczema nor altered disease severity in AD affected children, but was associated with an increased rate of recurrent episodes of wheezing bronchitis in the study children (Pediatrics 2008;121:e850–6).

The German researchers concluded that Lactobacillus GG cannot be generally recommended for primary prevention of atopic eczema.

CHICAGO — Despite bone-chilling temperatures and the risk of frostbite, patients who underwent experimental whole-body cryotherapy for atopic dermatitis said they were willing to do it again.

This Finnish experience with whole-body cryotherapy was just one of three "outside-the-box" treatments for atopic dermatitis to emerge in recent months and was highlighted by Dr. Albert C. Yan, chief of the dermatology section at Children's Hospital of Philadelphia, during an atopic dermatitis symposium at the American Academy of Dermatology Academy 2008 summer meeting.

▸ Whole-body cryotherapy. This therapy has been used to treat rheumatic inflammation and pain since the 1970s. The rationale for the therapy in atopic dermatitis is based on reports that very cold air increases the body's antioxidative capacity and reduces the conduction velocity of peripheral nerves and the nerve ganglia capacity to synthesize acetylcholine, which is considered a neurotransmitter in atopic pruritus, according to Dr. Yan.

Investigators at the Skin and Allergy Hospital in Helsinki applied whole-body cryotherapy to 18 adults with mild to moderate atopic dermatitis three times a week for 4 weeks, followed by an 8-week follow-up period.

Topical anti-inflammatory preparations or systemic antihistamines were not allowed for 1 week before or at any time during the study, and there was a 6-week washout period for systemic therapy and phototherapy.

The Univers Cryo-Combi whole-body cryotherapy device (Oy MJG Univers Ab, Helsinki) consists of two precooling chambers set at −30° C and −60° C, where patients remained for a very short time, and a third chamber that reaches −110° C, where patients remained for 1 to 3 minutes wearing a bathing suit or trunks, with acral parts covered.

The study's primary end point of change in the Scoring of Atopic Dermatitis (SCORAD) index (scale 0–103) decreased almost 20% from 38.7 to 31.1 (Arch. Dermatol. 2008;144:806–8).

Pruritus, sleep loss, and SCORAD rating tended to improve after the 4 weeks of treatment.

Three patients had treatment-related adverse events, all mild acral frostbite. Sixteen of the 18 patients completed therapy, an average of 11 sessions (range from 9 to 12 sessions).

One patient left the study because of worsening dermatitis, and another left because of work schedule. All patients were willing to undergo further treatment.

The device used in the study is the first to use both liquid nitrogen and compressor technology to produce cold air. This maintains an optimal oxygen level of 22% in the chamber that allows even patients with asthma to undergo the treatment, according to lead author Dr. Taras Klimenko and colleagues, who reported no conflicts of interest.

The study was supported by grants from The Finnish Society of Dermatology and The Finnish Society of Dermatopathology.

▸ Vitamin D supplementation. Supplements of vitamin D helped improve wintertime onset or exacerbation of atopic dermatitis in children aged 2–13 years who were randomized to oral ergocalciferol 1000 IU in a double-blind, pilot study (Br. J. Dermatol. 2008;159:245–7).

The Investigator's Global Assessment—based on six categories, ranging from clear (1) to very severe (6)—improved by one category in four (80%) of five children on vitamin D versus one (17%) of six children on placebo. Similar improvements were seen in Eczema Area and Severity Index scores.

Lead author Dr. Robert Sidbury of Children's Hospital Boston and his associates suggested that the favorable impact of vitamin D on atopic dermatitis is biologically plausible.

The active form of vitamin D, 1,25-dihydroxyvitamin D₃, induces expression of antimicrobial peptides that help prevent skin infection and possess immunosuppressive properties in the skin. Recent research also has drawn attention to the connection between vitamin D-mediated activation of toll-like receptors, production of the antimicrobial peptide cathelicidin, and human susceptibility to bacterial infection.

"Thus, vitamin D deficiency could contribute to the hallmark signs of AD: altered barrier function, immune dysregulation, and inadequate bacterial defence," wrote the authors, who reported no conflicts of interest.

The study was supported by a grant from the Massachusetts General Hospital Center for D-receptor Activation Research in Boston.

▸ Rosiglitazone maleate. Used as an add-on therapy at doses of 2–4 mg twice daily, rosiglitazone (Avandia) was associated with increased control of severe atopic dermatitis in 6 patients nonresponsive to first- and second-line therapies, according to a retrospective review (Arch. Dermatol. 2008;144:84–8).

The six patients, aged 16–75 years, showed decreased extent of the disease, of inflammation, and of number of flares. In addition, rosiglitazone, which is indicated for the treatment of type II diabetes, allowed for gradual reduction or elimination of systemic steroids in the three patients who used them.

Major clinical improvement appeared between weeks 4 and 12, which suggests that some patients may require at least 3 months for a clinical response, according to lead author Ramona Behshad, principal investigator Dr. Kevin Cooper, and senior author Dr. Neil Korman, all of whom are with Case University, Cleveland.

No serious adverse events were seen in the study patients. The investigators suggested rosiglitazone may serve as a "good alternative to current systemic immunosuppressants used for severe AD," but urged caution in interpreting the promising results because of study design limitations and two previous randomized trials of rosiglitazone in psoriasis that failed to demonstrate any notable efficacy, compared with placebo.

The study was supported in part by the National Institute of Arthritis and Case Medical Center.

No financial disclosures were reported by the authors.

CHICAGO — Despite bone-chilling temperatures and the risk of frostbite, patients who underwent experimental whole-body cryotherapy for atopic dermatitis said they were willing to do it again.

This Finnish experience with whole-body cryotherapy was just one of three "outside-the-box" treatments for atopic dermatitis to emerge in recent months and was highlighted by Dr. Albert C. Yan, chief of the dermatology section at Children's Hospital of Philadelphia, during an atopic dermatitis symposium at the American Academy of Dermatology Academy 2008 summer meeting.

▸ Whole-body cryotherapy. This therapy has been used to treat rheumatic inflammation and pain since the 1970s. The rationale for the therapy in atopic dermatitis is based on reports that very cold air increases the body's antioxidative capacity and reduces the conduction velocity of peripheral nerves and the nerve ganglia capacity to synthesize acetylcholine, which is considered a neurotransmitter in atopic pruritus, according to Dr. Yan.

Investigators at the Skin and Allergy Hospital in Helsinki applied whole-body cryotherapy to 18 adults with mild to moderate atopic dermatitis three times a week for 4 weeks, followed by an 8-week follow-up period.

Topical anti-inflammatory preparations or systemic antihistamines were not allowed for 1 week before or at any time during the study, and there was a 6-week washout period for systemic therapy and phototherapy.

The Univers Cryo-Combi whole-body cryotherapy device (Oy MJG Univers Ab, Helsinki) consists of two precooling chambers set at −30° C and −60° C, where patients remained for a very short time, and a third chamber that reaches −110° C, where patients remained for 1 to 3 minutes wearing a bathing suit or trunks, with acral parts covered.

The study's primary end point of change in the Scoring of Atopic Dermatitis (SCORAD) index (scale 0–103) decreased almost 20% from 38.7 to 31.1 (Arch. Dermatol. 2008;144:806–8).

Pruritus, sleep loss, and SCORAD rating tended to improve after the 4 weeks of treatment.

Three patients had treatment-related adverse events, all mild acral frostbite. Sixteen of the 18 patients completed therapy, an average of 11 sessions (range from 9 to 12 sessions).

One patient left the study because of worsening dermatitis, and another left because of work schedule. All patients were willing to undergo further treatment.

The device used in the study is the first to use both liquid nitrogen and compressor technology to produce cold air. This maintains an optimal oxygen level of 22% in the chamber that allows even patients with asthma to undergo the treatment, according to lead author Dr. Taras Klimenko and colleagues, who reported no conflicts of interest.

The study was supported by grants from The Finnish Society of Dermatology and The Finnish Society of Dermatopathology.

▸ Vitamin D supplementation. Supplements of vitamin D helped improve wintertime onset or exacerbation of atopic dermatitis in children aged 2–13 years who were randomized to oral ergocalciferol 1000 IU in a double-blind, pilot study (Br. J. Dermatol. 2008;159:245–7).

The Investigator's Global Assessment—based on six categories, ranging from clear (1) to very severe (6)—improved by one category in four (80%) of five children on vitamin D versus one (17%) of six children on placebo. Similar improvements were seen in Eczema Area and Severity Index scores.

Lead author Dr. Robert Sidbury of Children's Hospital Boston and his associates suggested that the favorable impact of vitamin D on atopic dermatitis is biologically plausible.

The active form of vitamin D, 1,25-dihydroxyvitamin D₃, induces expression of antimicrobial peptides that help prevent skin infection and possess immunosuppressive properties in the skin. Recent research also has drawn attention to the connection between vitamin D-mediated activation of toll-like receptors, production of the antimicrobial peptide cathelicidin, and human susceptibility to bacterial infection.

"Thus, vitamin D deficiency could contribute to the hallmark signs of AD: altered barrier function, immune dysregulation, and inadequate bacterial defence," wrote the authors, who reported no conflicts of interest.

The study was supported by a grant from the Massachusetts General Hospital Center for D-receptor Activation Research in Boston.

▸ Rosiglitazone maleate. Used as an add-on therapy at doses of 2–4 mg twice daily, rosiglitazone (Avandia) was associated with increased control of severe atopic dermatitis in 6 patients nonresponsive to first- and second-line therapies, according to a retrospective review (Arch. Dermatol. 2008;144:84–8).

The six patients, aged 16–75 years, showed decreased extent of the disease, of inflammation, and of number of flares. In addition, rosiglitazone, which is indicated for the treatment of type II diabetes, allowed for gradual reduction or elimination of systemic steroids in the three patients who used them.

Major clinical improvement appeared between weeks 4 and 12, which suggests that some patients may require at least 3 months for a clinical response, according to lead author Ramona Behshad, principal investigator Dr. Kevin Cooper, and senior author Dr. Neil Korman, all of whom are with Case University, Cleveland.

No serious adverse events were seen in the study patients. The investigators suggested rosiglitazone may serve as a "good alternative to current systemic immunosuppressants used for severe AD," but urged caution in interpreting the promising results because of study design limitations and two previous randomized trials of rosiglitazone in psoriasis that failed to demonstrate any notable efficacy, compared with placebo.

The study was supported in part by the National Institute of Arthritis and Case Medical Center.

No financial disclosures were reported by the authors.

CHICAGO — Despite bone-chilling temperatures and the risk of frostbite, patients who underwent experimental whole-body cryotherapy for atopic dermatitis said they were willing to do it again.

This Finnish experience with whole-body cryotherapy was just one of three "outside-the-box" treatments for atopic dermatitis to emerge in recent months and was highlighted by Dr. Albert C. Yan, chief of the dermatology section at Children's Hospital of Philadelphia, during an atopic dermatitis symposium at the American Academy of Dermatology Academy 2008 summer meeting.

▸ Whole-body cryotherapy. This therapy has been used to treat rheumatic inflammation and pain since the 1970s. The rationale for the therapy in atopic dermatitis is based on reports that very cold air increases the body's antioxidative capacity and reduces the conduction velocity of peripheral nerves and the nerve ganglia capacity to synthesize acetylcholine, which is considered a neurotransmitter in atopic pruritus, according to Dr. Yan.

Investigators at the Skin and Allergy Hospital in Helsinki applied whole-body cryotherapy to 18 adults with mild to moderate atopic dermatitis three times a week for 4 weeks, followed by an 8-week follow-up period.

Topical anti-inflammatory preparations or systemic antihistamines were not allowed for 1 week before or at any time during the study, and there was a 6-week washout period for systemic therapy and phototherapy.

The Univers Cryo-Combi whole-body cryotherapy device (Oy MJG Univers Ab, Helsinki) consists of two precooling chambers set at −30° C and −60° C, where patients remained for a very short time, and a third chamber that reaches −110° C, where patients remained for 1 to 3 minutes wearing a bathing suit or trunks, with acral parts covered.

The study's primary end point of change in the Scoring of Atopic Dermatitis (SCORAD) index (scale 0–103) decreased almost 20% from 38.7 to 31.1 (Arch. Dermatol. 2008;144:806–8).

Pruritus, sleep loss, and SCORAD rating tended to improve after the 4 weeks of treatment.

Three patients had treatment-related adverse events, all mild acral frostbite. Sixteen of the 18 patients completed therapy, an average of 11 sessions (range from 9 to 12 sessions).

One patient left the study because of worsening dermatitis, and another left because of work schedule. All patients were willing to undergo further treatment.

The device used in the study is the first to use both liquid nitrogen and compressor technology to produce cold air. This maintains an optimal oxygen level of 22% in the chamber that allows even patients with asthma to undergo the treatment, according to lead author Dr. Taras Klimenko and colleagues, who reported no conflicts of interest.

The study was supported by grants from The Finnish Society of Dermatology and The Finnish Society of Dermatopathology.

▸ Vitamin D supplementation. Supplements of vitamin D helped improve wintertime onset or exacerbation of atopic dermatitis in children aged 2–13 years who were randomized to oral ergocalciferol 1000 IU in a double-blind, pilot study (Br. J. Dermatol. 2008;159:245–7).

The Investigator's Global Assessment—based on six categories, ranging from clear (1) to very severe (6)—improved by one category in four (80%) of five children on vitamin D versus one (17%) of six children on placebo. Similar improvements were seen in Eczema Area and Severity Index scores.

Lead author Dr. Robert Sidbury of Children's Hospital Boston and his associates suggested that the favorable impact of vitamin D on atopic dermatitis is biologically plausible.

The active form of vitamin D, 1,25-dihydroxyvitamin D₃, induces expression of antimicrobial peptides that help prevent skin infection and possess immunosuppressive properties in the skin. Recent research also has drawn attention to the connection between vitamin D-mediated activation of toll-like receptors, production of the antimicrobial peptide cathelicidin, and human susceptibility to bacterial infection.

"Thus, vitamin D deficiency could contribute to the hallmark signs of AD: altered barrier function, immune dysregulation, and inadequate bacterial defence," wrote the authors, who reported no conflicts of interest.

The study was supported by a grant from the Massachusetts General Hospital Center for D-receptor Activation Research in Boston.

▸ Rosiglitazone maleate. Used as an add-on therapy at doses of 2–4 mg twice daily, rosiglitazone (Avandia) was associated with increased control of severe atopic dermatitis in 6 patients nonresponsive to first- and second-line therapies, according to a retrospective review (Arch. Dermatol. 2008;144:84–8).

The six patients, aged 16–75 years, showed decreased extent of the disease, of inflammation, and of number of flares. In addition, rosiglitazone, which is indicated for the treatment of type II diabetes, allowed for gradual reduction or elimination of systemic steroids in the three patients who used them.

Major clinical improvement appeared between weeks 4 and 12, which suggests that some patients may require at least 3 months for a clinical response, according to lead author Ramona Behshad, principal investigator Dr. Kevin Cooper, and senior author Dr. Neil Korman, all of whom are with Case University, Cleveland.

