Psoriasis

WAIKOLOA, HAWAII – Guttate psoriasis in children warrants more aggressive monitoring and treatment in an effort to head off more severe disease later, according to Dr. Wynnis L. Tom.

Pediatric psoriasis presenting initially as guttate disease is more likely to progress to severe psoriasis prior to adulthood than if the initial presentation took the form of plaque psoriasis, according to data from a multicenter U.S. study of the clinical manifestations of pediatric psoriasis.

The cross-sectional study included 181 children aged 5-17 years with plaque psoriasis, and the results highlighted important differences between childhood-onset and adult-onset disease, Dr. Tom said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

About 40% of cases of pediatric psoriasis that presented initially as guttate psoriasis progressed to chronic disease. That was not a higher proportion than in children whose initial disease was plaque psoriasis, said Dr. Tom of the University of California, San Diego, and Rady Children’s Hospital. However, 36% of youths with severe psoriasis had a history of disease onset with guttate morphology compared with 22% of those with mild disease, she said.

The peak severity of psoriasis was defined historically as either mild or severe based upon body surface area involvement and Physician Global Assessment.

Overall, 79% of study participants had a history of scalp psoriasis and 39% had a history of nail involvement. However, these disease expressions were unrelated to psoriasis severity.

Boys were three times more likely than girls to have had nail involvement, but 60% less likely to have a history of scalp involvement. These sex-related differences probably reflect koebnerization, Dr. Tom said.

Approximately 5% of the patients had psoriasis restricted to their face alone. Among those with body involvement, the face was included in nearly half of cases.

Session chair Dr. Lawrence F. Eichenfield praised this study (Pediatr. Dermatol. 2013;30:424-8), on which Dr. Tom was a coauthor, as one of the top articles in the field of pediatric dermatology published within the past year. Although various studies indicate that 27%-45% of all cases of psoriasis begin in childhood, the clinical aspects of pediatric psoriasis haven’t been well characterized until now, said Dr. Eichenfield, professor of clinical pediatrics and medicine and chief of pediatric and adolescent dermatology at the University of California, San Diego.

Dr. Eichenfield also singled out Dr. Tom as coauthor of yet another of his top picks of recently published studies on the topic of pediatric psoriasis. This cross-sectional study included 409 psoriasis patients aged 5-17 years in nine countries. The prevalence of excess adiposity as defined by a body mass index at the 85th percentile or greater was 38% among the psoriatic children compared with 21% in matched controls. The likelihood of obesity as defined by a BMI in the 95th percentile or higher was 4.9-fold greater in children with severe psoriasis than in controls, and 3.6-fold greater in those with mild psoriasis compared than in controls. Among U.S. patients, the psoriasis/obesity association was magnified such that American children with severe and mild psoriasis were respectively 7.6-fold and 4.7-fold more likely to be obese than controls (JAMA Dermatol. 2013;149:166-76).

Central adiposity – an element of metabolic syndrome associated with increased cardiovascular risk in adults – was present as defined by waist circumference greater than the 90th percentile in 21% of youths with severe psoriasis, 14% with mild disease, and 9% of controls. In U.S. participants, these figures ballooned to 31%, 21%, and 12%, respectively.

Dr. Tom cited evidence from yet another study in which she was a coinvestigator suggesting that obesity may be a risk factor for pediatric psoriasis, rather than the other way around. In this three-center study, nearly all of a group of pediatric psoriasis patients were overweight or obese for at least 2 years prior to their psoriasis onset.

Current National Psoriasis Foundation guidelines recommend initiating cardiovascular risk factor screening "as early as age 20." Dr. Tom is among those seeking to revise the guidelines to extend screening to pediatric psoriasis patients. She said she now recommends consideration of cardiovascular screening in overweight and obese pediatric psoriasis patients – including monitoring of blood pressure, lipids, fasting blood glucose, and liver enzymes – along with hard-hitting guidance on dietary modifications, weight loss, and the importance of exercise.

"Ongoing studies are assessing the need for screening labs for nonoverweight children with psoriasis. Hopefully this will be sorted out soon as a group in our field. We’re hoping for updated guidelines," she said.

Dr. Tom disclosed serving as a financially uncompensated investigator for Amgen and Anacor.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Guttate psoriasis in children warrants more aggressive monitoring and treatment in an effort to head off more severe disease later, according to Dr. Wynnis L. Tom.

Pediatric psoriasis presenting initially as guttate disease is more likely to progress to severe psoriasis prior to adulthood than if the initial presentation took the form of plaque psoriasis, according to data from a multicenter U.S. study of the clinical manifestations of pediatric psoriasis.

The cross-sectional study included 181 children aged 5-17 years with plaque psoriasis, and the results highlighted important differences between childhood-onset and adult-onset disease, Dr. Tom said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

About 40% of cases of pediatric psoriasis that presented initially as guttate psoriasis progressed to chronic disease. That was not a higher proportion than in children whose initial disease was plaque psoriasis, said Dr. Tom of the University of California, San Diego, and Rady Children’s Hospital. However, 36% of youths with severe psoriasis had a history of disease onset with guttate morphology compared with 22% of those with mild disease, she said.

The peak severity of psoriasis was defined historically as either mild or severe based upon body surface area involvement and Physician Global Assessment.

Overall, 79% of study participants had a history of scalp psoriasis and 39% had a history of nail involvement. However, these disease expressions were unrelated to psoriasis severity.

Boys were three times more likely than girls to have had nail involvement, but 60% less likely to have a history of scalp involvement. These sex-related differences probably reflect koebnerization, Dr. Tom said.

Approximately 5% of the patients had psoriasis restricted to their face alone. Among those with body involvement, the face was included in nearly half of cases.

Session chair Dr. Lawrence F. Eichenfield praised this study (Pediatr. Dermatol. 2013;30:424-8), on which Dr. Tom was a coauthor, as one of the top articles in the field of pediatric dermatology published within the past year. Although various studies indicate that 27%-45% of all cases of psoriasis begin in childhood, the clinical aspects of pediatric psoriasis haven’t been well characterized until now, said Dr. Eichenfield, professor of clinical pediatrics and medicine and chief of pediatric and adolescent dermatology at the University of California, San Diego.

Dr. Eichenfield also singled out Dr. Tom as coauthor of yet another of his top picks of recently published studies on the topic of pediatric psoriasis. This cross-sectional study included 409 psoriasis patients aged 5-17 years in nine countries. The prevalence of excess adiposity as defined by a body mass index at the 85th percentile or greater was 38% among the psoriatic children compared with 21% in matched controls. The likelihood of obesity as defined by a BMI in the 95th percentile or higher was 4.9-fold greater in children with severe psoriasis than in controls, and 3.6-fold greater in those with mild psoriasis compared than in controls. Among U.S. patients, the psoriasis/obesity association was magnified such that American children with severe and mild psoriasis were respectively 7.6-fold and 4.7-fold more likely to be obese than controls (JAMA Dermatol. 2013;149:166-76).

Central adiposity – an element of metabolic syndrome associated with increased cardiovascular risk in adults – was present as defined by waist circumference greater than the 90th percentile in 21% of youths with severe psoriasis, 14% with mild disease, and 9% of controls. In U.S. participants, these figures ballooned to 31%, 21%, and 12%, respectively.

Dr. Tom cited evidence from yet another study in which she was a coinvestigator suggesting that obesity may be a risk factor for pediatric psoriasis, rather than the other way around. In this three-center study, nearly all of a group of pediatric psoriasis patients were overweight or obese for at least 2 years prior to their psoriasis onset.

Current National Psoriasis Foundation guidelines recommend initiating cardiovascular risk factor screening "as early as age 20." Dr. Tom is among those seeking to revise the guidelines to extend screening to pediatric psoriasis patients. She said she now recommends consideration of cardiovascular screening in overweight and obese pediatric psoriasis patients – including monitoring of blood pressure, lipids, fasting blood glucose, and liver enzymes – along with hard-hitting guidance on dietary modifications, weight loss, and the importance of exercise.

"Ongoing studies are assessing the need for screening labs for nonoverweight children with psoriasis. Hopefully this will be sorted out soon as a group in our field. We’re hoping for updated guidelines," she said.

Dr. Tom disclosed serving as a financially uncompensated investigator for Amgen and Anacor.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Guttate psoriasis in children warrants more aggressive monitoring and treatment in an effort to head off more severe disease later, according to Dr. Wynnis L. Tom.

Pediatric psoriasis presenting initially as guttate disease is more likely to progress to severe psoriasis prior to adulthood than if the initial presentation took the form of plaque psoriasis, according to data from a multicenter U.S. study of the clinical manifestations of pediatric psoriasis.

The cross-sectional study included 181 children aged 5-17 years with plaque psoriasis, and the results highlighted important differences between childhood-onset and adult-onset disease, Dr. Tom said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

About 40% of cases of pediatric psoriasis that presented initially as guttate psoriasis progressed to chronic disease. That was not a higher proportion than in children whose initial disease was plaque psoriasis, said Dr. Tom of the University of California, San Diego, and Rady Children’s Hospital. However, 36% of youths with severe psoriasis had a history of disease onset with guttate morphology compared with 22% of those with mild disease, she said.