No serious adverse events were seen in the study patients. The investigators suggested rosiglitazone may serve as a "good alternative to current systemic immunosuppressants used for severe AD," but urged caution in interpreting the promising results because of study design limitations and two previous randomized trials of rosiglitazone in psoriasis that failed to demonstrate any notable efficacy, compared with placebo.

The study was supported in part by the National Institute of Arthritis and Case Medical Center.

No financial disclosures were reported by the authors.

KYOTO, JAPAN — Children heterozygous for a filaggrin gene loss-of-function mutation are at an 8.2-fold increased risk for moderate to severe atopic dermatitis, while those who are homozygous for the defect carry a staggering 169-fold elevated risk, according to a case-control study.

This Irish study of mutations in the gene expressing filaggrin, a key skin barrier function protein, involved 262 children with dermatologist-diagnosed moderate to severe atopic dermatitis and 736 matched controls. As in other studies of people of Northern European ancestry, almost one-half of the atopic dermatitis patients possessed a filaggrin mutation, Dr. Gráinne M. O'Regan reported at an international investigative dermatology meeting.

The study also turned up three previously unknown filaggrin mutations, noted Dr. O'Regan of Our Lady's Children's Hospital, Dublin.

Her coinvestigator, W.H. Irwin McLean, Ph.D., noted that this brings the total number of filaggrin loss-of-function or null mutations identified to 39, mostly in the European and Far Eastern populations where studies thus far have been concentrated.

"The mutations are completely ethnic specific. The mutations you find in white people are not found in Japan, for example, with very, very few exceptions," he explained in his René Touraine Lecture at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

There is little doubt that other skin barrier genes just as replicable as filaggrin will emerge in the future. And additional filaggrin mutations await discovery, added Dr. McLean, professor of human genetics at the University of Dundee (Scotland).

"We don't know much yet about filaggrin mutations in black populations," he noted. "It's very difficult to analyze populations. It takes probably a year to do each ethnic group."

Heterozygotes for a filaggrin null mutation make half the normal amount of filaggrin. Homozygotes make none. In heterozygotes the penetrance is 40%, meaning 40% of bearers of one mutant allele have atopic dermatitis. The penetrance in homozygotes is 90% or more, and they tend to have the most severe skin disease.

The newest data on the prevalence of filaggrin null mutations in the general population come from an epidemiologic study in the north of England, where 1 in 7 individuals was found to carry one mutation and 1 in 90 carried two.

Two years ago, Dr. McLean and his coworkers shook up the dermatology world with their landmark discovery that filaggrin mutations strongly predispose to atopic dermatitis.

Their report brought forth a new appreciation of impaired skin barrier function as a driving force in the pathophysiology of this common inflammatory skin disease.

Since then, Dr. McLean said, one of the most common questions physicians ask him is this: Is atopic dermatitis fundamentally a skin barrier problem or an immunologic disorder?

"I think that's too simple a question," he added. Instead, the Irishman drew an analogy between atopic dermatitis and the St. Patrick's three-leafed shamrock. The "leaves" of atopic dermatitis are the skin barrier, the immune system, and the environment.

"If you have no barrier, every environmental trigger is going to cause eczema. And you can have some people who have a good barrier and a very, very sensitive immune system, so the environmental trigger gets through. But I think a lot of people will fall in the middle, where there's a barrier defect, there's something going on with the immune system, and there's an environmental trigger. The incidence of atopic dermatitis has increased over the years, and that's due to the changed environment. The genes controlling these two other things have stayed the same," Dr. McLean said.

His filaggrin research is funded by the British Skin Foundation, the National Eczema Society, and the Medical Research Council.

KYOTO, JAPAN — Children heterozygous for a filaggrin gene loss-of-function mutation are at an 8.2-fold increased risk for moderate to severe atopic dermatitis, while those who are homozygous for the defect carry a staggering 169-fold elevated risk, according to a case-control study.

This Irish study of mutations in the gene expressing filaggrin, a key skin barrier function protein, involved 262 children with dermatologist-diagnosed moderate to severe atopic dermatitis and 736 matched controls. As in other studies of people of Northern European ancestry, almost one-half of the atopic dermatitis patients possessed a filaggrin mutation, Dr. Gráinne M. O'Regan reported at an international investigative dermatology meeting.

The study also turned up three previously unknown filaggrin mutations, noted Dr. O'Regan of Our Lady's Children's Hospital, Dublin.

Her coinvestigator, W.H. Irwin McLean, Ph.D., noted that this brings the total number of filaggrin loss-of-function or null mutations identified to 39, mostly in the European and Far Eastern populations where studies thus far have been concentrated.

"The mutations are completely ethnic specific. The mutations you find in white people are not found in Japan, for example, with very, very few exceptions," he explained in his René Touraine Lecture at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

There is little doubt that other skin barrier genes just as replicable as filaggrin will emerge in the future. And additional filaggrin mutations await discovery, added Dr. McLean, professor of human genetics at the University of Dundee (Scotland).

"We don't know much yet about filaggrin mutations in black populations," he noted. "It's very difficult to analyze populations. It takes probably a year to do each ethnic group."

Heterozygotes for a filaggrin null mutation make half the normal amount of filaggrin. Homozygotes make none. In heterozygotes the penetrance is 40%, meaning 40% of bearers of one mutant allele have atopic dermatitis. The penetrance in homozygotes is 90% or more, and they tend to have the most severe skin disease.

The newest data on the prevalence of filaggrin null mutations in the general population come from an epidemiologic study in the north of England, where 1 in 7 individuals was found to carry one mutation and 1 in 90 carried two.

Two years ago, Dr. McLean and his coworkers shook up the dermatology world with their landmark discovery that filaggrin mutations strongly predispose to atopic dermatitis.

Their report brought forth a new appreciation of impaired skin barrier function as a driving force in the pathophysiology of this common inflammatory skin disease.

Since then, Dr. McLean said, one of the most common questions physicians ask him is this: Is atopic dermatitis fundamentally a skin barrier problem or an immunologic disorder?

"I think that's too simple a question," he added. Instead, the Irishman drew an analogy between atopic dermatitis and the St. Patrick's three-leafed shamrock. The "leaves" of atopic dermatitis are the skin barrier, the immune system, and the environment.

"If you have no barrier, every environmental trigger is going to cause eczema. And you can have some people who have a good barrier and a very, very sensitive immune system, so the environmental trigger gets through. But I think a lot of people will fall in the middle, where there's a barrier defect, there's something going on with the immune system, and there's an environmental trigger. The incidence of atopic dermatitis has increased over the years, and that's due to the changed environment. The genes controlling these two other things have stayed the same," Dr. McLean said.

His filaggrin research is funded by the British Skin Foundation, the National Eczema Society, and the Medical Research Council.

KYOTO, JAPAN — Children heterozygous for a filaggrin gene loss-of-function mutation are at an 8.2-fold increased risk for moderate to severe atopic dermatitis, while those who are homozygous for the defect carry a staggering 169-fold elevated risk, according to a case-control study.

This Irish study of mutations in the gene expressing filaggrin, a key skin barrier function protein, involved 262 children with dermatologist-diagnosed moderate to severe atopic dermatitis and 736 matched controls. As in other studies of people of Northern European ancestry, almost one-half of the atopic dermatitis patients possessed a filaggrin mutation, Dr. Gráinne M. O'Regan reported at an international investigative dermatology meeting.

The study also turned up three previously unknown filaggrin mutations, noted Dr. O'Regan of Our Lady's Children's Hospital, Dublin.

Her coinvestigator, W.H. Irwin McLean, Ph.D., noted that this brings the total number of filaggrin loss-of-function or null mutations identified to 39, mostly in the European and Far Eastern populations where studies thus far have been concentrated.

"The mutations are completely ethnic specific. The mutations you find in white people are not found in Japan, for example, with very, very few exceptions," he explained in his René Touraine Lecture at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

There is little doubt that other skin barrier genes just as replicable as filaggrin will emerge in the future. And additional filaggrin mutations await discovery, added Dr. McLean, professor of human genetics at the University of Dundee (Scotland).

"We don't know much yet about filaggrin mutations in black populations," he noted. "It's very difficult to analyze populations. It takes probably a year to do each ethnic group."

Heterozygotes for a filaggrin null mutation make half the normal amount of filaggrin. Homozygotes make none. In heterozygotes the penetrance is 40%, meaning 40% of bearers of one mutant allele have atopic dermatitis. The penetrance in homozygotes is 90% or more, and they tend to have the most severe skin disease.

The newest data on the prevalence of filaggrin null mutations in the general population come from an epidemiologic study in the north of England, where 1 in 7 individuals was found to carry one mutation and 1 in 90 carried two.

Two years ago, Dr. McLean and his coworkers shook up the dermatology world with their landmark discovery that filaggrin mutations strongly predispose to atopic dermatitis.

Their report brought forth a new appreciation of impaired skin barrier function as a driving force in the pathophysiology of this common inflammatory skin disease.

Since then, Dr. McLean said, one of the most common questions physicians ask him is this: Is atopic dermatitis fundamentally a skin barrier problem or an immunologic disorder?

"I think that's too simple a question," he added. Instead, the Irishman drew an analogy between atopic dermatitis and the St. Patrick's three-leafed shamrock. The "leaves" of atopic dermatitis are the skin barrier, the immune system, and the environment.

"If you have no barrier, every environmental trigger is going to cause eczema. And you can have some people who have a good barrier and a very, very sensitive immune system, so the environmental trigger gets through. But I think a lot of people will fall in the middle, where there's a barrier defect, there's something going on with the immune system, and there's an environmental trigger. The incidence of atopic dermatitis has increased over the years, and that's due to the changed environment. The genes controlling these two other things have stayed the same," Dr. McLean said.

His filaggrin research is funded by the British Skin Foundation, the National Eczema Society, and the Medical Research Council.

The American Academy of Dermatology has launched a new program called DermBase that will help members collaborate on research into rare diseases from multiple sites. The Web-based tool provides an online forum for dermatologists to submit ideas for clinical studies, receive feedback for those studies, conduct studies, and publish findings. For more information, visit www.dermbase.com

The American Academy of Dermatology has launched a new program called DermBase that will help members collaborate on research into rare diseases from multiple sites. The Web-based tool provides an online forum for dermatologists to submit ideas for clinical studies, receive feedback for those studies, conduct studies, and publish findings. For more information, visit www.dermbase.com

The American Academy of Dermatology has launched a new program called DermBase that will help members collaborate on research into rare diseases from multiple sites. The Web-based tool provides an online forum for dermatologists to submit ideas for clinical studies, receive feedback for those studies, conduct studies, and publish findings. For more information, visit www.dermbase.com

KYOTO, JAPAN — Filaggrin mutations are potent risk factors for allergic rhinitis and eczema-related asthma, the results of two large population-based studies have shown.

Loss-of-function mutations in the filaggrin gene have previously been found to be the cause of ichthyosis vulgaris, as well as being a predisposing factor in atopic dermatitis. (See related story below.)

Filaggrin is an abundant protein that plays a critical role in the formation of a healthy stratum corneum. It is thus a key contributor to the skin's barrier function, and it also regulates stratum corneum hydration, W.H. Irwin McLean, Ph.D., noted in his René Touraine Lecture at an international investigative dermatology meeting.

The filaggrin gene is part of the epidermal differentiation complex located on chromosome 1q21. Recently, it has become evident that mutations causing low or no filaggrin expression are found the world over and are particularly prevalent in individuals of European ancestry, added Dr. McLean, professor of human genetics at the University of Dundee (Scotland).

Dr. McLean was the senior author of two landmark papers first linking filaggrin mutations to ichthyosis vulgaris (Nat. Genet. 2006;38:337–42) and atopic dermatitis (Nat. Genet. 2006;38:441–6). He was also a coauthor of the recent population-based studies that identified filaggrin mutations as conferring significant risks for allergic rhinitis and eczema-related asthma.

The first study involved 3,099 German children aged 9–11 years recruited as part of phase II of the International Study of Asthma and Allergies in Childhood. Investigators headquartered at the Technical University of Munich assessed the children for two common filaggrin null mutations—R501X and 2282del4—and three other recently identified rare ones.

The presence of a target filaggrin mutation was associated with a 3.1-fold increased risk of atopic dermatitis, which is similar to previous results in other studies, he noted. In addition, filaggrin mutations independently conferred a 2.6-fold increased risk for allergic rhinitis and a 3.5-fold risk of asthma with a history of eczema. However, filaggrin mutations were not associated with an increased risk of asthma alone.

The population-attributable risk of atopic dermatitis associated with the filaggrin mutations—that is, the proportion of cases of the skin disease believed to be due to these genetic variants—was 13.5%, said Dr. McLean. The population-attributable risk was estimated at 10.8% for allergic rhinitis, 15.6% for atopic dermatitis plus asthma, and 20.1% for atopic dermatitis plus allergic rhinitis.

Nasal biopsies showed strong expression of filaggrin in the anterior vestibular lining of the nose, but not in transitional and respiratory nasal epithelia (J. Allergy Clin. Immunol. 2008;121:1203–9).

In another large study, Dr. McLean and his coworkers at the University of Bristol (England) reported on the impact of the same two common filaggrin null mutations in 7,000 participants in the Avon Longitudinal Study of Parents and Children who were born in 1990–1991.

In this cohort, having either mutation was associated with a highly significant 1.8-fold increased risk of childhood asthma, a 3.0-fold risk of eczema plus early wheezing, and a 3.2-fold risk of atopic dermatitis plus asthma. Children with atopic dermatitis related to either of the filaggrin null alleles also tended to have markedly more persistent eczema than atopic dermatitis patients without a filaggrin mutation (J. Allergy Clin. Immunol. 2008;121:872–7).

The hope is that once treatments designed to correct filaggrin deficiency are available, early identification and treatment of children with filaggrin-associated atopic dermatitis will prevent the other atopic outcomes. Dr. McLean and his coworkers at the University of Dundee are now attempting to develop such therapies.

"My motto for the next few years is, 'Enough genetics—let's cure something,'" he said at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

He and his colleagues have identified one molecule he declined to name that more than doubles filaggrin expression in vitro in the setting of a single mutation with one normal and one silent allele. And aminoglycosides such as gentamicin can inhibit mutations in homozygous individuals who make no filaggrin at all and who therefore have particularly severe atopic disease, he said.

"When we treat human skin cells containing filaggrin mutations with gentamicin, we recover gene expression. We see improvement in the granular layer. Gentamicin is not an ideal drug … I think we can find a better one," Dr. McLean added.

His filaggrin research is funded by the British Skin Foundation, the National Eczema Society, and the Medical Research Council.

'My motto for the next few years is, "Enough genetics—let's cure something."' DR. MCLEAN

KYOTO, JAPAN — Filaggrin mutations are potent risk factors for allergic rhinitis and eczema-related asthma, the results of two large population-based studies have shown.

Loss-of-function mutations in the filaggrin gene have previously been found to be the cause of ichthyosis vulgaris, as well as being a predisposing factor in atopic dermatitis. (See related story below.)

Filaggrin is an abundant protein that plays a critical role in the formation of a healthy stratum corneum. It is thus a key contributor to the skin's barrier function, and it also regulates stratum corneum hydration, W.H. Irwin McLean, Ph.D., noted in his René Touraine Lecture at an international investigative dermatology meeting.

The filaggrin gene is part of the epidermal differentiation complex located on chromosome 1q21. Recently, it has become evident that mutations causing low or no filaggrin expression are found the world over and are particularly prevalent in individuals of European ancestry, added Dr. McLean, professor of human genetics at the University of Dundee (Scotland).

Dr. McLean was the senior author of two landmark papers first linking filaggrin mutations to ichthyosis vulgaris (Nat. Genet. 2006;38:337–42) and atopic dermatitis (Nat. Genet. 2006;38:441–6). He was also a coauthor of the recent population-based studies that identified filaggrin mutations as conferring significant risks for allergic rhinitis and eczema-related asthma.

The first study involved 3,099 German children aged 9–11 years recruited as part of phase II of the International Study of Asthma and Allergies in Childhood. Investigators headquartered at the Technical University of Munich assessed the children for two common filaggrin null mutations—R501X and 2282del4—and three other recently identified rare ones.

The presence of a target filaggrin mutation was associated with a 3.1-fold increased risk of atopic dermatitis, which is similar to previous results in other studies, he noted. In addition, filaggrin mutations independently conferred a 2.6-fold increased risk for allergic rhinitis and a 3.5-fold risk of asthma with a history of eczema. However, filaggrin mutations were not associated with an increased risk of asthma alone.

The population-attributable risk of atopic dermatitis associated with the filaggrin mutations—that is, the proportion of cases of the skin disease believed to be due to these genetic variants—was 13.5%, said Dr. McLean. The population-attributable risk was estimated at 10.8% for allergic rhinitis, 15.6% for atopic dermatitis plus asthma, and 20.1% for atopic dermatitis plus allergic rhinitis.

Nasal biopsies showed strong expression of filaggrin in the anterior vestibular lining of the nose, but not in transitional and respiratory nasal epithelia (J. Allergy Clin. Immunol. 2008;121:1203–9).

In another large study, Dr. McLean and his coworkers at the University of Bristol (England) reported on the impact of the same two common filaggrin null mutations in 7,000 participants in the Avon Longitudinal Study of Parents and Children who were born in 1990–1991.

In this cohort, having either mutation was associated with a highly significant 1.8-fold increased risk of childhood asthma, a 3.0-fold risk of eczema plus early wheezing, and a 3.2-fold risk of atopic dermatitis plus asthma. Children with atopic dermatitis related to either of the filaggrin null alleles also tended to have markedly more persistent eczema than atopic dermatitis patients without a filaggrin mutation (J. Allergy Clin. Immunol. 2008;121:872–7).

The hope is that once treatments designed to correct filaggrin deficiency are available, early identification and treatment of children with filaggrin-associated atopic dermatitis will prevent the other atopic outcomes. Dr. McLean and his coworkers at the University of Dundee are now attempting to develop such therapies.

"My motto for the next few years is, 'Enough genetics—let's cure something,'" he said at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

He and his colleagues have identified one molecule he declined to name that more than doubles filaggrin expression in vitro in the setting of a single mutation with one normal and one silent allele. And aminoglycosides such as gentamicin can inhibit mutations in homozygous individuals who make no filaggrin at all and who therefore have particularly severe atopic disease, he said.

"When we treat human skin cells containing filaggrin mutations with gentamicin, we recover gene expression. We see improvement in the granular layer. Gentamicin is not an ideal drug … I think we can find a better one," Dr. McLean added.

His filaggrin research is funded by the British Skin Foundation, the National Eczema Society, and the Medical Research Council.

'My motto for the next few years is, "Enough genetics—let's cure something."' DR. MCLEAN

KYOTO, JAPAN — Filaggrin mutations are potent risk factors for allergic rhinitis and eczema-related asthma, the results of two large population-based studies have shown.

Loss-of-function mutations in the filaggrin gene have previously been found to be the cause of ichthyosis vulgaris, as well as being a predisposing factor in atopic dermatitis. (See related story below.)

Filaggrin is an abundant protein that plays a critical role in the formation of a healthy stratum corneum. It is thus a key contributor to the skin's barrier function, and it also regulates stratum corneum hydration, W.H. Irwin McLean, Ph.D., noted in his René Touraine Lecture at an international investigative dermatology meeting.

The filaggrin gene is part of the epidermal differentiation complex located on chromosome 1q21. Recently, it has become evident that mutations causing low or no filaggrin expression are found the world over and are particularly prevalent in individuals of European ancestry, added Dr. McLean, professor of human genetics at the University of Dundee (Scotland).

Dr. McLean was the senior author of two landmark papers first linking filaggrin mutations to ichthyosis vulgaris (Nat. Genet. 2006;38:337–42) and atopic dermatitis (Nat. Genet. 2006;38:441–6). He was also a coauthor of the recent population-based studies that identified filaggrin mutations as conferring significant risks for allergic rhinitis and eczema-related asthma.

The first study involved 3,099 German children aged 9–11 years recruited as part of phase II of the International Study of Asthma and Allergies in Childhood. Investigators headquartered at the Technical University of Munich assessed the children for two common filaggrin null mutations—R501X and 2282del4—and three other recently identified rare ones.

The presence of a target filaggrin mutation was associated with a 3.1-fold increased risk of atopic dermatitis, which is similar to previous results in other studies, he noted. In addition, filaggrin mutations independently conferred a 2.6-fold increased risk for allergic rhinitis and a 3.5-fold risk of asthma with a history of eczema. However, filaggrin mutations were not associated with an increased risk of asthma alone.

The population-attributable risk of atopic dermatitis associated with the filaggrin mutations—that is, the proportion of cases of the skin disease believed to be due to these genetic variants—was 13.5%, said Dr. McLean. The population-attributable risk was estimated at 10.8% for allergic rhinitis, 15.6% for atopic dermatitis plus asthma, and 20.1% for atopic dermatitis plus allergic rhinitis.

Nasal biopsies showed strong expression of filaggrin in the anterior vestibular lining of the nose, but not in transitional and respiratory nasal epithelia (J. Allergy Clin. Immunol. 2008;121:1203–9).

In another large study, Dr. McLean and his coworkers at the University of Bristol (England) reported on the impact of the same two common filaggrin null mutations in 7,000 participants in the Avon Longitudinal Study of Parents and Children who were born in 1990–1991.

In this cohort, having either mutation was associated with a highly significant 1.8-fold increased risk of childhood asthma, a 3.0-fold risk of eczema plus early wheezing, and a 3.2-fold risk of atopic dermatitis plus asthma. Children with atopic dermatitis related to either of the filaggrin null alleles also tended to have markedly more persistent eczema than atopic dermatitis patients without a filaggrin mutation (J. Allergy Clin. Immunol. 2008;121:872–7).

The hope is that once treatments designed to correct filaggrin deficiency are available, early identification and treatment of children with filaggrin-associated atopic dermatitis will prevent the other atopic outcomes. Dr. McLean and his coworkers at the University of Dundee are now attempting to develop such therapies.

"My motto for the next few years is, 'Enough genetics—let's cure something,'" he said at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

He and his colleagues have identified one molecule he declined to name that more than doubles filaggrin expression in vitro in the setting of a single mutation with one normal and one silent allele. And aminoglycosides such as gentamicin can inhibit mutations in homozygous individuals who make no filaggrin at all and who therefore have particularly severe atopic disease, he said.

"When we treat human skin cells containing filaggrin mutations with gentamicin, we recover gene expression. We see improvement in the granular layer. Gentamicin is not an ideal drug … I think we can find a better one," Dr. McLean added.

His filaggrin research is funded by the British Skin Foundation, the National Eczema Society, and the Medical Research Council.

'My motto for the next few years is, "Enough genetics—let's cure something."' DR. MCLEAN

DENVER — Any child with atopic dermatitis who has increasing pain, erythema, edema, heat, and purulent exudate is superinfected and requires antibiotics and emollients, according to an expert in pediatric dermatology.

A culture is necessary only for prescribing the correct antibiotic.

"I'm here to plead with you that infection is a clinical diagnosis, not a microbiological diagnosis," said Dr. H. Alan Arbuckle, a dermatologist and pediatrician at the University of Colorado, Denver, and Children's Hospital in Aurora, Colo.

"Doing a culture in a superinfected AD kid is worthless if your goal is to make the diagnosis of infection.

"All of these kids are going to be colonized. All are going to be positive. If you tell me the age of the wound, I'll tell you what organisms are in there, because if you look at acute and chronic wounds, they march through a sequential order of which organisms are present," he said. The increasingly relevant purpose of doing a culture on such a child is to direct antibiotic therapy by determining sensitivities of the involved organisms.

"All children with AD are colonized with staph [Staphylococcus] and strep [Streptococcus], predominantly Staph aureus and Strep pyogenes," he said at a meeting on pediatric hospital medicine.

Recent research findings provide perspective on the course of severe atopic dermatitis, according to Dr. Arbuckle.

Most pivotally, the evidence is mounting that "the problem in atopic dermatitis is … an abnormal barrier function," he said at the meeting, which was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the American Pediatric Association.

In years past, pediatric dermatologists argued with pediatric allergists over the primary etiology of atopic dermatitis, with allergists arguing that immune dysfunction was to blame.

The issue was put to rest when Japanese researchers discovered that the vast majority of children with atopic dermatitis have a genetic defect in filaggrin, a protein that bundles keratin and provides the "mortar" in the brick-and-mortar type construction of the stratum corneum.

"We kind of had a big kumbaya, kissed, and made up. Dermatologists [had always said], well, there is an immune component, but how did the antigen get there? It got there because [the skin] had an improper barrier," Dr. Arbuckle commented.

Microcracks and microfissures, exacerbated by itching prompted by exposed nerve fibers in the epidermis, open the door to allergens, bacteria, and viruses. Compounding the problem is transepidermal water loss 600 times normal in the skin of children and adults with atopic dermatitis.

"We always knew that atopic kids have higher colony counts even when they aren't superinfected," said Dr. Arbuckle. "[It turns out], S. aureus is very adaptable, and upregulates certain adhesion proteins in a very dry environment."

Treatment is imperative in the face of superinfection, because children can harbor a profound bacterial load and develop sepsis, Dr. Arbuckle emphasized.

First-generation cephalosporins are "probably fine" as a first-line choice, but it depends on one's community and culture results, he said.

Once a proper antibiotic is selected, "You've got to restore barrier function. If you don't do this, they're not going to get better," Dr. Arbuckle emphasized.

In Denver's dry climate, he said he prefers petrolatum-based products, the simpler the better to avoid allergic responses. Plain petroleum jelly contains no lanolin or other additives that might cause a reaction. Choose topical steroids in ointment form, because creams often contain propylene glycol, which "stings like Hades," he suggested.

The "biggest failure" of most physicians is undertreatment of pruritus, which is often so severe it can preclude rapid eye movement sleep. Sedating antihistamines should be prescribed for night time and nonsedating antihistamines in the morning.

"Children with atopic dermatitis are perennially, horrifically itchy," he said, noting that he tells residents that if they prescribe an antihistamine as needed, "I will slap you upside the head."

Dr. Arbuckle disclosed no relevant conflicts of interest regarding any product used to treat atopic dermatitis.

DENVER — Any child with atopic dermatitis who has increasing pain, erythema, edema, heat, and purulent exudate is superinfected and requires antibiotics and emollients, according to an expert in pediatric dermatology.

A culture is necessary only for prescribing the correct antibiotic.

"I'm here to plead with you that infection is a clinical diagnosis, not a microbiological diagnosis," said Dr. H. Alan Arbuckle, a dermatologist and pediatrician at the University of Colorado, Denver, and Children's Hospital in Aurora, Colo.

"Doing a culture in a superinfected AD kid is worthless if your goal is to make the diagnosis of infection.

"All of these kids are going to be colonized. All are going to be positive. If you tell me the age of the wound, I'll tell you what organisms are in there, because if you look at acute and chronic wounds, they march through a sequential order of which organisms are present," he said. The increasingly relevant purpose of doing a culture on such a child is to direct antibiotic therapy by determining sensitivities of the involved organisms.

"All children with AD are colonized with staph [Staphylococcus] and strep [Streptococcus], predominantly Staph aureus and Strep pyogenes," he said at a meeting on pediatric hospital medicine.

Recent research findings provide perspective on the course of severe atopic dermatitis, according to Dr. Arbuckle.

Most pivotally, the evidence is mounting that "the problem in atopic dermatitis is … an abnormal barrier function," he said at the meeting, which was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the American Pediatric Association.

In years past, pediatric dermatologists argued with pediatric allergists over the primary etiology of atopic dermatitis, with allergists arguing that immune dysfunction was to blame.

The issue was put to rest when Japanese researchers discovered that the vast majority of children with atopic dermatitis have a genetic defect in filaggrin, a protein that bundles keratin and provides the "mortar" in the brick-and-mortar type construction of the stratum corneum.

"We kind of had a big kumbaya, kissed, and made up. Dermatologists [had always said], well, there is an immune component, but how did the antigen get there? It got there because [the skin] had an improper barrier," Dr. Arbuckle commented.

Microcracks and microfissures, exacerbated by itching prompted by exposed nerve fibers in the epidermis, open the door to allergens, bacteria, and viruses. Compounding the problem is transepidermal water loss 600 times normal in the skin of children and adults with atopic dermatitis.

"We always knew that atopic kids have higher colony counts even when they aren't superinfected," said Dr. Arbuckle. "[It turns out], S. aureus is very adaptable, and upregulates certain adhesion proteins in a very dry environment."

Treatment is imperative in the face of superinfection, because children can harbor a profound bacterial load and develop sepsis, Dr. Arbuckle emphasized.

First-generation cephalosporins are "probably fine" as a first-line choice, but it depends on one's community and culture results, he said.

Once a proper antibiotic is selected, "You've got to restore barrier function. If you don't do this, they're not going to get better," Dr. Arbuckle emphasized.

In Denver's dry climate, he said he prefers petrolatum-based products, the simpler the better to avoid allergic responses. Plain petroleum jelly contains no lanolin or other additives that might cause a reaction. Choose topical steroids in ointment form, because creams often contain propylene glycol, which "stings like Hades," he suggested.

The "biggest failure" of most physicians is undertreatment of pruritus, which is often so severe it can preclude rapid eye movement sleep. Sedating antihistamines should be prescribed for night time and nonsedating antihistamines in the morning.

"Children with atopic dermatitis are perennially, horrifically itchy," he said, noting that he tells residents that if they prescribe an antihistamine as needed, "I will slap you upside the head."

Dr. Arbuckle disclosed no relevant conflicts of interest regarding any product used to treat atopic dermatitis.

DENVER — Any child with atopic dermatitis who has increasing pain, erythema, edema, heat, and purulent exudate is superinfected and requires antibiotics and emollients, according to an expert in pediatric dermatology.

A culture is necessary only for prescribing the correct antibiotic.