The peak severity of psoriasis was defined historically as either mild or severe based upon body surface area involvement and Physician Global Assessment.

Overall, 79% of study participants had a history of scalp psoriasis and 39% had a history of nail involvement. However, these disease expressions were unrelated to psoriasis severity.

Boys were three times more likely than girls to have had nail involvement, but 60% less likely to have a history of scalp involvement. These sex-related differences probably reflect koebnerization, Dr. Tom said.

Approximately 5% of the patients had psoriasis restricted to their face alone. Among those with body involvement, the face was included in nearly half of cases.

Session chair Dr. Lawrence F. Eichenfield praised this study (Pediatr. Dermatol. 2013;30:424-8), on which Dr. Tom was a coauthor, as one of the top articles in the field of pediatric dermatology published within the past year. Although various studies indicate that 27%-45% of all cases of psoriasis begin in childhood, the clinical aspects of pediatric psoriasis haven’t been well characterized until now, said Dr. Eichenfield, professor of clinical pediatrics and medicine and chief of pediatric and adolescent dermatology at the University of California, San Diego.

Dr. Eichenfield also singled out Dr. Tom as coauthor of yet another of his top picks of recently published studies on the topic of pediatric psoriasis. This cross-sectional study included 409 psoriasis patients aged 5-17 years in nine countries. The prevalence of excess adiposity as defined by a body mass index at the 85th percentile or greater was 38% among the psoriatic children compared with 21% in matched controls. The likelihood of obesity as defined by a BMI in the 95th percentile or higher was 4.9-fold greater in children with severe psoriasis than in controls, and 3.6-fold greater in those with mild psoriasis compared than in controls. Among U.S. patients, the psoriasis/obesity association was magnified such that American children with severe and mild psoriasis were respectively 7.6-fold and 4.7-fold more likely to be obese than controls (JAMA Dermatol. 2013;149:166-76).

Central adiposity – an element of metabolic syndrome associated with increased cardiovascular risk in adults – was present as defined by waist circumference greater than the 90th percentile in 21% of youths with severe psoriasis, 14% with mild disease, and 9% of controls. In U.S. participants, these figures ballooned to 31%, 21%, and 12%, respectively.

Dr. Tom cited evidence from yet another study in which she was a coinvestigator suggesting that obesity may be a risk factor for pediatric psoriasis, rather than the other way around. In this three-center study, nearly all of a group of pediatric psoriasis patients were overweight or obese for at least 2 years prior to their psoriasis onset.

Current National Psoriasis Foundation guidelines recommend initiating cardiovascular risk factor screening "as early as age 20." Dr. Tom is among those seeking to revise the guidelines to extend screening to pediatric psoriasis patients. She said she now recommends consideration of cardiovascular screening in overweight and obese pediatric psoriasis patients – including monitoring of blood pressure, lipids, fasting blood glucose, and liver enzymes – along with hard-hitting guidance on dietary modifications, weight loss, and the importance of exercise.

"Ongoing studies are assessing the need for screening labs for nonoverweight children with psoriasis. Hopefully this will be sorted out soon as a group in our field. We’re hoping for updated guidelines," she said.

Dr. Tom disclosed serving as a financially uncompensated investigator for Amgen and Anacor.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – The anti-interleukin-12/23 biologic agents ustekinumab and briakinumab were associated with a statistically significant 4.23-fold increased risk of major adverse cardiac events in the latest meta-analysis of placebo-controlled clinical trials conducted in patients with chronic plaque psoriasis.

"What are the implications? It’s probably a class effect. That’s the way I practice. I think there is a slightly increased risk of myocardial infarction in our anti-IL-12/23-treated patients. So I think you should consider all of your options when selecting a biologic therapy. We know that our psoriasis patients typically have multiple cardiac risk factors, and that TNF antagonists are cardioprotective," Dr. Craig L. Leonardi said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

The latest industry-independent meta-analysis (J. Eur. Acad. Dermatol. Venereol. 2013;27:622-7), led by dermatologists at Dessau (Germany) Medical Center, examined the same nine phase-II and phase-III placebo-controlled randomized trials scrutinized in an earlier meta-analysis, also industry independent, carried out by Dr. Leonardi and coinvestigators (JAMA 2011;306:864-71).

The earlier meta-analysis identified 10 major adverse cardiovascular events (MACE) in 3,179 IL-12/23-treated subjects and none among 1,474 placebo-treated controls. This signal was deemed not statistically significant, although Dr. Leonardi and coworkers noted that their meta-analysis may have been underpowered to detect a small increase in risk.

Given that the two meta-analyses relied upon essentially the same data, how did they reach such different conclusions? It’s all in the statistical methods. Without getting geeky about the statistical fine points, Dr. Leonardi noted that his group used the Mantel-Haenszel fixed-effects model, while the Dessau group employed the Peto method, which their statisticians deemed more appropriate on the basis of its previously established superior performance in detecting rare events.

The Peto method is named for Sir Richard Peto, a renowned University of Oxford epidemiologist knighted for his statistical contributions.

Dr. Leonardi, a dermatologist in private practice in St. Louis and a clinical professor of dermatology at Saint Louis University, wasn’t about to quibble about statistics. Taken together, he said, the story conveyed by the two meta-analyses is one of a small but real increase in the absolute risk of MACE in psoriasis patients exposed to anti-IL-12/23 biologics. Based upon this evidence, when he starts a psoriasis patient on ustekinumab (Stelara), he now generally does so at the lower 45-mg dose regardless of the patient’s weight, even though the 90-mg dose is approved for use in patients weighing more than 100 kg.

"And I’m placing my patients on aspirin at 81 mg/day while we await further data," he added.

He anticipates that clinically meaningful data will eventually come from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study, an ongoing observational registry that has enrolled nearly 12,000 psoriasis patients for a planned follow-up period of at least 8 years at 266 investigative sites in 15 countries. The Janssen-funded registry includes roughly 3,800 patients on ustekinumab, lesser numbers on the other biologics, as well as a large group on phototherapy and no biologics.

Dr. Leonardi presented an early interim analysis in which the rate of MACE in the ustekinumab group was 0.28 per 100 patient-years. This was numerically slightly lower than but still comparable to the rates observed with infliximab and other biologics, and half the rate in patients on no biologics. He stressed, however, that these are unadjusted rates. Planned formal comparisons will require longer follow-up periods, more MACE, and multivariate analysis to control for baseline differences in comorbid conditions and cardiovascular risk factors. The no-biologics group, for example, was significantly older than patients on biologic agents, because once patients become Medicare eligible it is quite difficult to get a prescription for a biologic. And of course cardiovascular risk climbs with advancing age.

Dr. Leonardi is a PSOLAR coinvestigator, and a big fan of the project’s potential.

"Don’t wait for an NIH-sponsored disease-specific registry. The fact is the government is not going to fund it, so we have to do the best we can with the tools we have. PSOLAR is the largest psoriasis registry in the world. It will allow us to answer questions about the emergence of comorbid diseases like psoriatic arthritis and cardiovascular disease, and treatment-specific questions like rates of infection, cancer, and MACE, as well as unanticipated issues nobody knew about," he said.

Dr. Leonardi disclosed ties with Janssen and nearly two dozen other pharmaceutical companies.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – The anti-interleukin-12/23 biologic agents ustekinumab and briakinumab were associated with a statistically significant 4.23-fold increased risk of major adverse cardiac events in the latest meta-analysis of placebo-controlled clinical trials conducted in patients with chronic plaque psoriasis.

"What are the implications? It’s probably a class effect. That’s the way I practice. I think there is a slightly increased risk of myocardial infarction in our anti-IL-12/23-treated patients. So I think you should consider all of your options when selecting a biologic therapy. We know that our psoriasis patients typically have multiple cardiac risk factors, and that TNF antagonists are cardioprotective," Dr. Craig L. Leonardi said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

The latest industry-independent meta-analysis (J. Eur. Acad. Dermatol. Venereol. 2013;27:622-7), led by dermatologists at Dessau (Germany) Medical Center, examined the same nine phase-II and phase-III placebo-controlled randomized trials scrutinized in an earlier meta-analysis, also industry independent, carried out by Dr. Leonardi and coinvestigators (JAMA 2011;306:864-71).

The earlier meta-analysis identified 10 major adverse cardiovascular events (MACE) in 3,179 IL-12/23-treated subjects and none among 1,474 placebo-treated controls. This signal was deemed not statistically significant, although Dr. Leonardi and coworkers noted that their meta-analysis may have been underpowered to detect a small increase in risk.

Given that the two meta-analyses relied upon essentially the same data, how did they reach such different conclusions? It’s all in the statistical methods. Without getting geeky about the statistical fine points, Dr. Leonardi noted that his group used the Mantel-Haenszel fixed-effects model, while the Dessau group employed the Peto method, which their statisticians deemed more appropriate on the basis of its previously established superior performance in detecting rare events.