"I'm here to plead with you that infection is a clinical diagnosis, not a microbiological diagnosis," said Dr. H. Alan Arbuckle, a dermatologist and pediatrician at the University of Colorado, Denver, and Children's Hospital in Aurora, Colo.

"Doing a culture in a superinfected AD kid is worthless if your goal is to make the diagnosis of infection.

"All of these kids are going to be colonized. All are going to be positive. If you tell me the age of the wound, I'll tell you what organisms are in there, because if you look at acute and chronic wounds, they march through a sequential order of which organisms are present," he said. The increasingly relevant purpose of doing a culture on such a child is to direct antibiotic therapy by determining sensitivities of the involved organisms.

"All children with AD are colonized with staph [Staphylococcus] and strep [Streptococcus], predominantly Staph aureus and Strep pyogenes," he said at a meeting on pediatric hospital medicine.

Recent research findings provide perspective on the course of severe atopic dermatitis, according to Dr. Arbuckle.

Most pivotally, the evidence is mounting that "the problem in atopic dermatitis is … an abnormal barrier function," he said at the meeting, which was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the American Pediatric Association.

In years past, pediatric dermatologists argued with pediatric allergists over the primary etiology of atopic dermatitis, with allergists arguing that immune dysfunction was to blame.

The issue was put to rest when Japanese researchers discovered that the vast majority of children with atopic dermatitis have a genetic defect in filaggrin, a protein that bundles keratin and provides the "mortar" in the brick-and-mortar type construction of the stratum corneum.

"We kind of had a big kumbaya, kissed, and made up. Dermatologists [had always said], well, there is an immune component, but how did the antigen get there? It got there because [the skin] had an improper barrier," Dr. Arbuckle commented.

Microcracks and microfissures, exacerbated by itching prompted by exposed nerve fibers in the epidermis, open the door to allergens, bacteria, and viruses. Compounding the problem is transepidermal water loss 600 times normal in the skin of children and adults with atopic dermatitis.

"We always knew that atopic kids have higher colony counts even when they aren't superinfected," said Dr. Arbuckle. "[It turns out], S. aureus is very adaptable, and upregulates certain adhesion proteins in a very dry environment."

Treatment is imperative in the face of superinfection, because children can harbor a profound bacterial load and develop sepsis, Dr. Arbuckle emphasized.

First-generation cephalosporins are "probably fine" as a first-line choice, but it depends on one's community and culture results, he said.

Once a proper antibiotic is selected, "You've got to restore barrier function. If you don't do this, they're not going to get better," Dr. Arbuckle emphasized.

In Denver's dry climate, he said he prefers petrolatum-based products, the simpler the better to avoid allergic responses. Plain petroleum jelly contains no lanolin or other additives that might cause a reaction. Choose topical steroids in ointment form, because creams often contain propylene glycol, which "stings like Hades," he suggested.

The "biggest failure" of most physicians is undertreatment of pruritus, which is often so severe it can preclude rapid eye movement sleep. Sedating antihistamines should be prescribed for night time and nonsedating antihistamines in the morning.

"Children with atopic dermatitis are perennially, horrifically itchy," he said, noting that he tells residents that if they prescribe an antihistamine as needed, "I will slap you upside the head."

Dr. Arbuckle disclosed no relevant conflicts of interest regarding any product used to treat atopic dermatitis.

SAN DIEGO — While the number of patients diagnosed with atopic disease is on the rise, the general public might be overestimating the prevalence of food allergy, according to Dr. Jonathan M. Spergel.

At a meeting on skin disorders sponsored by Rady Children's Hospital, Dr. Spergel said that Americans perceive the prevalence of food allergy to be in the range of 20%–25%, whereas the actual prevalence ranges from 6%–8% in infants and young children and 2%–3.5% in adults.

The prevalence is higher in those with atopic dermatitis, certain pollen allergens, and latex allergies. "And [as with] all atopic diseases, the prevalence has risen," said Dr. Spergel, allergy section chief in the division of allergy and immunology at the Children's Hospital of Philadelphia. "It probably has quadrupled in the last 20 years."

Conducting a thorough history is vital and should include asking about symptoms, reproducibility, diet, concurrent exercise, use of nonsteroidal anti-inflammatory medications, and timing of reaction. "The timing is an important thing," he said. "If you eat a food and then react 12 hours later, that's not an IgE-mediated reaction. It may be a non-IgE-mediated reaction."

If you suspect an IgE-mediated allergy, broad screening should not be done without supporting history because of the high rate of false positives. Skin prick tests indicate the presence of IgE antibody but not clinical reactivity. They have a sensitivity rate of 90%, a specificity rate of 50%, and a false-positive rate of 20%–60%, depending on the individual food.

"When you do a skin prick test, look for a wheal or a flare about 15 minutes later," Dr. Spergel said. "They work very well. They're relatively painless … and they're safe. The youngest I've done it was on a 1-week-old. He was a newborn in the nursery. They gave him a bottle of milk and he got hives."

Milk, egg, and peanut account for 85% of food allergies, he said. A predictive value on whether a child will react is based on the size of the wheal from the skin test. The age of the child also affects the size. For example, 95% of children aged 0–2 years with a wheal size of 5 mm or greater will react to egg, while a wheal size of 7 mm or greater is the 95% cutoff for older children.

Unproven or experimental tests for food allergy include intradermal skin tests, "which should never be done," Dr. Spergel warned. "It has a risk of systemic reactions and death. And in people who don't have IgE reactions, there is a fair amount of false positives."

Other unproven tests include provocation/neutralization tests, cytotoxic test, applied kinesiology, hair analysis, electrodermal testing, and food-specific IgG or IgG4. "Some of these tests cost a fortune," he said. "They make some labs very rich but they don't work. Do not recommend them."

Elimination diets for 1–6 weeks might be the most useful for patients with atopic dermatitis, gastrointestinal syndromes, or other chronic diseases.

"For food allergy, the 100% test is an oral food challenge where you give a food and see what happens," Dr. Spergel said. "This may need to be supervised by a physician, and you might need emergency medications available."

If testing for specific IgE antibody is negative, reintroduce the food unless a convincing history warrants a supervised challenge. If it is positive, start the patient on an elimination diet, he said.

If the elimination diet is associated with no resolution, reintroduce the food unless a convincing history warrants a supervised challenge. If the elimination diet is associated with resolution, conduct open or single-blind challenge testing, or double-blind, placebo-controlled testing for equivocal open challenges.

Dr. Spergel disclosed that he has received grant support from Novartis and Ception Therapeutics Inc. and speaker fees from GlaxoSmithKline and Astra-Zeneca Pharmaceuticals LP.

SAN DIEGO — While the number of patients diagnosed with atopic disease is on the rise, the general public might be overestimating the prevalence of food allergy, according to Dr. Jonathan M. Spergel.

At a meeting on skin disorders sponsored by Rady Children's Hospital, Dr. Spergel said that Americans perceive the prevalence of food allergy to be in the range of 20%–25%, whereas the actual prevalence ranges from 6%–8% in infants and young children and 2%–3.5% in adults.

The prevalence is higher in those with atopic dermatitis, certain pollen allergens, and latex allergies. "And [as with] all atopic diseases, the prevalence has risen," said Dr. Spergel, allergy section chief in the division of allergy and immunology at the Children's Hospital of Philadelphia. "It probably has quadrupled in the last 20 years."

Conducting a thorough history is vital and should include asking about symptoms, reproducibility, diet, concurrent exercise, use of nonsteroidal anti-inflammatory medications, and timing of reaction. "The timing is an important thing," he said. "If you eat a food and then react 12 hours later, that's not an IgE-mediated reaction. It may be a non-IgE-mediated reaction."

If you suspect an IgE-mediated allergy, broad screening should not be done without supporting history because of the high rate of false positives. Skin prick tests indicate the presence of IgE antibody but not clinical reactivity. They have a sensitivity rate of 90%, a specificity rate of 50%, and a false-positive rate of 20%–60%, depending on the individual food.

"When you do a skin prick test, look for a wheal or a flare about 15 minutes later," Dr. Spergel said. "They work very well. They're relatively painless … and they're safe. The youngest I've done it was on a 1-week-old. He was a newborn in the nursery. They gave him a bottle of milk and he got hives."

Milk, egg, and peanut account for 85% of food allergies, he said. A predictive value on whether a child will react is based on the size of the wheal from the skin test. The age of the child also affects the size. For example, 95% of children aged 0–2 years with a wheal size of 5 mm or greater will react to egg, while a wheal size of 7 mm or greater is the 95% cutoff for older children.

Unproven or experimental tests for food allergy include intradermal skin tests, "which should never be done," Dr. Spergel warned. "It has a risk of systemic reactions and death. And in people who don't have IgE reactions, there is a fair amount of false positives."

Other unproven tests include provocation/neutralization tests, cytotoxic test, applied kinesiology, hair analysis, electrodermal testing, and food-specific IgG or IgG4. "Some of these tests cost a fortune," he said. "They make some labs very rich but they don't work. Do not recommend them."

Elimination diets for 1–6 weeks might be the most useful for patients with atopic dermatitis, gastrointestinal syndromes, or other chronic diseases.

"For food allergy, the 100% test is an oral food challenge where you give a food and see what happens," Dr. Spergel said. "This may need to be supervised by a physician, and you might need emergency medications available."

If testing for specific IgE antibody is negative, reintroduce the food unless a convincing history warrants a supervised challenge. If it is positive, start the patient on an elimination diet, he said.

If the elimination diet is associated with no resolution, reintroduce the food unless a convincing history warrants a supervised challenge. If the elimination diet is associated with resolution, conduct open or single-blind challenge testing, or double-blind, placebo-controlled testing for equivocal open challenges.

Dr. Spergel disclosed that he has received grant support from Novartis and Ception Therapeutics Inc. and speaker fees from GlaxoSmithKline and Astra-Zeneca Pharmaceuticals LP.

SAN DIEGO — While the number of patients diagnosed with atopic disease is on the rise, the general public might be overestimating the prevalence of food allergy, according to Dr. Jonathan M. Spergel.

At a meeting on skin disorders sponsored by Rady Children's Hospital, Dr. Spergel said that Americans perceive the prevalence of food allergy to be in the range of 20%–25%, whereas the actual prevalence ranges from 6%–8% in infants and young children and 2%–3.5% in adults.

The prevalence is higher in those with atopic dermatitis, certain pollen allergens, and latex allergies. "And [as with] all atopic diseases, the prevalence has risen," said Dr. Spergel, allergy section chief in the division of allergy and immunology at the Children's Hospital of Philadelphia. "It probably has quadrupled in the last 20 years."

Conducting a thorough history is vital and should include asking about symptoms, reproducibility, diet, concurrent exercise, use of nonsteroidal anti-inflammatory medications, and timing of reaction. "The timing is an important thing," he said. "If you eat a food and then react 12 hours later, that's not an IgE-mediated reaction. It may be a non-IgE-mediated reaction."

If you suspect an IgE-mediated allergy, broad screening should not be done without supporting history because of the high rate of false positives. Skin prick tests indicate the presence of IgE antibody but not clinical reactivity. They have a sensitivity rate of 90%, a specificity rate of 50%, and a false-positive rate of 20%–60%, depending on the individual food.

"When you do a skin prick test, look for a wheal or a flare about 15 minutes later," Dr. Spergel said. "They work very well. They're relatively painless … and they're safe. The youngest I've done it was on a 1-week-old. He was a newborn in the nursery. They gave him a bottle of milk and he got hives."

Milk, egg, and peanut account for 85% of food allergies, he said. A predictive value on whether a child will react is based on the size of the wheal from the skin test. The age of the child also affects the size. For example, 95% of children aged 0–2 years with a wheal size of 5 mm or greater will react to egg, while a wheal size of 7 mm or greater is the 95% cutoff for older children.

Unproven or experimental tests for food allergy include intradermal skin tests, "which should never be done," Dr. Spergel warned. "It has a risk of systemic reactions and death. And in people who don't have IgE reactions, there is a fair amount of false positives."

Other unproven tests include provocation/neutralization tests, cytotoxic test, applied kinesiology, hair analysis, electrodermal testing, and food-specific IgG or IgG4. "Some of these tests cost a fortune," he said. "They make some labs very rich but they don't work. Do not recommend them."

Elimination diets for 1–6 weeks might be the most useful for patients with atopic dermatitis, gastrointestinal syndromes, or other chronic diseases.

"For food allergy, the 100% test is an oral food challenge where you give a food and see what happens," Dr. Spergel said. "This may need to be supervised by a physician, and you might need emergency medications available."

If testing for specific IgE antibody is negative, reintroduce the food unless a convincing history warrants a supervised challenge. If it is positive, start the patient on an elimination diet, he said.

If the elimination diet is associated with no resolution, reintroduce the food unless a convincing history warrants a supervised challenge. If the elimination diet is associated with resolution, conduct open or single-blind challenge testing, or double-blind, placebo-controlled testing for equivocal open challenges.

Dr. Spergel disclosed that he has received grant support from Novartis and Ception Therapeutics Inc. and speaker fees from GlaxoSmithKline and Astra-Zeneca Pharmaceuticals LP.

Itch, also known as pruritus, is defined as "an unpleasant cutaneous sensation which provokes the desire to scratch."1 Itch may be classified by its mechanisms. It is typically divided into one of several categories: pruritoceptive, neurogenic, neuropathic, and psychogenic.2 Pruritoceptive itch originates in the skin, is mediated locally by molecules such as histamine, and is transmitted by C nerve fibers. Neurogenic itch is caused by circulating mediators acting centrally, such as opioid neuropeptides in cholestasis acting centrally on opioid receptors. Neuropathic itch is caused by peripheral or central nervous system (CNS) lesions along the afferent neural pathway leading from the skin to the brain. Finally, psychogenic itch is secondary to primary psychiatric disorders, such as delusions of parasitosis. It is possible to have pruritus of more than one type simultaneously. For example, a patient with psoriasis also may have generalized pruritus secondary to cholestasis. When a pruritic patient is first seen by a physician, a thorough history and general physical examination are completed and the physician typically looks for primary cutaneous lesions that could provide clues to the etiology of the patient's complaint. If found, lesions likely would lead the physician to consider a differential diagnosis consisting mostly of pruritoceptive disorders. If no lesions are present, the condition is known as pruritus sine materia. The next logical step would be to evaluate the patient for an internal etiology for the itching sensation, such as uremia. Both pruritoceptive and neurogenic itch are mediated by identifiable organic causes. Challenging cases arise when patients present with no primary cutaneous lesions and their extensive medical workup does not reveal any abnormalities. The physician may be tempted to conclude that the pruritus is secondary to some underlying psychiatric or supratentorial process and refer the patient to a mental health professional; however, this conclusion may be premature because neuropathic pruritus also is a possibility. If psychogenic pruritus is ultimately diagnosed, optimal care for patients results from a dermatologist working closely with a mental health professional. Therefore, it is beneficial for dermatologists to be updated on the management of these patients. This article reviews and updates diagnostic possibilities and available therapeutic options for patients with pruritus that exhibit no identifiable primary cutaneous lesions and have no apparent systemic medical condition accounting for their symptoms.

Neuropathic and Psychogenic Pruritus
To review the literature on pruritus sine materia, a MEDLINE/PubMed search was performed for English language articles and abstracts from 1960 to 2006 containing the keywords neuropathic, psychogenic, pruritus, itch, and therapy. Additional articles were obtained by reviewing the references cited in articles retrieved using the MEDLINE search. Neuropathic Pruritus—The sensation of itch is carried by specialized C fibers that originate in the skin and carry information to the dorsal horn of the spinal cord.2 These fibers are anatomically indistinct from fibers carrying pain signals. Itch impulses are transmitted via the spinothalamic tract to the thalamus and then to the somatosensory cortex. Pruritus as a solitary or dominant symptom following CNS injury is rare but well-documented in the medical literature. Multiple CNS lesions have been implicated, including brain tumors, aneurysms, abscesses, multiple sclerosis, stroke, transverse myelitis, and spinal cord hemangioma, as well as postherpetic neuralgia.3-9 The pruritus that results may be intermittent or constant and onset may or may not be immediate. The distribution often corresponds to a particular spinal segment but may be either bilateral or unilateral. Often a sensory deficit or an aberration in sensory perception such as allodynia (nonpainful stimuli evoke pain), allokinesis (sensation of itch produced by innocuous stimuli that would not ordinarily induce itch), or hyperpathia (evoked pain grossly out of proportion to painful stimuli) is present. One example of neuropathic pruritus is brachioradial pruritus, which is characteristically localized to the dorsolateral aspect of the upper arm.10 The etiology is unknown, but one study demonstrated cervical spine pathology on radiographs corresponding to the location of pruritus in 11 of 22 patients.11 Notalgia paresthetica, characterized by pruritus on the back in a dermatomal distribution and occasionally associated with pain, paresthesia, or hyperesthesia, is thought to be attributable to neurologic pathology at the spinal level corresponding to the affected dermatomes.12 Because neuropathic pruritus is caused by neuronal damage anywhere along the afferent neural pathway, it can occur in a specific dermatomal pattern or in a more broad distribution. Therefore, a careful history and a high index of suspicion are required for diagnosis in a patient with no evidence of pruritoceptive or neurogenic pruritus. Psychogenic Pruritus—It is estimated that up to 75% of dermatology patients have a psychogenic component to their skin complaints.13 Most psychogenic skin disorders have an underlying psychiatric component of depression, anxiety, obsessive-compulsive disorder (OCD), or psychosis.14 Dermatologic diagnoses that are considered to have a primary psychogenic etiology include delusions of parasitosis, neurotic excoriations, and dermatitis artefacta. Some conditions, such as prurigo nodularis and lichen simplex chronicus, have both psychogenic and physiologic etiology; these disorders have an organic basis but also are strongly affected by psychologic factors. Because pruritus may be associated with one or more underlying psychiatric diagnoses, it is often difficult to determine if the psychiatric disorder is the cause of the patient's pruritus. Depression is commonly associated with psychogenic pruritus.15 These patients with psychogenic pruritus secondary to depression also may present with prominent anxiety and agitation. Careful pharmacologic management is essential, as use of anxiolytic agents with depressant effects (ie, older benzodiazepines such as diazepam and chlordiazepoxide) in the absence of antidepressant therapy may exacerbate the underlying depression.16 Dopamine pathways in serious depression also have been implicated in the development of chronic tactile hallucinations that are manifested by sensations of itching, crawling, and burning in the absence of delusions.17 Patients with monosymptomatic hypochondriacal psychosis have a delusional preoccupation with a solitary hypochondriacal ideation (eg, an erroneous belief that one's skin is infested with parasites). Hallucinations experienced as formication, a sensation of crawling, biting, or stinging, frequently accompany the delusion. These patients typically do not have any other abnormal psychiatric function.18 The primary etiology is a psychiatric disorder, but healthy skin may be secondarily damaged from manipulation by the patient. The delusion occasionally is experienced by the patient's spouse or a close relative or friend, as they come to believe in the delusion. Dopamine pathways have been implicated in hallucinations and delusions, as dopamine-blocking drugs are effective in treating these symptoms.19 Neurotic excoriations also have a primarily psychogenic etiology. Patients with neurotic excoriations are driven to pick, scratch, or rub healthy skin or skin with minor irregularities, such as minor blemishes. The lesions vary in size from a few millimeters in diameter to large craters and often are weeping, crusting, or scarring, with surrounding postinflammatory pigmentation changes.20 Interestingly, pruritus is not always predominant in these patients. This behavior can lead to serious complications, such as chronic skin ulcers, extensive scarring, and abscesses. Neurotic excoriations often are associated with depression and OCD.21,22 If associated with OCD, despite full awareness of their behavior and the potential consequences, patients find themselves unable to cease the destructive activity. Dermatitis artefacta differs from neurotic excoriations in that the patients deny their participation in the development of the lesions and usually use more than just their fingernails (eg, sharp instruments, lighted cigarettes) to inflict damage on their skin. These patients typically are unable to give a reliable history regarding the evolution of the lesions. The lesions have varying morphology and may present as blisters, purpura, ulcers, erythema, edema, sinuses, or nodules, depending on how they were created by the patient.23 In a study of patients with different forms of self-inflicted dermatoses, depressive illness was found in 46% (12/26).24 

Treatment Pharmacologic Therapy—Despite the different etiologies of neuropathic and psychogenic pruritus, similar classes of pharmacologic and adjunctive therapies are useful for both. A simple approach to therapy for these disorders is to divide treatment types, namely topical, supportive, and CNS-directed therapies. Topical therapy consists of medications directed at the skin itself. Because the etiology of neuropathic and psychogenic pruritus is not primarily cutaneous, it seems unlikely that topical therapy would be helpful. However, topical therapy may be useful in patients with overlapping central and pruritoceptive pruritus. In addition, the empirical use of topical agents such as a eutectic mixture of local anesthetics, an anesthetic agent combining lidocaine 2.5% and prilocaine 2.5%, can help distinguish central from pruritoceptive pruritus. In addition, anesthetic cream has been effective in treating notalgia paresthetica.25 Capsaicin, an alkaloid isolated from red pepper plants, relieves pruritus by depleting substance P from cutaneous nerve endings involved in pain and itch, resulting in the inhibition of itch signal transmission from the skin to the CNS.26 Side effects include localized feelings of burning, stinging, and hyperalgesia. Pretreatment with topical anesthetic creams may reduce these side effects.27 Capsaicin has been shown to be effective for notalgia paresthetica,28,29 brachioradial pruritus,³⁰ and prurigo nodularis.31 Supportive therapies combined with other therapeutic options augment overall management of these patients. Occlusion of pruritic areas with Unna boot, Duoderm, or nonlatex gloves may help the patient break the itch-scratch cycle.13 If a patient has identifiable discrete lesions that are pruritic, such as prurigo nodularis or lichen simplex chronicus, intralesional steroid injections, laser therapy, or cryotherapy may control the pruritus associated with these lesions.13,15,32-34 Occlusion alone or combined with topical and intralesional corticosteroid therapy is effective for notalgia paresthetica.15 Goeckerman treatment, consisting of daily application of coal tar and UVB or psoralen plus UVA phototherapy, may provide benefit to patients with pruritus sine materia as well as prurigo nodularis and lichen simplex chronicus.13,35,36 Central nervous system–directed therapy in the treatment of neuropathic and psychogenic pruritus usually targets the suspected underlying etiology of the pruritus, such as depression and anxiety. Often, however, psychotropic agents are empirically used. Many of the same medications that show efficacy in the treatment of neuropathic pain also demonstrate therapeutic effect in neuropathic pruritus. Other than tricyclic antidepressants, there have been no controlled studies; therefore, the merits of most of these options are based on anecdotal reports. Carbamazepine, an antiepileptic agent, is beneficial in pruritus and dysesthesia in multiple sclerosis.37 Aplastic anemia and agranulocytosis rarely have been reported. Even though there is a low incidence of these side effects, hematologic testing at baseline (pretreatment) as well as periodic monitoring is recommended. Oxcarbazepine, an analogue of carbamazepine, has efficacy in the treatment of brachioradial pruritus.38 Oxcarbazepine lacks the hematologic risks associated with carbamazepine and does not require monitoring, but it does carry a risk of hyponatremia and Stevens-Johnson syndrome. Lamotrigine, another antiepileptic agent, is of benefit in brachioradial pruritus but also has been reported to cause Stevens-Johnson syndrome.10 Therefore, oxcarbazepine and lamotrigine should be discontinued at the first sign of drug eruption. Gabapentin, a structural analogue of the neurotransmitter γ-aminobutyric acid, treats epilepsy and postherpetic neuralgia. It shows efficacy in the treatment of brachioradial pruritus, pruritus induced by multiple sclerosis, and pruritus of unknown origin.39-42 Gabapentin should not be discontinued abruptly but rather should be tapered gradually to prevent withdrawal-related adverse events. Thalidomide, an immunomodulatory drug, has shown benefit in treating prurigo nodularis.43-45 It is a powerful central depressant and has a sedative-related property. In addition, it inhibits C-fiber function and therefore may have a primary antipruritic effect. It also has anti- inflammatory action by which it inhibits synthesis of tumor necrosis factor α, a cytokine that may induce pruritus. The major adverse side effects of thalidomide are severe fatigue, peripheral neuropathy, and teratogenicity. Antidepressants have demonstrated efficacy in reducing pruritus, presumably through neurotransmitter modulation. Tricyclic compounds, such as doxepin, and selective serotonin reuptake inhibitors (SSRIs) have been beneficial in psychogenic pruritus. Tricyclic antidepressants have antihistaminic effects and inhibit the reuptake of norepinephrine and serotonin in the CNS and peripheral nervous system. Although the sedative and antihistaminic effects of these drugs occur promptly, the antidepressive effects can take 2 weeks or longer to manifest after reaching an adequate dose. However, the negative side-effect profile of tricyclic antidepressants, including cardiac conduction abnormalities, seizures, and drug interactions, limits their clinical utility. Amitriptyline is effective in the treatment of postherpetic neuralgia and brachioradial pruritus. Doxepin has shown benefit in the treatment of neurotic excoriations.46 Doses of these agents should be more conservative in elderly patients. Selective serotonin reuptake inhibitors specifically inhibit serotonin reuptake and increase serotonin synaptic activity. Examples of drugs in this class are fluoxetine, paroxetine, and sertraline. These drugs have fewer problems with the sedative or antihistaminic properties compared with the tricyclic antidepressants, which improves their safety profile, but their antidepressant effects also can take weeks to manifest. Selective serotonin reuptake inhibitors target many of the underlying psychopathologies in psychogenic pruritus, such as depression, anxiety, and OCD. There have been many reports of their efficacy in the treatment of neurotic excoriations.21,47-56 Although these drugs are associated with fewer serious adverse events than tricyclic antidepressants, they can be associated with side effects that patients may find distressing, including nervousness, insomnia, fatigue, weight gain, and sexual dysfunction. Children or adolescents taking any of the SSRIs should be monitored closely for increased depression and suicidal ideation. In addition, if the medication is discontinued abruptly, a withdrawal syndrome can occur in rare cases, resulting in dizziness, tremor, anxiety, and dysphoria, which may be minimized or avoided by gradually tapering the dose. Mirtazapine is a noradrenergic and specific serotonergic antidepressant and antihistamine that has been used for the treatment of psychogenic pruritus. It facilitates norepinephrine neurotransmission and selectively increases serotonin neurotransmission. Compared with other antidepressants used for this purpose, mirtazapine has a more favorable side-effect profile, with fewer incidences of nausea and sexual dysfunction. However, as with SSRIs, children or adolescents taking mirtazapine should be monitored for rare occurrence of increased depression and suicidal ideation. Anecdotally, mirtazapine has been effective in reducing nocturnal itching in a case of chronic neurotic excoriation, with the onset of action within 2 weeks.57 Discontinuation of mirtazapine resulted in recurrence of pruritus. Pimozide is an antipsychotic medication that is useful in the treatment of delusions of parasitosis.58 Its effect in reducing delusions is mediated primarily by its antidopaminergic effect. However, the antipruritic effect of pimozide may be attributed to its opiate-blocking effect.59 As with other antipsychotic agents, there are many potential side effects, including prolongation of the QT interval; ventricular arrhythmias; neuroleptic malignant syndrome; and extrapyramidal side effects, such as restlessness, acute dystonic reactions, Parkinsonlike symptoms, and tardive dyskinesia. These effects usually are dependent on the dose and length of use and are not always reversible on discontinuation of the drug. The extrapyramidal side effects of pimozide may be minimized with the concurrent use of diphenhydramine. Olanzapine, an atypical antipsychotic agent, has shown efficacy in treating neurotic excoriations in nonpsychotic patients.60,61 Caution should be used when prescribing this drug in elderly patients, as the risk of cerebrovascular accidents and dementia-related psychosis is higher in this population. Other adverse side effects include hyperglycemia, diabetes mellitus, neuroleptic malignant syndrome, and tardive dyskinesia. Nonpharmacologic Therapy—Some nonpharmacologic therapies have been anecdotally shown to benefit patients with pruritus of neurogenic and psychogenic etiology. When the underlying psychiatric diagnosis is obvious to the physician, he/she must first consider if the patient should be confronted with the diagnosis. If the patient is unable to recognize his/her emotional distress, then early confrontation may produce anxiety and anger, resulting in loss of therapeutic rapport.62 Rather, a strong physician-patient alliance is essential.63 Once a trusting relationship has been established, psychotherapeutic options may be introduced. In dermatitis artefacta, a supportive and empathic approach is recommended, avoiding discussion of the self-inflicted nature of the lesions.23,64-67 When a strong therapeutic relationship has been developed, a more insight-oriented psychotherapeutic approach may be helpful.65,68 Some patients with pruritus of a psychogenic etiology may have awareness of their participation in the development of skin lesions, such as patients with neurotic excoriations. Despite this awareness, a trusting physician-patient relationship should still be cultivated before broaching a discussion about participation in their disease.69 Once a trusting physician-patient alliance is established, the underlying psychopathology may be openly discussed and treated, and nonpharmacologic psychocutaneous interventions may be discussed. The benefits of these interventions appear to result from stress reduction, the patient's increased sense of control of the illness, and normalization of the psychoneuroendocrine function.70 More importantly, these therapeutic strategies do not cause the patient any harm and are likely to improve the patient's overall quality of life. Cognitive behavior psychotherapy and behavior techniques coupled with biofeedback, minocycline, and sertraline were effective in reducing picking behavior in a young woman with acne excoriée.70 Most reports of the effectiveness of psychotherapy are anecdotal. However, healing of neurotic excoriation lesions has been reported for up to 5 years after cessation of therapy in 17 of 20 patients who underwent psychotherapy with insight-oriented and behavior components.71 Hypnotic trance is defined as a heightened state of focus that can be helpful in reducing pruritus while simultaneously inducing favorable physiologic changes.70 Direct suggestion while in the hypnotic state is the most commonly used method of decreasing pruritus.72 In addition, retraining the subconscious through hypnosis to replace a destructive habit pattern with a more constructive one, called symptom substitution, can be helpful in patients with self-inflicted lesions.73 There have been 2 reported cases of control of acne excoriée using posthypnotic suggestion.74

Comment There is considerable overlap between neuropathic disorders and psychologic factors. As this review demonstrates, the presentation of neuropathic and psychogenic pruritus can be similar. In addition, therapy that is effective for one disorder often can be effective for the other disorder. However, despite the variety of medications used to treat these disorders, it is an underdeveloped field. There is a paucity of controlled studies, and most reports of efficacy are based on anecdotal evidence. As a result, it is difficult to practice evidence-based medicine when treating patients with neuropathic and psychogenic pruritus. Neuropathic and psychogenic pruritus constitutes an area of medicine in which expertise from specialists in the fields of dermatology, psychiatry, and neurology would be immensely helpful. Although a dermatologic approach to treating these conditions is effective, there also is benefit in therapies typically used in psychiatry and neurology. Therefore, interdisciplinary cooperation between these 3 fields will likely result in optimal treatment of patients with neurogenic and psychogenic pruritus. When approaching treatment of patients with these conditions, it may be beneficial to try a multimodality therapeutic approach, using agents from several medical disciplines. 