The Peto method is named for Sir Richard Peto, a renowned University of Oxford epidemiologist knighted for his statistical contributions.

Dr. Leonardi, a dermatologist in private practice in St. Louis and a clinical professor of dermatology at Saint Louis University, wasn’t about to quibble about statistics. Taken together, he said, the story conveyed by the two meta-analyses is one of a small but real increase in the absolute risk of MACE in psoriasis patients exposed to anti-IL-12/23 biologics. Based upon this evidence, when he starts a psoriasis patient on ustekinumab (Stelara), he now generally does so at the lower 45-mg dose regardless of the patient’s weight, even though the 90-mg dose is approved for use in patients weighing more than 100 kg.

"And I’m placing my patients on aspirin at 81 mg/day while we await further data," he added.

He anticipates that clinically meaningful data will eventually come from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study, an ongoing observational registry that has enrolled nearly 12,000 psoriasis patients for a planned follow-up period of at least 8 years at 266 investigative sites in 15 countries. The Janssen-funded registry includes roughly 3,800 patients on ustekinumab, lesser numbers on the other biologics, as well as a large group on phototherapy and no biologics.

Dr. Leonardi presented an early interim analysis in which the rate of MACE in the ustekinumab group was 0.28 per 100 patient-years. This was numerically slightly lower than but still comparable to the rates observed with infliximab and other biologics, and half the rate in patients on no biologics. He stressed, however, that these are unadjusted rates. Planned formal comparisons will require longer follow-up periods, more MACE, and multivariate analysis to control for baseline differences in comorbid conditions and cardiovascular risk factors. The no-biologics group, for example, was significantly older than patients on biologic agents, because once patients become Medicare eligible it is quite difficult to get a prescription for a biologic. And of course cardiovascular risk climbs with advancing age.

Dr. Leonardi is a PSOLAR coinvestigator, and a big fan of the project’s potential.

"Don’t wait for an NIH-sponsored disease-specific registry. The fact is the government is not going to fund it, so we have to do the best we can with the tools we have. PSOLAR is the largest psoriasis registry in the world. It will allow us to answer questions about the emergence of comorbid diseases like psoriatic arthritis and cardiovascular disease, and treatment-specific questions like rates of infection, cancer, and MACE, as well as unanticipated issues nobody knew about," he said.

Dr. Leonardi disclosed ties with Janssen and nearly two dozen other pharmaceutical companies.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – The anti-interleukin-12/23 biologic agents ustekinumab and briakinumab were associated with a statistically significant 4.23-fold increased risk of major adverse cardiac events in the latest meta-analysis of placebo-controlled clinical trials conducted in patients with chronic plaque psoriasis.

"What are the implications? It’s probably a class effect. That’s the way I practice. I think there is a slightly increased risk of myocardial infarction in our anti-IL-12/23-treated patients. So I think you should consider all of your options when selecting a biologic therapy. We know that our psoriasis patients typically have multiple cardiac risk factors, and that TNF antagonists are cardioprotective," Dr. Craig L. Leonardi said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

The latest industry-independent meta-analysis (J. Eur. Acad. Dermatol. Venereol. 2013;27:622-7), led by dermatologists at Dessau (Germany) Medical Center, examined the same nine phase-II and phase-III placebo-controlled randomized trials scrutinized in an earlier meta-analysis, also industry independent, carried out by Dr. Leonardi and coinvestigators (JAMA 2011;306:864-71).

The earlier meta-analysis identified 10 major adverse cardiovascular events (MACE) in 3,179 IL-12/23-treated subjects and none among 1,474 placebo-treated controls. This signal was deemed not statistically significant, although Dr. Leonardi and coworkers noted that their meta-analysis may have been underpowered to detect a small increase in risk.

Given that the two meta-analyses relied upon essentially the same data, how did they reach such different conclusions? It’s all in the statistical methods. Without getting geeky about the statistical fine points, Dr. Leonardi noted that his group used the Mantel-Haenszel fixed-effects model, while the Dessau group employed the Peto method, which their statisticians deemed more appropriate on the basis of its previously established superior performance in detecting rare events.

The Peto method is named for Sir Richard Peto, a renowned University of Oxford epidemiologist knighted for his statistical contributions.

Dr. Leonardi, a dermatologist in private practice in St. Louis and a clinical professor of dermatology at Saint Louis University, wasn’t about to quibble about statistics. Taken together, he said, the story conveyed by the two meta-analyses is one of a small but real increase in the absolute risk of MACE in psoriasis patients exposed to anti-IL-12/23 biologics. Based upon this evidence, when he starts a psoriasis patient on ustekinumab (Stelara), he now generally does so at the lower 45-mg dose regardless of the patient’s weight, even though the 90-mg dose is approved for use in patients weighing more than 100 kg.

"And I’m placing my patients on aspirin at 81 mg/day while we await further data," he added.

He anticipates that clinically meaningful data will eventually come from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study, an ongoing observational registry that has enrolled nearly 12,000 psoriasis patients for a planned follow-up period of at least 8 years at 266 investigative sites in 15 countries. The Janssen-funded registry includes roughly 3,800 patients on ustekinumab, lesser numbers on the other biologics, as well as a large group on phototherapy and no biologics.

Dr. Leonardi presented an early interim analysis in which the rate of MACE in the ustekinumab group was 0.28 per 100 patient-years. This was numerically slightly lower than but still comparable to the rates observed with infliximab and other biologics, and half the rate in patients on no biologics. He stressed, however, that these are unadjusted rates. Planned formal comparisons will require longer follow-up periods, more MACE, and multivariate analysis to control for baseline differences in comorbid conditions and cardiovascular risk factors. The no-biologics group, for example, was significantly older than patients on biologic agents, because once patients become Medicare eligible it is quite difficult to get a prescription for a biologic. And of course cardiovascular risk climbs with advancing age.

Dr. Leonardi is a PSOLAR coinvestigator, and a big fan of the project’s potential.

"Don’t wait for an NIH-sponsored disease-specific registry. The fact is the government is not going to fund it, so we have to do the best we can with the tools we have. PSOLAR is the largest psoriasis registry in the world. It will allow us to answer questions about the emergence of comorbid diseases like psoriatic arthritis and cardiovascular disease, and treatment-specific questions like rates of infection, cancer, and MACE, as well as unanticipated issues nobody knew about," he said.

Dr. Leonardi disclosed ties with Janssen and nearly two dozen other pharmaceutical companies.

SDEF and this news organization are owned by the same parent company.

[email protected]

An investigational topical drug that targets a nerve sensitization pathway showed good efficacy against chronic itch in patients with pruritic psoriasis.

CT327 works by inhibiting the kinase pathway of TrkA, a receptor that controls uptake of nerve growth factor, Dr. Gil Yosipovitch said at the annual meeting of the American Academy of Dermatology.

In a placebo-controlled trial of 160 patients with pruritic psoriasis, CT327 reduced itch by a mean of 60%, said Dr. Yosipovitch, chair of dermatology at the Temple University, Philadelphia.

"Sixty percent is not 90%," he said. "But when we consider that most of the antipruritic drugs have about a 15% efficacy in comparison to a vehicle, this is an effect we should consider. It’s well tolerated, and there were no application site reactions. I see potential in this drug."

CT327, developed by Creabilis, is a selective kinase inhibitor that targets TrkA, the receptor for nerve growth factor (NGF). NGF, which is overexpressed in atopic dermatitis and psoriatic skin, sensitizes neural networks that transmit the itch sensation to the brain, Dr. Yosipovitch said.

© abdone/Thinkstockphotos.com

The phase IIb study comprised 160 adults with mild to moderate psoriasis, with at least a 10% body surface area involvement. Their mean score on the modified Psoriasis Area and Severity Index (mPASI) was about 9. Most (97%) had pruritus; 69% reported this as at least moderate, with a score of 40 on a 100-point visual analog scale (VAS). A third of the group reported severe pruritus, with a VAS of more than 70. They were randomized to four groups: an emollient placebo or CT327 in concentrations of 0.05%, 0.1%, or 0.5%.

The primary endpoint was reduction on a validated 100-point pruritus visual analog scale. The secondary endpoint was change on the mPASI.

By the end of 8 weeks, most patients (108) had experienced a significant reduction on the pruritus VAS. Reductions were about 35 points for the 0.1% group and 38 points for the 0.05% and 0.5% groups. These changes represented about a 60% decrease overall, Dr. Yosipovitch said.

Changes began early and continued along a steep trajectory, reaching a significant difference from baseline by week 2. However, he pointed out, by that point, the placebo group was similarly improved. This was probably because of the benefit of the daily emollient vehicle, he noted.

The curves began to separate shortly thereafter. By week 4, all of the treatment groups had experienced about a 30-point reduction on the VAS, while the placebo group had actually increased its score slightly. The active groups continued to improve over the next 4 weeks, while the placebo group plateaued at about a 20-point decrease from baseline.

The study concluded with 4 weeks of non–treatment follow-up. During that time, the placebo group stayed at about a 20-point decline and the active groups rebounded to about that level, "suggesting that there really is something going on here biologically," Dr. Yosipovitch said.