Conclusion
The diagnosis and treatment of neurogenic and psychogenic pruritus were reviewed and updated. Evidence-based studies regarding therapies available for these conditions are sparse. Despite considerable overlap of dermatology, psychiatry, and neurology, pruritus sine materia is a neglected area of medicine, both clinically and scientifically. More interdisciplinary cooperation and studies are essential for further progress. 

Itch, also known as pruritus, is defined as "an unpleasant cutaneous sensation which provokes the desire to scratch."1 Itch may be classified by its mechanisms. It is typically divided into one of several categories: pruritoceptive, neurogenic, neuropathic, and psychogenic.2 Pruritoceptive itch originates in the skin, is mediated locally by molecules such as histamine, and is transmitted by C nerve fibers. Neurogenic itch is caused by circulating mediators acting centrally, such as opioid neuropeptides in cholestasis acting centrally on opioid receptors. Neuropathic itch is caused by peripheral or central nervous system (CNS) lesions along the afferent neural pathway leading from the skin to the brain. Finally, psychogenic itch is secondary to primary psychiatric disorders, such as delusions of parasitosis. It is possible to have pruritus of more than one type simultaneously. For example, a patient with psoriasis also may have generalized pruritus secondary to cholestasis. When a pruritic patient is first seen by a physician, a thorough history and general physical examination are completed and the physician typically looks for primary cutaneous lesions that could provide clues to the etiology of the patient's complaint. If found, lesions likely would lead the physician to consider a differential diagnosis consisting mostly of pruritoceptive disorders. If no lesions are present, the condition is known as pruritus sine materia. The next logical step would be to evaluate the patient for an internal etiology for the itching sensation, such as uremia. Both pruritoceptive and neurogenic itch are mediated by identifiable organic causes. Challenging cases arise when patients present with no primary cutaneous lesions and their extensive medical workup does not reveal any abnormalities. The physician may be tempted to conclude that the pruritus is secondary to some underlying psychiatric or supratentorial process and refer the patient to a mental health professional; however, this conclusion may be premature because neuropathic pruritus also is a possibility. If psychogenic pruritus is ultimately diagnosed, optimal care for patients results from a dermatologist working closely with a mental health professional. Therefore, it is beneficial for dermatologists to be updated on the management of these patients. This article reviews and updates diagnostic possibilities and available therapeutic options for patients with pruritus that exhibit no identifiable primary cutaneous lesions and have no apparent systemic medical condition accounting for their symptoms.

Neuropathic and Psychogenic Pruritus
To review the literature on pruritus sine materia, a MEDLINE/PubMed search was performed for English language articles and abstracts from 1960 to 2006 containing the keywords neuropathic, psychogenic, pruritus, itch, and therapy. Additional articles were obtained by reviewing the references cited in articles retrieved using the MEDLINE search. Neuropathic Pruritus—The sensation of itch is carried by specialized C fibers that originate in the skin and carry information to the dorsal horn of the spinal cord.2 These fibers are anatomically indistinct from fibers carrying pain signals. Itch impulses are transmitted via the spinothalamic tract to the thalamus and then to the somatosensory cortex. Pruritus as a solitary or dominant symptom following CNS injury is rare but well-documented in the medical literature. Multiple CNS lesions have been implicated, including brain tumors, aneurysms, abscesses, multiple sclerosis, stroke, transverse myelitis, and spinal cord hemangioma, as well as postherpetic neuralgia.3-9 The pruritus that results may be intermittent or constant and onset may or may not be immediate. The distribution often corresponds to a particular spinal segment but may be either bilateral or unilateral. Often a sensory deficit or an aberration in sensory perception such as allodynia (nonpainful stimuli evoke pain), allokinesis (sensation of itch produced by innocuous stimuli that would not ordinarily induce itch), or hyperpathia (evoked pain grossly out of proportion to painful stimuli) is present. One example of neuropathic pruritus is brachioradial pruritus, which is characteristically localized to the dorsolateral aspect of the upper arm.10 The etiology is unknown, but one study demonstrated cervical spine pathology on radiographs corresponding to the location of pruritus in 11 of 22 patients.11 Notalgia paresthetica, characterized by pruritus on the back in a dermatomal distribution and occasionally associated with pain, paresthesia, or hyperesthesia, is thought to be attributable to neurologic pathology at the spinal level corresponding to the affected dermatomes.12 Because neuropathic pruritus is caused by neuronal damage anywhere along the afferent neural pathway, it can occur in a specific dermatomal pattern or in a more broad distribution. Therefore, a careful history and a high index of suspicion are required for diagnosis in a patient with no evidence of pruritoceptive or neurogenic pruritus. Psychogenic Pruritus—It is estimated that up to 75% of dermatology patients have a psychogenic component to their skin complaints.13 Most psychogenic skin disorders have an underlying psychiatric component of depression, anxiety, obsessive-compulsive disorder (OCD), or psychosis.14 Dermatologic diagnoses that are considered to have a primary psychogenic etiology include delusions of parasitosis, neurotic excoriations, and dermatitis artefacta. Some conditions, such as prurigo nodularis and lichen simplex chronicus, have both psychogenic and physiologic etiology; these disorders have an organic basis but also are strongly affected by psychologic factors. Because pruritus may be associated with one or more underlying psychiatric diagnoses, it is often difficult to determine if the psychiatric disorder is the cause of the patient's pruritus. Depression is commonly associated with psychogenic pruritus.15 These patients with psychogenic pruritus secondary to depression also may present with prominent anxiety and agitation. Careful pharmacologic management is essential, as use of anxiolytic agents with depressant effects (ie, older benzodiazepines such as diazepam and chlordiazepoxide) in the absence of antidepressant therapy may exacerbate the underlying depression.16 Dopamine pathways in serious depression also have been implicated in the development of chronic tactile hallucinations that are manifested by sensations of itching, crawling, and burning in the absence of delusions.17 Patients with monosymptomatic hypochondriacal psychosis have a delusional preoccupation with a solitary hypochondriacal ideation (eg, an erroneous belief that one's skin is infested with parasites). Hallucinations experienced as formication, a sensation of crawling, biting, or stinging, frequently accompany the delusion. These patients typically do not have any other abnormal psychiatric function.18 The primary etiology is a psychiatric disorder, but healthy skin may be secondarily damaged from manipulation by the patient. The delusion occasionally is experienced by the patient's spouse or a close relative or friend, as they come to believe in the delusion. Dopamine pathways have been implicated in hallucinations and delusions, as dopamine-blocking drugs are effective in treating these symptoms.19 Neurotic excoriations also have a primarily psychogenic etiology. Patients with neurotic excoriations are driven to pick, scratch, or rub healthy skin or skin with minor irregularities, such as minor blemishes. The lesions vary in size from a few millimeters in diameter to large craters and often are weeping, crusting, or scarring, with surrounding postinflammatory pigmentation changes.20 Interestingly, pruritus is not always predominant in these patients. This behavior can lead to serious complications, such as chronic skin ulcers, extensive scarring, and abscesses. Neurotic excoriations often are associated with depression and OCD.21,22 If associated with OCD, despite full awareness of their behavior and the potential consequences, patients find themselves unable to cease the destructive activity. Dermatitis artefacta differs from neurotic excoriations in that the patients deny their participation in the development of the lesions and usually use more than just their fingernails (eg, sharp instruments, lighted cigarettes) to inflict damage on their skin. These patients typically are unable to give a reliable history regarding the evolution of the lesions. The lesions have varying morphology and may present as blisters, purpura, ulcers, erythema, edema, sinuses, or nodules, depending on how they were created by the patient.23 In a study of patients with different forms of self-inflicted dermatoses, depressive illness was found in 46% (12/26).24 

Treatment Pharmacologic Therapy—Despite the different etiologies of neuropathic and psychogenic pruritus, similar classes of pharmacologic and adjunctive therapies are useful for both. A simple approach to therapy for these disorders is to divide treatment types, namely topical, supportive, and CNS-directed therapies. Topical therapy consists of medications directed at the skin itself. Because the etiology of neuropathic and psychogenic pruritus is not primarily cutaneous, it seems unlikely that topical therapy would be helpful. However, topical therapy may be useful in patients with overlapping central and pruritoceptive pruritus. In addition, the empirical use of topical agents such as a eutectic mixture of local anesthetics, an anesthetic agent combining lidocaine 2.5% and prilocaine 2.5%, can help distinguish central from pruritoceptive pruritus. In addition, anesthetic cream has been effective in treating notalgia paresthetica.25 Capsaicin, an alkaloid isolated from red pepper plants, relieves pruritus by depleting substance P from cutaneous nerve endings involved in pain and itch, resulting in the inhibition of itch signal transmission from the skin to the CNS.26 Side effects include localized feelings of burning, stinging, and hyperalgesia. Pretreatment with topical anesthetic creams may reduce these side effects.27 Capsaicin has been shown to be effective for notalgia paresthetica,28,29 brachioradial pruritus,³⁰ and prurigo nodularis.31 Supportive therapies combined with other therapeutic options augment overall management of these patients. Occlusion of pruritic areas with Unna boot, Duoderm, or nonlatex gloves may help the patient break the itch-scratch cycle.13 If a patient has identifiable discrete lesions that are pruritic, such as prurigo nodularis or lichen simplex chronicus, intralesional steroid injections, laser therapy, or cryotherapy may control the pruritus associated with these lesions.13,15,32-34 Occlusion alone or combined with topical and intralesional corticosteroid therapy is effective for notalgia paresthetica.15 Goeckerman treatment, consisting of daily application of coal tar and UVB or psoralen plus UVA phototherapy, may provide benefit to patients with pruritus sine materia as well as prurigo nodularis and lichen simplex chronicus.13,35,36 Central nervous system–directed therapy in the treatment of neuropathic and psychogenic pruritus usually targets the suspected underlying etiology of the pruritus, such as depression and anxiety. Often, however, psychotropic agents are empirically used. Many of the same medications that show efficacy in the treatment of neuropathic pain also demonstrate therapeutic effect in neuropathic pruritus. Other than tricyclic antidepressants, there have been no controlled studies; therefore, the merits of most of these options are based on anecdotal reports. Carbamazepine, an antiepileptic agent, is beneficial in pruritus and dysesthesia in multiple sclerosis.37 Aplastic anemia and agranulocytosis rarely have been reported. Even though there is a low incidence of these side effects, hematologic testing at baseline (pretreatment) as well as periodic monitoring is recommended. Oxcarbazepine, an analogue of carbamazepine, has efficacy in the treatment of brachioradial pruritus.38 Oxcarbazepine lacks the hematologic risks associated with carbamazepine and does not require monitoring, but it does carry a risk of hyponatremia and Stevens-Johnson syndrome. Lamotrigine, another antiepileptic agent, is of benefit in brachioradial pruritus but also has been reported to cause Stevens-Johnson syndrome.10 Therefore, oxcarbazepine and lamotrigine should be discontinued at the first sign of drug eruption. Gabapentin, a structural analogue of the neurotransmitter γ-aminobutyric acid, treats epilepsy and postherpetic neuralgia. It shows efficacy in the treatment of brachioradial pruritus, pruritus induced by multiple sclerosis, and pruritus of unknown origin.39-42 Gabapentin should not be discontinued abruptly but rather should be tapered gradually to prevent withdrawal-related adverse events. Thalidomide, an immunomodulatory drug, has shown benefit in treating prurigo nodularis.43-45 It is a powerful central depressant and has a sedative-related property. In addition, it inhibits C-fiber function and therefore may have a primary antipruritic effect. It also has anti- inflammatory action by which it inhibits synthesis of tumor necrosis factor α, a cytokine that may induce pruritus. The major adverse side effects of thalidomide are severe fatigue, peripheral neuropathy, and teratogenicity. Antidepressants have demonstrated efficacy in reducing pruritus, presumably through neurotransmitter modulation. Tricyclic compounds, such as doxepin, and selective serotonin reuptake inhibitors (SSRIs) have been beneficial in psychogenic pruritus. Tricyclic antidepressants have antihistaminic effects and inhibit the reuptake of norepinephrine and serotonin in the CNS and peripheral nervous system. Although the sedative and antihistaminic effects of these drugs occur promptly, the antidepressive effects can take 2 weeks or longer to manifest after reaching an adequate dose. However, the negative side-effect profile of tricyclic antidepressants, including cardiac conduction abnormalities, seizures, and drug interactions, limits their clinical utility. Amitriptyline is effective in the treatment of postherpetic neuralgia and brachioradial pruritus. Doxepin has shown benefit in the treatment of neurotic excoriations.46 Doses of these agents should be more conservative in elderly patients. Selective serotonin reuptake inhibitors specifically inhibit serotonin reuptake and increase serotonin synaptic activity. Examples of drugs in this class are fluoxetine, paroxetine, and sertraline. These drugs have fewer problems with the sedative or antihistaminic properties compared with the tricyclic antidepressants, which improves their safety profile, but their antidepressant effects also can take weeks to manifest. Selective serotonin reuptake inhibitors target many of the underlying psychopathologies in psychogenic pruritus, such as depression, anxiety, and OCD. There have been many reports of their efficacy in the treatment of neurotic excoriations.21,47-56 Although these drugs are associated with fewer serious adverse events than tricyclic antidepressants, they can be associated with side effects that patients may find distressing, including nervousness, insomnia, fatigue, weight gain, and sexual dysfunction. Children or adolescents taking any of the SSRIs should be monitored closely for increased depression and suicidal ideation. In addition, if the medication is discontinued abruptly, a withdrawal syndrome can occur in rare cases, resulting in dizziness, tremor, anxiety, and dysphoria, which may be minimized or avoided by gradually tapering the dose. Mirtazapine is a noradrenergic and specific serotonergic antidepressant and antihistamine that has been used for the treatment of psychogenic pruritus. It facilitates norepinephrine neurotransmission and selectively increases serotonin neurotransmission. Compared with other antidepressants used for this purpose, mirtazapine has a more favorable side-effect profile, with fewer incidences of nausea and sexual dysfunction. However, as with SSRIs, children or adolescents taking mirtazapine should be monitored for rare occurrence of increased depression and suicidal ideation. Anecdotally, mirtazapine has been effective in reducing nocturnal itching in a case of chronic neurotic excoriation, with the onset of action within 2 weeks.57 Discontinuation of mirtazapine resulted in recurrence of pruritus. Pimozide is an antipsychotic medication that is useful in the treatment of delusions of parasitosis.58 Its effect in reducing delusions is mediated primarily by its antidopaminergic effect. However, the antipruritic effect of pimozide may be attributed to its opiate-blocking effect.59 As with other antipsychotic agents, there are many potential side effects, including prolongation of the QT interval; ventricular arrhythmias; neuroleptic malignant syndrome; and extrapyramidal side effects, such as restlessness, acute dystonic reactions, Parkinsonlike symptoms, and tardive dyskinesia. These effects usually are dependent on the dose and length of use and are not always reversible on discontinuation of the drug. The extrapyramidal side effects of pimozide may be minimized with the concurrent use of diphenhydramine. Olanzapine, an atypical antipsychotic agent, has shown efficacy in treating neurotic excoriations in nonpsychotic patients.60,61 Caution should be used when prescribing this drug in elderly patients, as the risk of cerebrovascular accidents and dementia-related psychosis is higher in this population. Other adverse side effects include hyperglycemia, diabetes mellitus, neuroleptic malignant syndrome, and tardive dyskinesia. Nonpharmacologic Therapy—Some nonpharmacologic therapies have been anecdotally shown to benefit patients with pruritus of neurogenic and psychogenic etiology. When the underlying psychiatric diagnosis is obvious to the physician, he/she must first consider if the patient should be confronted with the diagnosis. If the patient is unable to recognize his/her emotional distress, then early confrontation may produce anxiety and anger, resulting in loss of therapeutic rapport.62 Rather, a strong physician-patient alliance is essential.63 Once a trusting relationship has been established, psychotherapeutic options may be introduced. In dermatitis artefacta, a supportive and empathic approach is recommended, avoiding discussion of the self-inflicted nature of the lesions.23,64-67 When a strong therapeutic relationship has been developed, a more insight-oriented psychotherapeutic approach may be helpful.65,68 Some patients with pruritus of a psychogenic etiology may have awareness of their participation in the development of skin lesions, such as patients with neurotic excoriations. Despite this awareness, a trusting physician-patient relationship should still be cultivated before broaching a discussion about participation in their disease.69 Once a trusting physician-patient alliance is established, the underlying psychopathology may be openly discussed and treated, and nonpharmacologic psychocutaneous interventions may be discussed. The benefits of these interventions appear to result from stress reduction, the patient's increased sense of control of the illness, and normalization of the psychoneuroendocrine function.70 More importantly, these therapeutic strategies do not cause the patient any harm and are likely to improve the patient's overall quality of life. Cognitive behavior psychotherapy and behavior techniques coupled with biofeedback, minocycline, and sertraline were effective in reducing picking behavior in a young woman with acne excoriée.70 Most reports of the effectiveness of psychotherapy are anecdotal. However, healing of neurotic excoriation lesions has been reported for up to 5 years after cessation of therapy in 17 of 20 patients who underwent psychotherapy with insight-oriented and behavior components.71 Hypnotic trance is defined as a heightened state of focus that can be helpful in reducing pruritus while simultaneously inducing favorable physiologic changes.70 Direct suggestion while in the hypnotic state is the most commonly used method of decreasing pruritus.72 In addition, retraining the subconscious through hypnosis to replace a destructive habit pattern with a more constructive one, called symptom substitution, can be helpful in patients with self-inflicted lesions.73 There have been 2 reported cases of control of acne excoriée using posthypnotic suggestion.74