Patients using CT327 also experienced significant – although not overwhelming – benefit on the mPASI score. About 45% responded at the 50% level, compared with 23% of those using the emollient placebo. The active groups had similar improvements, with reductions on the mPASI of between 3 and 4 points. Those in the placebo group experienced about a 1-point improvement.

Dr. Yosipovitch said he was "not too impressed" with the mPASI changes. However, he noted, "Breaking the itch-scratch cycle at its source may have broader effects on other symptoms of psoriasis."

Based on the study results, Creabilis has decided to move forward into phase III testing with the 0.05% concentration. "Preparations are already underway," Dr. Yosipovitch said in an interview. "We also have a second phase IIb study ongoing that is investigating CT327 in patients with atopic dermatitis, which will be used to help finalize our phase III programs. This study should be completed in the middle of this year."

The NGF/TrkA pathway is implicated in other disorders as well, Dr. Yosipovitch said. CT327 might be investigated in some of these.

"These include disorders [in which] pruritus is important, such as pruritus with cutaneous T cell lymphoma, where NGF/TrkA has been shown to play a role. The pathway has also been shown to play an important role in chronic neuropathic and inflammatory pain. Molecules targeting NGF have already shown clinical efficacy."

Creabilis is investigating a related molecule, CT340, an inhibitor of both TrkA and MAP2K kinase, for treating those chronic pain conditions.

Creabilis funded the study. Dr. Yosipovitch is on the company’s scientific advisory board.

[email protected]

On Twitter @alz_gal

An investigational topical drug that targets a nerve sensitization pathway showed good efficacy against chronic itch in patients with pruritic psoriasis.

CT327 works by inhibiting the kinase pathway of TrkA, a receptor that controls uptake of nerve growth factor, Dr. Gil Yosipovitch said at the annual meeting of the American Academy of Dermatology.

In a placebo-controlled trial of 160 patients with pruritic psoriasis, CT327 reduced itch by a mean of 60%, said Dr. Yosipovitch, chair of dermatology at the Temple University, Philadelphia.

"Sixty percent is not 90%," he said. "But when we consider that most of the antipruritic drugs have about a 15% efficacy in comparison to a vehicle, this is an effect we should consider. It’s well tolerated, and there were no application site reactions. I see potential in this drug."

CT327, developed by Creabilis, is a selective kinase inhibitor that targets TrkA, the receptor for nerve growth factor (NGF). NGF, which is overexpressed in atopic dermatitis and psoriatic skin, sensitizes neural networks that transmit the itch sensation to the brain, Dr. Yosipovitch said.

© abdone/Thinkstockphotos.com

The phase IIb study comprised 160 adults with mild to moderate psoriasis, with at least a 10% body surface area involvement. Their mean score on the modified Psoriasis Area and Severity Index (mPASI) was about 9. Most (97%) had pruritus; 69% reported this as at least moderate, with a score of 40 on a 100-point visual analog scale (VAS). A third of the group reported severe pruritus, with a VAS of more than 70. They were randomized to four groups: an emollient placebo or CT327 in concentrations of 0.05%, 0.1%, or 0.5%.

The primary endpoint was reduction on a validated 100-point pruritus visual analog scale. The secondary endpoint was change on the mPASI.

By the end of 8 weeks, most patients (108) had experienced a significant reduction on the pruritus VAS. Reductions were about 35 points for the 0.1% group and 38 points for the 0.05% and 0.5% groups. These changes represented about a 60% decrease overall, Dr. Yosipovitch said.

Changes began early and continued along a steep trajectory, reaching a significant difference from baseline by week 2. However, he pointed out, by that point, the placebo group was similarly improved. This was probably because of the benefit of the daily emollient vehicle, he noted.

The curves began to separate shortly thereafter. By week 4, all of the treatment groups had experienced about a 30-point reduction on the VAS, while the placebo group had actually increased its score slightly. The active groups continued to improve over the next 4 weeks, while the placebo group plateaued at about a 20-point decrease from baseline.

The study concluded with 4 weeks of non–treatment follow-up. During that time, the placebo group stayed at about a 20-point decline and the active groups rebounded to about that level, "suggesting that there really is something going on here biologically," Dr. Yosipovitch said.

Patients using CT327 also experienced significant – although not overwhelming – benefit on the mPASI score. About 45% responded at the 50% level, compared with 23% of those using the emollient placebo. The active groups had similar improvements, with reductions on the mPASI of between 3 and 4 points. Those in the placebo group experienced about a 1-point improvement.

Dr. Yosipovitch said he was "not too impressed" with the mPASI changes. However, he noted, "Breaking the itch-scratch cycle at its source may have broader effects on other symptoms of psoriasis."

Based on the study results, Creabilis has decided to move forward into phase III testing with the 0.05% concentration. "Preparations are already underway," Dr. Yosipovitch said in an interview. "We also have a second phase IIb study ongoing that is investigating CT327 in patients with atopic dermatitis, which will be used to help finalize our phase III programs. This study should be completed in the middle of this year."

The NGF/TrkA pathway is implicated in other disorders as well, Dr. Yosipovitch said. CT327 might be investigated in some of these.

"These include disorders [in which] pruritus is important, such as pruritus with cutaneous T cell lymphoma, where NGF/TrkA has been shown to play a role. The pathway has also been shown to play an important role in chronic neuropathic and inflammatory pain. Molecules targeting NGF have already shown clinical efficacy."

Creabilis is investigating a related molecule, CT340, an inhibitor of both TrkA and MAP2K kinase, for treating those chronic pain conditions.

Creabilis funded the study. Dr. Yosipovitch is on the company’s scientific advisory board.

[email protected]

On Twitter @alz_gal

An investigational topical drug that targets a nerve sensitization pathway showed good efficacy against chronic itch in patients with pruritic psoriasis.

CT327 works by inhibiting the kinase pathway of TrkA, a receptor that controls uptake of nerve growth factor, Dr. Gil Yosipovitch said at the annual meeting of the American Academy of Dermatology.

In a placebo-controlled trial of 160 patients with pruritic psoriasis, CT327 reduced itch by a mean of 60%, said Dr. Yosipovitch, chair of dermatology at the Temple University, Philadelphia.

"Sixty percent is not 90%," he said. "But when we consider that most of the antipruritic drugs have about a 15% efficacy in comparison to a vehicle, this is an effect we should consider. It’s well tolerated, and there were no application site reactions. I see potential in this drug."

CT327, developed by Creabilis, is a selective kinase inhibitor that targets TrkA, the receptor for nerve growth factor (NGF). NGF, which is overexpressed in atopic dermatitis and psoriatic skin, sensitizes neural networks that transmit the itch sensation to the brain, Dr. Yosipovitch said.

© abdone/Thinkstockphotos.com

The phase IIb study comprised 160 adults with mild to moderate psoriasis, with at least a 10% body surface area involvement. Their mean score on the modified Psoriasis Area and Severity Index (mPASI) was about 9. Most (97%) had pruritus; 69% reported this as at least moderate, with a score of 40 on a 100-point visual analog scale (VAS). A third of the group reported severe pruritus, with a VAS of more than 70. They were randomized to four groups: an emollient placebo or CT327 in concentrations of 0.05%, 0.1%, or 0.5%.

The primary endpoint was reduction on a validated 100-point pruritus visual analog scale. The secondary endpoint was change on the mPASI.

By the end of 8 weeks, most patients (108) had experienced a significant reduction on the pruritus VAS. Reductions were about 35 points for the 0.1% group and 38 points for the 0.05% and 0.5% groups. These changes represented about a 60% decrease overall, Dr. Yosipovitch said.

Changes began early and continued along a steep trajectory, reaching a significant difference from baseline by week 2. However, he pointed out, by that point, the placebo group was similarly improved. This was probably because of the benefit of the daily emollient vehicle, he noted.

The curves began to separate shortly thereafter. By week 4, all of the treatment groups had experienced about a 30-point reduction on the VAS, while the placebo group had actually increased its score slightly. The active groups continued to improve over the next 4 weeks, while the placebo group plateaued at about a 20-point decrease from baseline.

The study concluded with 4 weeks of non–treatment follow-up. During that time, the placebo group stayed at about a 20-point decline and the active groups rebounded to about that level, "suggesting that there really is something going on here biologically," Dr. Yosipovitch said.

Patients using CT327 also experienced significant – although not overwhelming – benefit on the mPASI score. About 45% responded at the 50% level, compared with 23% of those using the emollient placebo. The active groups had similar improvements, with reductions on the mPASI of between 3 and 4 points. Those in the placebo group experienced about a 1-point improvement.

Dr. Yosipovitch said he was "not too impressed" with the mPASI changes. However, he noted, "Breaking the itch-scratch cycle at its source may have broader effects on other symptoms of psoriasis."

Based on the study results, Creabilis has decided to move forward into phase III testing with the 0.05% concentration. "Preparations are already underway," Dr. Yosipovitch said in an interview. "We also have a second phase IIb study ongoing that is investigating CT327 in patients with atopic dermatitis, which will be used to help finalize our phase III programs. This study should be completed in the middle of this year."

The NGF/TrkA pathway is implicated in other disorders as well, Dr. Yosipovitch said. CT327 might be investigated in some of these.

"These include disorders [in which] pruritus is important, such as pruritus with cutaneous T cell lymphoma, where NGF/TrkA has been shown to play a role. The pathway has also been shown to play an important role in chronic neuropathic and inflammatory pain. Molecules targeting NGF have already shown clinical efficacy."

Creabilis is investigating a related molecule, CT340, an inhibitor of both TrkA and MAP2K kinase, for treating those chronic pain conditions.

Creabilis funded the study. Dr. Yosipovitch is on the company’s scientific advisory board.

[email protected]

On Twitter @alz_gal

DENVER – Key results from a phase III trial found that an investigational Janus kinase inhibitor was noninferior to a biologic agent for treating psoriasis.

During a late-breaking session at the annual meeting of the American Academy of Dermatology, Dr. Fernando Valenzuela presented findings from a multicenter, double-dummy 12-week comparison of tofacitinib vs. etanercept or placebo for the treatment of patients with moderate to severe psoriasis. Tofacitinib is an investigational Janus kinase inhibitor being developed by Pfizer.

Twice-daily tofacitinib at 5 mg and 10 mg was effective in patients with moderate to severe psoriasis, and the efficacy of twice-daily tofacitinib at 10 mg was similar to twice-weekly etanercept at 50 mg and was superior to placebo.

"Plaque psoriasis is a chronic, immune-mediated systemic disease [that] can lead to major quality of life impairment in its moderate to severe forms," said Dr. Valenzuela of the department of dermatology at the University of Chile Clinical Hospital, Santiago. "The JAK/STAT [Janus kinase/signal transducers and activators of transcription] signaling pathway is implicated in the pathogenesis of chronic immune-mediated diseases including psoriasis. Tofacitinib has previously demonstrated significant efficacy in a placebo-controlled, phase II study in patients with moderate to severe plaque psoriasis."

In the 12-week multicenter trial known as OPT Compare, which was conducted in 23 countries outside of North America, he and his associates assessed the noninferiority/superiority of two doses of oral tofacitinib vs. high-dose etanercept or placebo. To be eligible for the trial, patients had to be at least 18 years of age; have moderate to severe chronic plaque psoriasis; be candidates for systemic therapy or phototherapy; have a Psoriasis Area and Severity Index (PASI) of 12 or greater; have a Physician’s Global Assessment (PGA) of moderate or severe; have psoriasis involvement of 10% or greater body surface area; and had failed to respond, tolerate, or have a contraindication to at least one systemic therapy. Patients previously treated with etanercept or who previously experienced failure to treatment with a tumor necrosis factor therapy were excluded from the trial.

Patients were randomized 3:3:3:1 in the following fashion over a 12-week period: 329 received tofacitinib b.i.d.; 330 received tofacitinib 10 mg b.i.d.; 335 received etanercept 50 mg subcutaneously twice weekly; and 107 received placebo. The coprimary efficacy endpoints were the proportion of patients achieving at least a 75% reduction in PASI score at week 12 from baseline and a PGA score of "clear" or "almost clear" at week 12. The researchers used a fixed sequence procedure to assess noninferiority/superiority sequentially in order to control overall type 1 error. The mean age of patients was 44 years and about 82% of patients had moderate disease.

Dr. Valenzuela reported that at 12 weeks, 39.5%, 63.6%, 58.8%, and 5.6% of patients achieved PASI 75 responses and 47.1%, 68.2%, 66.3%, and 15.0% achieved PGA responses with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, etanercept 50 mg twice weekly, and placebo, respectively. Tofacitinib 10 mg twice a day was noninferior to etanercept and superior to placebo (P less than .0001), but tofacitinib 5 mg twice a day did not meet the noninferiority criterion vs. etanercept.

Over 12 weeks, the safety and tolerability of either dose of tofacitinib was similar to that of etanercept. "The most frequent adverse events were infections, most commonly nasopharyngitis and upper respiratory tract infection," Dr. Valenzuela said. "Hypercholesterolemia and dyslipidemia were more common in tofacitinib recipients, as was an increase in creatine phosphokinase*." Injection site reactions were most frequent among etanercept recipients.

The study was sponsored by Pfizer. Dr. Valenzuela disclosed that he has been a principal investigator, member of a scientific advisory board, or speaker for Pfizer, Janssen, Eli Lilly, Merck, and Novartis.

[email protected]

*Correction, 3/27/2014: An earlier version of this article misstated the term creatine phosphokinase.

DENVER – Key results from a phase III trial found that an investigational Janus kinase inhibitor was noninferior to a biologic agent for treating psoriasis.

During a late-breaking session at the annual meeting of the American Academy of Dermatology, Dr. Fernando Valenzuela presented findings from a multicenter, double-dummy 12-week comparison of tofacitinib vs. etanercept or placebo for the treatment of patients with moderate to severe psoriasis. Tofacitinib is an investigational Janus kinase inhibitor being developed by Pfizer.

Twice-daily tofacitinib at 5 mg and 10 mg was effective in patients with moderate to severe psoriasis, and the efficacy of twice-daily tofacitinib at 10 mg was similar to twice-weekly etanercept at 50 mg and was superior to placebo.

"Plaque psoriasis is a chronic, immune-mediated systemic disease [that] can lead to major quality of life impairment in its moderate to severe forms," said Dr. Valenzuela of the department of dermatology at the University of Chile Clinical Hospital, Santiago. "The JAK/STAT [Janus kinase/signal transducers and activators of transcription] signaling pathway is implicated in the pathogenesis of chronic immune-mediated diseases including psoriasis. Tofacitinib has previously demonstrated significant efficacy in a placebo-controlled, phase II study in patients with moderate to severe plaque psoriasis."

In the 12-week multicenter trial known as OPT Compare, which was conducted in 23 countries outside of North America, he and his associates assessed the noninferiority/superiority of two doses of oral tofacitinib vs. high-dose etanercept or placebo. To be eligible for the trial, patients had to be at least 18 years of age; have moderate to severe chronic plaque psoriasis; be candidates for systemic therapy or phototherapy; have a Psoriasis Area and Severity Index (PASI) of 12 or greater; have a Physician’s Global Assessment (PGA) of moderate or severe; have psoriasis involvement of 10% or greater body surface area; and had failed to respond, tolerate, or have a contraindication to at least one systemic therapy. Patients previously treated with etanercept or who previously experienced failure to treatment with a tumor necrosis factor therapy were excluded from the trial.

Patients were randomized 3:3:3:1 in the following fashion over a 12-week period: 329 received tofacitinib b.i.d.; 330 received tofacitinib 10 mg b.i.d.; 335 received etanercept 50 mg subcutaneously twice weekly; and 107 received placebo. The coprimary efficacy endpoints were the proportion of patients achieving at least a 75% reduction in PASI score at week 12 from baseline and a PGA score of "clear" or "almost clear" at week 12. The researchers used a fixed sequence procedure to assess noninferiority/superiority sequentially in order to control overall type 1 error. The mean age of patients was 44 years and about 82% of patients had moderate disease.

Dr. Valenzuela reported that at 12 weeks, 39.5%, 63.6%, 58.8%, and 5.6% of patients achieved PASI 75 responses and 47.1%, 68.2%, 66.3%, and 15.0% achieved PGA responses with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, etanercept 50 mg twice weekly, and placebo, respectively. Tofacitinib 10 mg twice a day was noninferior to etanercept and superior to placebo (P less than .0001), but tofacitinib 5 mg twice a day did not meet the noninferiority criterion vs. etanercept.

Over 12 weeks, the safety and tolerability of either dose of tofacitinib was similar to that of etanercept. "The most frequent adverse events were infections, most commonly nasopharyngitis and upper respiratory tract infection," Dr. Valenzuela said. "Hypercholesterolemia and dyslipidemia were more common in tofacitinib recipients, as was an increase in creatine phosphokinase*." Injection site reactions were most frequent among etanercept recipients.

The study was sponsored by Pfizer. Dr. Valenzuela disclosed that he has been a principal investigator, member of a scientific advisory board, or speaker for Pfizer, Janssen, Eli Lilly, Merck, and Novartis.

[email protected]

*Correction, 3/27/2014: An earlier version of this article misstated the term creatine phosphokinase.

DENVER – Key results from a phase III trial found that an investigational Janus kinase inhibitor was noninferior to a biologic agent for treating psoriasis.

During a late-breaking session at the annual meeting of the American Academy of Dermatology, Dr. Fernando Valenzuela presented findings from a multicenter, double-dummy 12-week comparison of tofacitinib vs. etanercept or placebo for the treatment of patients with moderate to severe psoriasis. Tofacitinib is an investigational Janus kinase inhibitor being developed by Pfizer.

Twice-daily tofacitinib at 5 mg and 10 mg was effective in patients with moderate to severe psoriasis, and the efficacy of twice-daily tofacitinib at 10 mg was similar to twice-weekly etanercept at 50 mg and was superior to placebo.