Comment There is considerable overlap between neuropathic disorders and psychologic factors. As this review demonstrates, the presentation of neuropathic and psychogenic pruritus can be similar. In addition, therapy that is effective for one disorder often can be effective for the other disorder. However, despite the variety of medications used to treat these disorders, it is an underdeveloped field. There is a paucity of controlled studies, and most reports of efficacy are based on anecdotal evidence. As a result, it is difficult to practice evidence-based medicine when treating patients with neuropathic and psychogenic pruritus. Neuropathic and psychogenic pruritus constitutes an area of medicine in which expertise from specialists in the fields of dermatology, psychiatry, and neurology would be immensely helpful. Although a dermatologic approach to treating these conditions is effective, there also is benefit in therapies typically used in psychiatry and neurology. Therefore, interdisciplinary cooperation between these 3 fields will likely result in optimal treatment of patients with neurogenic and psychogenic pruritus. When approaching treatment of patients with these conditions, it may be beneficial to try a multimodality therapeutic approach, using agents from several medical disciplines. 

Conclusion
The diagnosis and treatment of neurogenic and psychogenic pruritus were reviewed and updated. Evidence-based studies regarding therapies available for these conditions are sparse. Despite considerable overlap of dermatology, psychiatry, and neurology, pruritus sine materia is a neglected area of medicine, both clinically and scientifically. More interdisciplinary cooperation and studies are essential for further progress. 

Itch, also known as pruritus, is defined as "an unpleasant cutaneous sensation which provokes the desire to scratch."1 Itch may be classified by its mechanisms. It is typically divided into one of several categories: pruritoceptive, neurogenic, neuropathic, and psychogenic.2 Pruritoceptive itch originates in the skin, is mediated locally by molecules such as histamine, and is transmitted by C nerve fibers. Neurogenic itch is caused by circulating mediators acting centrally, such as opioid neuropeptides in cholestasis acting centrally on opioid receptors. Neuropathic itch is caused by peripheral or central nervous system (CNS) lesions along the afferent neural pathway leading from the skin to the brain. Finally, psychogenic itch is secondary to primary psychiatric disorders, such as delusions of parasitosis. It is possible to have pruritus of more than one type simultaneously. For example, a patient with psoriasis also may have generalized pruritus secondary to cholestasis. When a pruritic patient is first seen by a physician, a thorough history and general physical examination are completed and the physician typically looks for primary cutaneous lesions that could provide clues to the etiology of the patient's complaint. If found, lesions likely would lead the physician to consider a differential diagnosis consisting mostly of pruritoceptive disorders. If no lesions are present, the condition is known as pruritus sine materia. The next logical step would be to evaluate the patient for an internal etiology for the itching sensation, such as uremia. Both pruritoceptive and neurogenic itch are mediated by identifiable organic causes. Challenging cases arise when patients present with no primary cutaneous lesions and their extensive medical workup does not reveal any abnormalities. The physician may be tempted to conclude that the pruritus is secondary to some underlying psychiatric or supratentorial process and refer the patient to a mental health professional; however, this conclusion may be premature because neuropathic pruritus also is a possibility. If psychogenic pruritus is ultimately diagnosed, optimal care for patients results from a dermatologist working closely with a mental health professional. Therefore, it is beneficial for dermatologists to be updated on the management of these patients. This article reviews and updates diagnostic possibilities and available therapeutic options for patients with pruritus that exhibit no identifiable primary cutaneous lesions and have no apparent systemic medical condition accounting for their symptoms.

Neuropathic and Psychogenic Pruritus
To review the literature on pruritus sine materia, a MEDLINE/PubMed search was performed for English language articles and abstracts from 1960 to 2006 containing the keywords neuropathic, psychogenic, pruritus, itch, and therapy. Additional articles were obtained by reviewing the references cited in articles retrieved using the MEDLINE search. Neuropathic Pruritus—The sensation of itch is carried by specialized C fibers that originate in the skin and carry information to the dorsal horn of the spinal cord.2 These fibers are anatomically indistinct from fibers carrying pain signals. Itch impulses are transmitted via the spinothalamic tract to the thalamus and then to the somatosensory cortex. Pruritus as a solitary or dominant symptom following CNS injury is rare but well-documented in the medical literature. Multiple CNS lesions have been implicated, including brain tumors, aneurysms, abscesses, multiple sclerosis, stroke, transverse myelitis, and spinal cord hemangioma, as well as postherpetic neuralgia.3-9 The pruritus that results may be intermittent or constant and onset may or may not be immediate. The distribution often corresponds to a particular spinal segment but may be either bilateral or unilateral. Often a sensory deficit or an aberration in sensory perception such as allodynia (nonpainful stimuli evoke pain), allokinesis (sensation of itch produced by innocuous stimuli that would not ordinarily induce itch), or hyperpathia (evoked pain grossly out of proportion to painful stimuli) is present. One example of neuropathic pruritus is brachioradial pruritus, which is characteristically localized to the dorsolateral aspect of the upper arm.10 The etiology is unknown, but one study demonstrated cervical spine pathology on radiographs corresponding to the location of pruritus in 11 of 22 patients.11 Notalgia paresthetica, characterized by pruritus on the back in a dermatomal distribution and occasionally associated with pain, paresthesia, or hyperesthesia, is thought to be attributable to neurologic pathology at the spinal level corresponding to the affected dermatomes.12 Because neuropathic pruritus is caused by neuronal damage anywhere along the afferent neural pathway, it can occur in a specific dermatomal pattern or in a more broad distribution. Therefore, a careful history and a high index of suspicion are required for diagnosis in a patient with no evidence of pruritoceptive or neurogenic pruritus. Psychogenic Pruritus—It is estimated that up to 75% of dermatology patients have a psychogenic component to their skin complaints.13 Most psychogenic skin disorders have an underlying psychiatric component of depression, anxiety, obsessive-compulsive disorder (OCD), or psychosis.14 Dermatologic diagnoses that are considered to have a primary psychogenic etiology include delusions of parasitosis, neurotic excoriations, and dermatitis artefacta. Some conditions, such as prurigo nodularis and lichen simplex chronicus, have both psychogenic and physiologic etiology; these disorders have an organic basis but also are strongly affected by psychologic factors. Because pruritus may be associated with one or more underlying psychiatric diagnoses, it is often difficult to determine if the psychiatric disorder is the cause of the patient's pruritus. Depression is commonly associated with psychogenic pruritus.15 These patients with psychogenic pruritus secondary to depression also may present with prominent anxiety and agitation. Careful pharmacologic management is essential, as use of anxiolytic agents with depressant effects (ie, older benzodiazepines such as diazepam and chlordiazepoxide) in the absence of antidepressant therapy may exacerbate the underlying depression.16 Dopamine pathways in serious depression also have been implicated in the development of chronic tactile hallucinations that are manifested by sensations of itching, crawling, and burning in the absence of delusions.17 Patients with monosymptomatic hypochondriacal psychosis have a delusional preoccupation with a solitary hypochondriacal ideation (eg, an erroneous belief that one's skin is infested with parasites). Hallucinations experienced as formication, a sensation of crawling, biting, or stinging, frequently accompany the delusion. These patients typically do not have any other abnormal psychiatric function.18 The primary etiology is a psychiatric disorder, but healthy skin may be secondarily damaged from manipulation by the patient. The delusion occasionally is experienced by the patient's spouse or a close relative or friend, as they come to believe in the delusion. Dopamine pathways have been implicated in hallucinations and delusions, as dopamine-blocking drugs are effective in treating these symptoms.19 Neurotic excoriations also have a primarily psychogenic etiology. Patients with neurotic excoriations are driven to pick, scratch, or rub healthy skin or skin with minor irregularities, such as minor blemishes. The lesions vary in size from a few millimeters in diameter to large craters and often are weeping, crusting, or scarring, with surrounding postinflammatory pigmentation changes.20 Interestingly, pruritus is not always predominant in these patients. This behavior can lead to serious complications, such as chronic skin ulcers, extensive scarring, and abscesses. Neurotic excoriations often are associated with depression and OCD.21,22 If associated with OCD, despite full awareness of their behavior and the potential consequences, patients find themselves unable to cease the destructive activity. Dermatitis artefacta differs from neurotic excoriations in that the patients deny their participation in the development of the lesions and usually use more than just their fingernails (eg, sharp instruments, lighted cigarettes) to inflict damage on their skin. These patients typically are unable to give a reliable history regarding the evolution of the lesions. The lesions have varying morphology and may present as blisters, purpura, ulcers, erythema, edema, sinuses, or nodules, depending on how they were created by the patient.23 In a study of patients with different forms of self-inflicted dermatoses, depressive illness was found in 46% (12/26).24 