"Plaque psoriasis is a chronic, immune-mediated systemic disease [that] can lead to major quality of life impairment in its moderate to severe forms," said Dr. Valenzuela of the department of dermatology at the University of Chile Clinical Hospital, Santiago. "The JAK/STAT [Janus kinase/signal transducers and activators of transcription] signaling pathway is implicated in the pathogenesis of chronic immune-mediated diseases including psoriasis. Tofacitinib has previously demonstrated significant efficacy in a placebo-controlled, phase II study in patients with moderate to severe plaque psoriasis."

In the 12-week multicenter trial known as OPT Compare, which was conducted in 23 countries outside of North America, he and his associates assessed the noninferiority/superiority of two doses of oral tofacitinib vs. high-dose etanercept or placebo. To be eligible for the trial, patients had to be at least 18 years of age; have moderate to severe chronic plaque psoriasis; be candidates for systemic therapy or phototherapy; have a Psoriasis Area and Severity Index (PASI) of 12 or greater; have a Physician’s Global Assessment (PGA) of moderate or severe; have psoriasis involvement of 10% or greater body surface area; and had failed to respond, tolerate, or have a contraindication to at least one systemic therapy. Patients previously treated with etanercept or who previously experienced failure to treatment with a tumor necrosis factor therapy were excluded from the trial.

Patients were randomized 3:3:3:1 in the following fashion over a 12-week period: 329 received tofacitinib b.i.d.; 330 received tofacitinib 10 mg b.i.d.; 335 received etanercept 50 mg subcutaneously twice weekly; and 107 received placebo. The coprimary efficacy endpoints were the proportion of patients achieving at least a 75% reduction in PASI score at week 12 from baseline and a PGA score of "clear" or "almost clear" at week 12. The researchers used a fixed sequence procedure to assess noninferiority/superiority sequentially in order to control overall type 1 error. The mean age of patients was 44 years and about 82% of patients had moderate disease.

Dr. Valenzuela reported that at 12 weeks, 39.5%, 63.6%, 58.8%, and 5.6% of patients achieved PASI 75 responses and 47.1%, 68.2%, 66.3%, and 15.0% achieved PGA responses with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, etanercept 50 mg twice weekly, and placebo, respectively. Tofacitinib 10 mg twice a day was noninferior to etanercept and superior to placebo (P less than .0001), but tofacitinib 5 mg twice a day did not meet the noninferiority criterion vs. etanercept.

Over 12 weeks, the safety and tolerability of either dose of tofacitinib was similar to that of etanercept. "The most frequent adverse events were infections, most commonly nasopharyngitis and upper respiratory tract infection," Dr. Valenzuela said. "Hypercholesterolemia and dyslipidemia were more common in tofacitinib recipients, as was an increase in creatine phosphokinase*." Injection site reactions were most frequent among etanercept recipients.

The study was sponsored by Pfizer. Dr. Valenzuela disclosed that he has been a principal investigator, member of a scientific advisory board, or speaker for Pfizer, Janssen, Eli Lilly, Merck, and Novartis.

[email protected]

*Correction, 3/27/2014: An earlier version of this article misstated the term creatine phosphokinase.

Apremilast, an oral phosphodiesterase-4 inhibitor, has been approved for treating adults with active psoriatic arthritis, based on the results of three studies of 1,493 patients, the Food and Drug Administration announced on March 21.

As a postmarketing requirement, the manufacturer will evaluate the effects of exposure to treatment in pregnant women with a pregnancy registry, according to an FDA statement.

In the three studies, the signs and symptoms of psoriatic arthritis improved among patients treated with apremilast, compared with those on placebo. Diarrhea, nausea, and headache were the most common adverse events associated with treatment. Depression was reported more frequently among those treated with apremilast in the studies, according to the FDA.

Results of the phase III studies were reported in 2013 at the American College of Rheumatology annual meeting and at the annual European Congress of Rheumatology.

During treatment, health care professionals are advised to regularly monitor the weight of patients, and "if unexplained or clinically significant weight loss occurs, the weight loss should be evaluated and discontinuation of treatment should be considered," the statement said. Celgene Corporation will market apremilast under the brand name Otezla.

[email protected]

Apremilast, an oral phosphodiesterase-4 inhibitor, has been approved for treating adults with active psoriatic arthritis, based on the results of three studies of 1,493 patients, the Food and Drug Administration announced on March 21.

As a postmarketing requirement, the manufacturer will evaluate the effects of exposure to treatment in pregnant women with a pregnancy registry, according to an FDA statement.

In the three studies, the signs and symptoms of psoriatic arthritis improved among patients treated with apremilast, compared with those on placebo. Diarrhea, nausea, and headache were the most common adverse events associated with treatment. Depression was reported more frequently among those treated with apremilast in the studies, according to the FDA.

Results of the phase III studies were reported in 2013 at the American College of Rheumatology annual meeting and at the annual European Congress of Rheumatology.

During treatment, health care professionals are advised to regularly monitor the weight of patients, and "if unexplained or clinically significant weight loss occurs, the weight loss should be evaluated and discontinuation of treatment should be considered," the statement said. Celgene Corporation will market apremilast under the brand name Otezla.

[email protected]

Apremilast, an oral phosphodiesterase-4 inhibitor, has been approved for treating adults with active psoriatic arthritis, based on the results of three studies of 1,493 patients, the Food and Drug Administration announced on March 21.

As a postmarketing requirement, the manufacturer will evaluate the effects of exposure to treatment in pregnant women with a pregnancy registry, according to an FDA statement.

In the three studies, the signs and symptoms of psoriatic arthritis improved among patients treated with apremilast, compared with those on placebo. Diarrhea, nausea, and headache were the most common adverse events associated with treatment. Depression was reported more frequently among those treated with apremilast in the studies, according to the FDA.

Results of the phase III studies were reported in 2013 at the American College of Rheumatology annual meeting and at the annual European Congress of Rheumatology.

During treatment, health care professionals are advised to regularly monitor the weight of patients, and "if unexplained or clinically significant weight loss occurs, the weight loss should be evaluated and discontinuation of treatment should be considered," the statement said. Celgene Corporation will market apremilast under the brand name Otezla.

[email protected]

Benzophenones, chemical ultraviolet light absorbers used in products ranging from sunscreens and hair sprays to plastic lens filters for color photography, have been named the American Contact Dermatitis Society’s 2014 Contact Allergen of the Year.

First used as a preserver to extend the shelf life of paints, varnishes, and other industrial products, benzophenones were added to sunscreens in the 1950s. Other personal care products that may contain benzophenones are hair dyes, perfumes, shampoos, detergent bars, and nail polishes. The agents are still used in number of industrial applications, including plastic lens filters for color photography, aerosol sprays to protect color prints, and transparent shades to protect window displays. According to a feature article in the January/February 2014 issue of the journal Dermatitis, benzophenones-3, -4, -8, and -10 rank as the four agents most commonly used in personal care products. In addition, the amount of benzophenone-3 used in United States sunscreens is more than all other benzophenones combined (Dermatitis 2014;25:3-10).

Today, benzophenone-3 "is not only the most common benzophenone to cause positive patch test reactions, but it also is the most common UV filter, overall, to cause allergy," wrote lead author Ashley R. Heurung, a fourth-year student at the University of Minnesota, Minneapolis, and her associates. "The most recent 10-year retrospective analysis of the North American Contact Dermatitis Group Data (NACDG; 2001-2010) found that of the 219 of 23,908 patch-tested patients with sunscreen listed as an allergen source, 70.2% had positive patch test reactions to benzophenone-3" (Dermatitis 2013;24:176-82).

In an interview, coauthor Erin M. Warshaw, chief of dermatology at the Minneapolis Veterans Affairs Medical Center, said that benzophenones were chosen as Allergen of the Year "to raise awareness that they are becoming more of a common allergen, and [to recommend] that they should be on a standard screening series, because they’re in so many products like sunscreen, shampoo, conditioner, perfumes, and hand sanitizers. If you’re not thinking about sunscreen [as a potential allergen], you’ll miss it," Dr. Warshaw said.

The American Contact Dermatitis Society’s Core Screening Series includes benzophenones, "but most dermatologists use T.R.U.E. Test, a prepackaged kit of 36 allergens," Dr. Warshaw noted. "Benzophenones are not on that series."

Reports of contact dermatitis triggered by benzophenone-4 have appeared in recent medical literature, but data regarding adverse reactions of benzophenones-8 and -10 are scarce. The authors noted that benzophenone-3 is the culprit in more photoallergic contact dermatitis reactions than any other UV filter available, although large photopatch studies have shown that benzophenone-4 is a leading cause of photoallergy in patients with adverse reactions to sunscreens. Benzophenones-10 and -2 also have been implicated in photopatch reaction tests, but no reports of photoallergy to benzophenone-8 have been documented.

The authors added that benzophenone-3 shows high rates of cross-reactivity with octocrylene and ketoprofen, and that at least two cases of anaphylaxis from topical application of benzophenone-3 have been published (J. Allergy Clin. Immunol. 2001;107:556-7 and Contact Dermatitis 2002;46:55-6). "Both cases resulted in generalized wheal and flare reactions and syncope after widespread application of a sunscreen or sunless tanning product with this filter," they wrote. "Contact urticaria developed after more limited exposure to benzophenone-3 in both cases."

The authors stated that they had relevant conflicts to disclose.

[email protected]

Benzophenones, chemical ultraviolet light absorbers used in products ranging from sunscreens and hair sprays to plastic lens filters for color photography, have been named the American Contact Dermatitis Society’s 2014 Contact Allergen of the Year.

First used as a preserver to extend the shelf life of paints, varnishes, and other industrial products, benzophenones were added to sunscreens in the 1950s. Other personal care products that may contain benzophenones are hair dyes, perfumes, shampoos, detergent bars, and nail polishes. The agents are still used in number of industrial applications, including plastic lens filters for color photography, aerosol sprays to protect color prints, and transparent shades to protect window displays. According to a feature article in the January/February 2014 issue of the journal Dermatitis, benzophenones-3, -4, -8, and -10 rank as the four agents most commonly used in personal care products. In addition, the amount of benzophenone-3 used in United States sunscreens is more than all other benzophenones combined (Dermatitis 2014;25:3-10).

Today, benzophenone-3 "is not only the most common benzophenone to cause positive patch test reactions, but it also is the most common UV filter, overall, to cause allergy," wrote lead author Ashley R. Heurung, a fourth-year student at the University of Minnesota, Minneapolis, and her associates. "The most recent 10-year retrospective analysis of the North American Contact Dermatitis Group Data (NACDG; 2001-2010) found that of the 219 of 23,908 patch-tested patients with sunscreen listed as an allergen source, 70.2% had positive patch test reactions to benzophenone-3" (Dermatitis 2013;24:176-82).

In an interview, coauthor Erin M. Warshaw, chief of dermatology at the Minneapolis Veterans Affairs Medical Center, said that benzophenones were chosen as Allergen of the Year "to raise awareness that they are becoming more of a common allergen, and [to recommend] that they should be on a standard screening series, because they’re in so many products like sunscreen, shampoo, conditioner, perfumes, and hand sanitizers. If you’re not thinking about sunscreen [as a potential allergen], you’ll miss it," Dr. Warshaw said.

The American Contact Dermatitis Society’s Core Screening Series includes benzophenones, "but most dermatologists use T.R.U.E. Test, a prepackaged kit of 36 allergens," Dr. Warshaw noted. "Benzophenones are not on that series."

Reports of contact dermatitis triggered by benzophenone-4 have appeared in recent medical literature, but data regarding adverse reactions of benzophenones-8 and -10 are scarce. The authors noted that benzophenone-3 is the culprit in more photoallergic contact dermatitis reactions than any other UV filter available, although large photopatch studies have shown that benzophenone-4 is a leading cause of photoallergy in patients with adverse reactions to sunscreens. Benzophenones-10 and -2 also have been implicated in photopatch reaction tests, but no reports of photoallergy to benzophenone-8 have been documented.

The authors added that benzophenone-3 shows high rates of cross-reactivity with octocrylene and ketoprofen, and that at least two cases of anaphylaxis from topical application of benzophenone-3 have been published (J. Allergy Clin. Immunol. 2001;107:556-7 and Contact Dermatitis 2002;46:55-6). "Both cases resulted in generalized wheal and flare reactions and syncope after widespread application of a sunscreen or sunless tanning product with this filter," they wrote. "Contact urticaria developed after more limited exposure to benzophenone-3 in both cases."

The authors stated that they had relevant conflicts to disclose.

[email protected]

Benzophenones, chemical ultraviolet light absorbers used in products ranging from sunscreens and hair sprays to plastic lens filters for color photography, have been named the American Contact Dermatitis Society’s 2014 Contact Allergen of the Year.

First used as a preserver to extend the shelf life of paints, varnishes, and other industrial products, benzophenones were added to sunscreens in the 1950s. Other personal care products that may contain benzophenones are hair dyes, perfumes, shampoos, detergent bars, and nail polishes. The agents are still used in number of industrial applications, including plastic lens filters for color photography, aerosol sprays to protect color prints, and transparent shades to protect window displays. According to a feature article in the January/February 2014 issue of the journal Dermatitis, benzophenones-3, -4, -8, and -10 rank as the four agents most commonly used in personal care products. In addition, the amount of benzophenone-3 used in United States sunscreens is more than all other benzophenones combined (Dermatitis 2014;25:3-10).

Today, benzophenone-3 "is not only the most common benzophenone to cause positive patch test reactions, but it also is the most common UV filter, overall, to cause allergy," wrote lead author Ashley R. Heurung, a fourth-year student at the University of Minnesota, Minneapolis, and her associates. "The most recent 10-year retrospective analysis of the North American Contact Dermatitis Group Data (NACDG; 2001-2010) found that of the 219 of 23,908 patch-tested patients with sunscreen listed as an allergen source, 70.2% had positive patch test reactions to benzophenone-3" (Dermatitis 2013;24:176-82).

In an interview, coauthor Erin M. Warshaw, chief of dermatology at the Minneapolis Veterans Affairs Medical Center, said that benzophenones were chosen as Allergen of the Year "to raise awareness that they are becoming more of a common allergen, and [to recommend] that they should be on a standard screening series, because they’re in so many products like sunscreen, shampoo, conditioner, perfumes, and hand sanitizers. If you’re not thinking about sunscreen [as a potential allergen], you’ll miss it," Dr. Warshaw said.

The American Contact Dermatitis Society’s Core Screening Series includes benzophenones, "but most dermatologists use T.R.U.E. Test, a prepackaged kit of 36 allergens," Dr. Warshaw noted. "Benzophenones are not on that series."

Reports of contact dermatitis triggered by benzophenone-4 have appeared in recent medical literature, but data regarding adverse reactions of benzophenones-8 and -10 are scarce. The authors noted that benzophenone-3 is the culprit in more photoallergic contact dermatitis reactions than any other UV filter available, although large photopatch studies have shown that benzophenone-4 is a leading cause of photoallergy in patients with adverse reactions to sunscreens. Benzophenones-10 and -2 also have been implicated in photopatch reaction tests, but no reports of photoallergy to benzophenone-8 have been documented.

The authors added that benzophenone-3 shows high rates of cross-reactivity with octocrylene and ketoprofen, and that at least two cases of anaphylaxis from topical application of benzophenone-3 have been published (J. Allergy Clin. Immunol. 2001;107:556-7 and Contact Dermatitis 2002;46:55-6). "Both cases resulted in generalized wheal and flare reactions and syncope after widespread application of a sunscreen or sunless tanning product with this filter," they wrote. "Contact urticaria developed after more limited exposure to benzophenone-3 in both cases."

The authors stated that they had relevant conflicts to disclose.

[email protected]

Autosomal recessive mutations in the gene CECR1 cause an inflammatory vasculopathy with a highly varied clinical presentation that often meets the criteria for polyarteritis nodosa and can occur with early-onset strokes, according to findings from two separate reports on families with several affected members as well as unrelated affected persons.

All but 2 of the combined total of 33 patients in both studies were younger than 18 years at the onset of disease, including 13 with a history of lacunar strokes and 12 who met criteria for polyarteritis nodosa (PAN) from the Paediatric Rheumatology European Society and the European League Against Rheumatism for those with an onset before 18 years of age or from the American College of Rheumatology at an onset of 18 years of age or older.

The studies identified 12 CECR1 (cat eye syndrome chromosome region, candidate 1) variants that encoded dysfunctional adenosine deaminase 2 (ADA2) proteins. In one report, Israeli and German researchers described individuals who presented primarily with features of polyarteritis nodosa. They identified mutations in 16 patients from five families of Georgian Jewish ancestry and four siblings from one family of German ancestry, as well as single cases in three unrelated patients of Georgian Jewish ancestry and 1 Turkish patient who had been referred to them (N. Engl. J. Med. 2014;370:921-31).

Maggie Bartlett, NHGRI

In the other report, researchers from the National Institutes of Health studied nine patients with pediatric onset of disease, including five patients from the United States, one from the United Kingdom, and three from Turkey, including one pair of siblings. Eight of the patients presented with a history of lacunar strokes (N. Engl. J. Med. 2014;370:911-20).

Both reports used whole-exome sequencing in most cases and candidate-gene sequencing in others to detect autosomally recessive mutations in CECR1 (cat’s eye syndrome chromosome region, candidate 1) that cause a deficiency in adenosine deaminase 2 (ADA2), including cases with heterozygous compound mutations. Cell culture experiments indicated that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and modeling of the mutations’ effects in zebrafish resulted in intracranial hemorrhages.

One of the main differences between the two studies was in the differing presentation of patients, with mainly strokes in the NIH study but more PAN-like disease and peripheral nervous system involvement in the Israeli and German study.