Treatment Pharmacologic Therapy—Despite the different etiologies of neuropathic and psychogenic pruritus, similar classes of pharmacologic and adjunctive therapies are useful for both. A simple approach to therapy for these disorders is to divide treatment types, namely topical, supportive, and CNS-directed therapies. Topical therapy consists of medications directed at the skin itself. Because the etiology of neuropathic and psychogenic pruritus is not primarily cutaneous, it seems unlikely that topical therapy would be helpful. However, topical therapy may be useful in patients with overlapping central and pruritoceptive pruritus. In addition, the empirical use of topical agents such as a eutectic mixture of local anesthetics, an anesthetic agent combining lidocaine 2.5% and prilocaine 2.5%, can help distinguish central from pruritoceptive pruritus. In addition, anesthetic cream has been effective in treating notalgia paresthetica.25 Capsaicin, an alkaloid isolated from red pepper plants, relieves pruritus by depleting substance P from cutaneous nerve endings involved in pain and itch, resulting in the inhibition of itch signal transmission from the skin to the CNS.26 Side effects include localized feelings of burning, stinging, and hyperalgesia. Pretreatment with topical anesthetic creams may reduce these side effects.27 Capsaicin has been shown to be effective for notalgia paresthetica,28,29 brachioradial pruritus,³⁰ and prurigo nodularis.31 Supportive therapies combined with other therapeutic options augment overall management of these patients. Occlusion of pruritic areas with Unna boot, Duoderm, or nonlatex gloves may help the patient break the itch-scratch cycle.13 If a patient has identifiable discrete lesions that are pruritic, such as prurigo nodularis or lichen simplex chronicus, intralesional steroid injections, laser therapy, or cryotherapy may control the pruritus associated with these lesions.13,15,32-34 Occlusion alone or combined with topical and intralesional corticosteroid therapy is effective for notalgia paresthetica.15 Goeckerman treatment, consisting of daily application of coal tar and UVB or psoralen plus UVA phototherapy, may provide benefit to patients with pruritus sine materia as well as prurigo nodularis and lichen simplex chronicus.13,35,36 Central nervous system–directed therapy in the treatment of neuropathic and psychogenic pruritus usually targets the suspected underlying etiology of the pruritus, such as depression and anxiety. Often, however, psychotropic agents are empirically used. Many of the same medications that show efficacy in the treatment of neuropathic pain also demonstrate therapeutic effect in neuropathic pruritus. Other than tricyclic antidepressants, there have been no controlled studies; therefore, the merits of most of these options are based on anecdotal reports. Carbamazepine, an antiepileptic agent, is beneficial in pruritus and dysesthesia in multiple sclerosis.37 Aplastic anemia and agranulocytosis rarely have been reported. Even though there is a low incidence of these side effects, hematologic testing at baseline (pretreatment) as well as periodic monitoring is recommended. Oxcarbazepine, an analogue of carbamazepine, has efficacy in the treatment of brachioradial pruritus.38 Oxcarbazepine lacks the hematologic risks associated with carbamazepine and does not require monitoring, but it does carry a risk of hyponatremia and Stevens-Johnson syndrome. Lamotrigine, another antiepileptic agent, is of benefit in brachioradial pruritus but also has been reported to cause Stevens-Johnson syndrome.10 Therefore, oxcarbazepine and lamotrigine should be discontinued at the first sign of drug eruption. Gabapentin, a structural analogue of the neurotransmitter γ-aminobutyric acid, treats epilepsy and postherpetic neuralgia. It shows efficacy in the treatment of brachioradial pruritus, pruritus induced by multiple sclerosis, and pruritus of unknown origin.39-42 Gabapentin should not be discontinued abruptly but rather should be tapered gradually to prevent withdrawal-related adverse events. Thalidomide, an immunomodulatory drug, has shown benefit in treating prurigo nodularis.43-45 It is a powerful central depressant and has a sedative-related property. In addition, it inhibits C-fiber function and therefore may have a primary antipruritic effect. It also has anti- inflammatory action by which it inhibits synthesis of tumor necrosis factor α, a cytokine that may induce pruritus. The major adverse side effects of thalidomide are severe fatigue, peripheral neuropathy, and teratogenicity. Antidepressants have demonstrated efficacy in reducing pruritus, presumably through neurotransmitter modulation. Tricyclic compounds, such as doxepin, and selective serotonin reuptake inhibitors (SSRIs) have been beneficial in psychogenic pruritus. Tricyclic antidepressants have antihistaminic effects and inhibit the reuptake of norepinephrine and serotonin in the CNS and peripheral nervous system. Although the sedative and antihistaminic effects of these drugs occur promptly, the antidepressive effects can take 2 weeks or longer to manifest after reaching an adequate dose. However, the negative side-effect profile of tricyclic antidepressants, including cardiac conduction abnormalities, seizures, and drug interactions, limits their clinical utility. Amitriptyline is effective in the treatment of postherpetic neuralgia and brachioradial pruritus. Doxepin has shown benefit in the treatment of neurotic excoriations.46 Doses of these agents should be more conservative in elderly patients. Selective serotonin reuptake inhibitors specifically inhibit serotonin reuptake and increase serotonin synaptic activity. Examples of drugs in this class are fluoxetine, paroxetine, and sertraline. These drugs have fewer problems with the sedative or antihistaminic properties compared with the tricyclic antidepressants, which improves their safety profile, but their antidepressant effects also can take weeks to manifest. Selective serotonin reuptake inhibitors target many of the underlying psychopathologies in psychogenic pruritus, such as depression, anxiety, and OCD. There have been many reports of their efficacy in the treatment of neurotic excoriations.21,47-56 Although these drugs are associated with fewer serious adverse events than tricyclic antidepressants, they can be associated with side effects that patients may find distressing, including nervousness, insomnia, fatigue, weight gain, and sexual dysfunction. Children or adolescents taking any of the SSRIs should be monitored closely for increased depression and suicidal ideation. In addition, if the medication is discontinued abruptly, a withdrawal syndrome can occur in rare cases, resulting in dizziness, tremor, anxiety, and dysphoria, which may be minimized or avoided by gradually tapering the dose. Mirtazapine is a noradrenergic and specific serotonergic antidepressant and antihistamine that has been used for the treatment of psychogenic pruritus. It facilitates norepinephrine neurotransmission and selectively increases serotonin neurotransmission. Compared with other antidepressants used for this purpose, mirtazapine has a more favorable side-effect profile, with fewer incidences of nausea and sexual dysfunction. However, as with SSRIs, children or adolescents taking mirtazapine should be monitored for rare occurrence of increased depression and suicidal ideation. Anecdotally, mirtazapine has been effective in reducing nocturnal itching in a case of chronic neurotic excoriation, with the onset of action within 2 weeks.57 Discontinuation of mirtazapine resulted in recurrence of pruritus. Pimozide is an antipsychotic medication that is useful in the treatment of delusions of parasitosis.58 Its effect in reducing delusions is mediated primarily by its antidopaminergic effect. However, the antipruritic effect of pimozide may be attributed to its opiate-blocking effect.59 As with other antipsychotic agents, there are many potential side effects, including prolongation of the QT interval; ventricular arrhythmias; neuroleptic malignant syndrome; and extrapyramidal side effects, such as restlessness, acute dystonic reactions, Parkinsonlike symptoms, and tardive dyskinesia. These effects usually are dependent on the dose and length of use and are not always reversible on discontinuation of the drug. The extrapyramidal side effects of pimozide may be minimized with the concurrent use of diphenhydramine. Olanzapine, an atypical antipsychotic agent, has shown efficacy in treating neurotic excoriations in nonpsychotic patients.60,61 Caution should be used when prescribing this drug in elderly patients, as the risk of cerebrovascular accidents and dementia-related psychosis is higher in this population. Other adverse side effects include hyperglycemia, diabetes mellitus, neuroleptic malignant syndrome, and tardive dyskinesia. Nonpharmacologic Therapy—Some nonpharmacologic therapies have been anecdotally shown to benefit patients with pruritus of neurogenic and psychogenic etiology. When the underlying psychiatric diagnosis is obvious to the physician, he/she must first consider if the patient should be confronted with the diagnosis. If the patient is unable to recognize his/her emotional distress, then early confrontation may produce anxiety and anger, resulting in loss of therapeutic rapport.62 Rather, a strong physician-patient alliance is essential.63 Once a trusting relationship has been established, psychotherapeutic options may be introduced. In dermatitis artefacta, a supportive and empathic approach is recommended, avoiding discussion of the self-inflicted nature of the lesions.23,64-67 When a strong therapeutic relationship has been developed, a more insight-oriented psychotherapeutic approach may be helpful.65,68 Some patients with pruritus of a psychogenic etiology may have awareness of their participation in the development of skin lesions, such as patients with neurotic excoriations. Despite this awareness, a trusting physician-patient relationship should still be cultivated before broaching a discussion about participation in their disease.69 Once a trusting physician-patient alliance is established, the underlying psychopathology may be openly discussed and treated, and nonpharmacologic psychocutaneous interventions may be discussed. The benefits of these interventions appear to result from stress reduction, the patient's increased sense of control of the illness, and normalization of the psychoneuroendocrine function.70 More importantly, these therapeutic strategies do not cause the patient any harm and are likely to improve the patient's overall quality of life. Cognitive behavior psychotherapy and behavior techniques coupled with biofeedback, minocycline, and sertraline were effective in reducing picking behavior in a young woman with acne excoriée.70 Most reports of the effectiveness of psychotherapy are anecdotal. However, healing of neurotic excoriation lesions has been reported for up to 5 years after cessation of therapy in 17 of 20 patients who underwent psychotherapy with insight-oriented and behavior components.71 Hypnotic trance is defined as a heightened state of focus that can be helpful in reducing pruritus while simultaneously inducing favorable physiologic changes.70 Direct suggestion while in the hypnotic state is the most commonly used method of decreasing pruritus.72 In addition, retraining the subconscious through hypnosis to replace a destructive habit pattern with a more constructive one, called symptom substitution, can be helpful in patients with self-inflicted lesions.73 There have been 2 reported cases of control of acne excoriée using posthypnotic suggestion.74

Comment There is considerable overlap between neuropathic disorders and psychologic factors. As this review demonstrates, the presentation of neuropathic and psychogenic pruritus can be similar. In addition, therapy that is effective for one disorder often can be effective for the other disorder. However, despite the variety of medications used to treat these disorders, it is an underdeveloped field. There is a paucity of controlled studies, and most reports of efficacy are based on anecdotal evidence. As a result, it is difficult to practice evidence-based medicine when treating patients with neuropathic and psychogenic pruritus. Neuropathic and psychogenic pruritus constitutes an area of medicine in which expertise from specialists in the fields of dermatology, psychiatry, and neurology would be immensely helpful. Although a dermatologic approach to treating these conditions is effective, there also is benefit in therapies typically used in psychiatry and neurology. Therefore, interdisciplinary cooperation between these 3 fields will likely result in optimal treatment of patients with neurogenic and psychogenic pruritus. When approaching treatment of patients with these conditions, it may be beneficial to try a multimodality therapeutic approach, using agents from several medical disciplines. 

Conclusion
The diagnosis and treatment of neurogenic and psychogenic pruritus were reviewed and updated. Evidence-based studies regarding therapies available for these conditions are sparse. Despite considerable overlap of dermatology, psychiatry, and neurology, pruritus sine materia is a neglected area of medicine, both clinically and scientifically. More interdisciplinary cooperation and studies are essential for further progress. 

KYOTO, JAPAN — Supplementation with oral vitamin D boosted chronically low levels of the antimicrobial peptide cathelicidin in the lesional skin of atopic dermatitis patients in a controlled trial, reported Dr. Tissa R. Hata.

These promising results of an initial 28-patient, 3-week, proof-of-concept study provide the rationale for larger and longer clinical trials testing the hypothesis that oral vitamin D supplementation will reduce the susceptibility of atopic dermatitis patients to recurrent skin infections, added Dr. Hata of the University of California, San Diego, at an international investigative dermatology meeting.

The expression of cathelicidin is abnormally low in the lesional skin of atopic dermatitis patients, she said. It is also known, based upon in vitro studies, that toll-like receptor stimulation of human macrophages induces expression of the vitamin D receptor as well as an enzyme, CYP27B1, which converts 25-hydroxycholecalciferol into immunologically active 1,25-dihydroxycholecalciferol, which then induces expression of cathelicidin in myeloid dendritic cells and keratinocytes. Dr. Hata and coworkers decided to see if this was also true in vivo.

She reported on 14 atopic dermatitis patients and 14 healthy controls who took 4,000 IU of oral vitamin D daily for 21 days. Two-millimeter punch biopsies were obtained before and after treatment.

After 3 weeks of vitamin D supplementation, cathelicidin expression in the lesional skin of atopic dermatitis patients increased significantly from a median baseline 2.7 relative copy units to 21.8 relative copy units.

Supplementation with oral vitamin D appeared to boost cathelicidin production in atopic lesional skin only. There was no significant change in cathelicidin levels in the control subjects' skin, nor in the nonlesional skin of atopic dermatitis patients, Dr. Hata noted at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

Her study builds upon the work of Dr. Robert L. Modlin and coworkers at the University of California, Los Angeles, who 2 years ago in a landmark study elucidated the physiologic mechanism for vitamin D's antimicrobial and immunologic effects.

The UCLA study (Science 2006;311:1770–3) triggered ongoing intense worldwide dermatologic research into the role of vitamin D in various inflammatory skin diseases. It also helped turn the role of vitamin D deficiency in a variety of diseases into a hot topic among the general public.

KYOTO, JAPAN — Supplementation with oral vitamin D boosted chronically low levels of the antimicrobial peptide cathelicidin in the lesional skin of atopic dermatitis patients in a controlled trial, reported Dr. Tissa R. Hata.

These promising results of an initial 28-patient, 3-week, proof-of-concept study provide the rationale for larger and longer clinical trials testing the hypothesis that oral vitamin D supplementation will reduce the susceptibility of atopic dermatitis patients to recurrent skin infections, added Dr. Hata of the University of California, San Diego, at an international investigative dermatology meeting.

The expression of cathelicidin is abnormally low in the lesional skin of atopic dermatitis patients, she said. It is also known, based upon in vitro studies, that toll-like receptor stimulation of human macrophages induces expression of the vitamin D receptor as well as an enzyme, CYP27B1, which converts 25-hydroxycholecalciferol into immunologically active 1,25-dihydroxycholecalciferol, which then induces expression of cathelicidin in myeloid dendritic cells and keratinocytes. Dr. Hata and coworkers decided to see if this was also true in vivo.

She reported on 14 atopic dermatitis patients and 14 healthy controls who took 4,000 IU of oral vitamin D daily for 21 days. Two-millimeter punch biopsies were obtained before and after treatment.

After 3 weeks of vitamin D supplementation, cathelicidin expression in the lesional skin of atopic dermatitis patients increased significantly from a median baseline 2.7 relative copy units to 21.8 relative copy units.

Supplementation with oral vitamin D appeared to boost cathelicidin production in atopic lesional skin only. There was no significant change in cathelicidin levels in the control subjects' skin, nor in the nonlesional skin of atopic dermatitis patients, Dr. Hata noted at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

Her study builds upon the work of Dr. Robert L. Modlin and coworkers at the University of California, Los Angeles, who 2 years ago in a landmark study elucidated the physiologic mechanism for vitamin D's antimicrobial and immunologic effects.

The UCLA study (Science 2006;311:1770–3) triggered ongoing intense worldwide dermatologic research into the role of vitamin D in various inflammatory skin diseases. It also helped turn the role of vitamin D deficiency in a variety of diseases into a hot topic among the general public.

KYOTO, JAPAN — Supplementation with oral vitamin D boosted chronically low levels of the antimicrobial peptide cathelicidin in the lesional skin of atopic dermatitis patients in a controlled trial, reported Dr. Tissa R. Hata.

These promising results of an initial 28-patient, 3-week, proof-of-concept study provide the rationale for larger and longer clinical trials testing the hypothesis that oral vitamin D supplementation will reduce the susceptibility of atopic dermatitis patients to recurrent skin infections, added Dr. Hata of the University of California, San Diego, at an international investigative dermatology meeting.

The expression of cathelicidin is abnormally low in the lesional skin of atopic dermatitis patients, she said. It is also known, based upon in vitro studies, that toll-like receptor stimulation of human macrophages induces expression of the vitamin D receptor as well as an enzyme, CYP27B1, which converts 25-hydroxycholecalciferol into immunologically active 1,25-dihydroxycholecalciferol, which then induces expression of cathelicidin in myeloid dendritic cells and keratinocytes. Dr. Hata and coworkers decided to see if this was also true in vivo.

She reported on 14 atopic dermatitis patients and 14 healthy controls who took 4,000 IU of oral vitamin D daily for 21 days. Two-millimeter punch biopsies were obtained before and after treatment.

After 3 weeks of vitamin D supplementation, cathelicidin expression in the lesional skin of atopic dermatitis patients increased significantly from a median baseline 2.7 relative copy units to 21.8 relative copy units.

Supplementation with oral vitamin D appeared to boost cathelicidin production in atopic lesional skin only. There was no significant change in cathelicidin levels in the control subjects' skin, nor in the nonlesional skin of atopic dermatitis patients, Dr. Hata noted at the meeting of the European Society for Dermatological Research, the Japanese Society for Investigative Dermatology, and the Society for Investigative Dermatology.

Her study builds upon the work of Dr. Robert L. Modlin and coworkers at the University of California, Los Angeles, who 2 years ago in a landmark study elucidated the physiologic mechanism for vitamin D's antimicrobial and immunologic effects.

The UCLA study (Science 2006;311:1770–3) triggered ongoing intense worldwide dermatologic research into the role of vitamin D in various inflammatory skin diseases. It also helped turn the role of vitamin D deficiency in a variety of diseases into a hot topic among the general public.