All of the patients in the Israeli and German study had highly variable disease severity, even within families. Of the 19 Georgian Jewish patients, 18 had cutaneous manifestation of the disease, mainly livedo reticularis, although some had ischemia and necrosis of the fingers and toes. Fever was present in 11, and myalgia and/or arthralgia occurred in 12. Ten had visceral features, six of which were gastrointestinal, and eight had neurologic disease, most of which occurred peripherally. Among the four German siblings, all had peripheral neuropathy, three had symptomatic or subclinical brain infarctions, three had cutaneous manifestations, and three had myalgia and/or arthralgia, but none had visceral involvement. The single Turkish patient had most of these clinical manifestations except for peripheral or central nervous system involvement. Not all of the 24 patients in the Israeli and German study were fully evaluated for PAN, but nearly all were suspected of having the disease.

The NIH team compiled cases that were most striking for the history of early-onset ischemic lacunar stroke in eight of the nine patients, including five from the United States who had strokes before the age of 5 years but showed no signs of cerebral vasculitis on MR angiography. Three patients also had hemorrhagic stroke or hemorrhagic transformation. All patients had recurrent fever, eight had livedo racemosa, and five had ophthalmologic involvement. Only the two Turkish siblings had a diagnosis of PAN.

The spectrum of disease observed in the studies could be related to what CECR1 mutation is present, with 12 overall reported in the two studies, according to one of the NIH study investigators, Dr. Daniel L. Kastner, a rheumatologist and scientific director of the National Human Genome Research Institute. He also is head of the inflammatory diseases section in the medical genetics branch of the Institute.

"It wouldn’t be surprising to me if certain mutations are associated with certain clinical presentations," he said in an interview.

The most common mutation reported among the Georgian Jewish patients – all of whom were diagnosed with PAN – was also found in the NIH study’s three Turkish patients, two of whom had a PAN diagnosis. This variant had a carrier frequency of about 10% in a control group of 246 unrelated Georgian Jewish controls, which would predict based on Mendelian genetic principles that 1 in 400 individuals in the Georgian Jewish population in Israel would carry two copies of the variant. The individuals who were homozygous for that variant in the Israeli and German study showed variability in phenotype, ranging from a diagnosis of diagnosed PAN to milder disease not meeting the full criteria for PAN. Given the relative commonality of the variant, ADA2-associated disease in Georgian Jewish people and other populations is likely underdiagnosed or being misdiagnosed for other conditions because of the clinical variability, Dr. Kastner said.

NIH investigators have talked with Dr. Peter Merkel, principal investigator and director of the Vasculitis Clinical Research Consortium, about conducting collaborative studies to look for variants of ADA2 in others who have nonfamilial PAN and did not have early-onset disease. "Even if they don’t [have variants in ADA2], it may still be the case that the pathway is somehow important and studies of biopsies from those patients would in some way allow us to connect that pathway to their disease. But that’s unknown," Dr. Kastner said.

When Dr. Kastner and his associates were looking for the mutations in other genetics databases, they found that whole-exome sequencing of 47 pairs of siblings with late-onset ischemic stroke in the Siblings With Ischemic Stroke Study had detected two brothers who each were heterozygous carriers of one of the mutations discovered in the study. Their ischemic strokes were similar in distribution to those seen in children with two mutations. "So it’s at least possible, although at this point it’s not formally proven, [that] that perhaps carrying one copy of this mutation, as opposed to having two as these kids have, could put you at some risk for having stroke later on in life. And it may be that, similarly, having one copy of a variant in this gene would predispose to other forms of vasculitis as well."

In three of the patients in the NIH study, treatment with low doses of fresh frozen plasma as a replacement therapy for ADA2 deficiency has appeared to be safe, but getting enough of it into patients and knowing whether it will last long enough are questions that the investigators are currently trying to answer, Dr. Kastner said. Initially, Dr. Kastner said his group was hesitant to use anti–tumor necrosis factor-alpha agents to treat patients because of the known, but small risk of demyelination with their use, which would not have been appropriate to try in patients who already had neurologic problems, because it would be very hard to tell if further lesions would be caused by underlying disease or the drug. However, when the Israeli group reported success with anti-TNF-alpha agents in their patients (and ultimately reported that 10 patients had a clinically significant therapeutic response), the NIH investigators decided to try them. Treatment with etanercept in five patients has reduced the occurrence of fevers in all and improved urticarial papules and plaques observed in three patients.

Pediatric rheumatologists who have patients with vasculitis or are suspected of having vasculitis should keep CECR1 mutations in mind now that the cause and some of the natural history and possible treatments for early-onset disease are known. Rheumatologists seeing adult patients with PAN could consider these mutations as a possible cause and at least note that some of these pathways may be important in their patients even if they don’t have mutations in CECR1, advised Dr. Kastner. He had no financial conflicts to disclose.

[email protected]

Autosomal recessive mutations in the gene CECR1 cause an inflammatory vasculopathy with a highly varied clinical presentation that often meets the criteria for polyarteritis nodosa and can occur with early-onset strokes, according to findings from two separate reports on families with several affected members as well as unrelated affected persons.

All but 2 of the combined total of 33 patients in both studies were younger than 18 years at the onset of disease, including 13 with a history of lacunar strokes and 12 who met criteria for polyarteritis nodosa (PAN) from the Paediatric Rheumatology European Society and the European League Against Rheumatism for those with an onset before 18 years of age or from the American College of Rheumatology at an onset of 18 years of age or older.

The studies identified 12 CECR1 (cat eye syndrome chromosome region, candidate 1) variants that encoded dysfunctional adenosine deaminase 2 (ADA2) proteins. In one report, Israeli and German researchers described individuals who presented primarily with features of polyarteritis nodosa. They identified mutations in 16 patients from five families of Georgian Jewish ancestry and four siblings from one family of German ancestry, as well as single cases in three unrelated patients of Georgian Jewish ancestry and 1 Turkish patient who had been referred to them (N. Engl. J. Med. 2014;370:921-31).

Maggie Bartlett, NHGRI

In the other report, researchers from the National Institutes of Health studied nine patients with pediatric onset of disease, including five patients from the United States, one from the United Kingdom, and three from Turkey, including one pair of siblings. Eight of the patients presented with a history of lacunar strokes (N. Engl. J. Med. 2014;370:911-20).

Both reports used whole-exome sequencing in most cases and candidate-gene sequencing in others to detect autosomally recessive mutations in CECR1 (cat’s eye syndrome chromosome region, candidate 1) that cause a deficiency in adenosine deaminase 2 (ADA2), including cases with heterozygous compound mutations. Cell culture experiments indicated that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and modeling of the mutations’ effects in zebrafish resulted in intracranial hemorrhages.

One of the main differences between the two studies was in the differing presentation of patients, with mainly strokes in the NIH study but more PAN-like disease and peripheral nervous system involvement in the Israeli and German study.

All of the patients in the Israeli and German study had highly variable disease severity, even within families. Of the 19 Georgian Jewish patients, 18 had cutaneous manifestation of the disease, mainly livedo reticularis, although some had ischemia and necrosis of the fingers and toes. Fever was present in 11, and myalgia and/or arthralgia occurred in 12. Ten had visceral features, six of which were gastrointestinal, and eight had neurologic disease, most of which occurred peripherally. Among the four German siblings, all had peripheral neuropathy, three had symptomatic or subclinical brain infarctions, three had cutaneous manifestations, and three had myalgia and/or arthralgia, but none had visceral involvement. The single Turkish patient had most of these clinical manifestations except for peripheral or central nervous system involvement. Not all of the 24 patients in the Israeli and German study were fully evaluated for PAN, but nearly all were suspected of having the disease.

The NIH team compiled cases that were most striking for the history of early-onset ischemic lacunar stroke in eight of the nine patients, including five from the United States who had strokes before the age of 5 years but showed no signs of cerebral vasculitis on MR angiography. Three patients also had hemorrhagic stroke or hemorrhagic transformation. All patients had recurrent fever, eight had livedo racemosa, and five had ophthalmologic involvement. Only the two Turkish siblings had a diagnosis of PAN.

The spectrum of disease observed in the studies could be related to what CECR1 mutation is present, with 12 overall reported in the two studies, according to one of the NIH study investigators, Dr. Daniel L. Kastner, a rheumatologist and scientific director of the National Human Genome Research Institute. He also is head of the inflammatory diseases section in the medical genetics branch of the Institute.

"It wouldn’t be surprising to me if certain mutations are associated with certain clinical presentations," he said in an interview.

The most common mutation reported among the Georgian Jewish patients – all of whom were diagnosed with PAN – was also found in the NIH study’s three Turkish patients, two of whom had a PAN diagnosis. This variant had a carrier frequency of about 10% in a control group of 246 unrelated Georgian Jewish controls, which would predict based on Mendelian genetic principles that 1 in 400 individuals in the Georgian Jewish population in Israel would carry two copies of the variant. The individuals who were homozygous for that variant in the Israeli and German study showed variability in phenotype, ranging from a diagnosis of diagnosed PAN to milder disease not meeting the full criteria for PAN. Given the relative commonality of the variant, ADA2-associated disease in Georgian Jewish people and other populations is likely underdiagnosed or being misdiagnosed for other conditions because of the clinical variability, Dr. Kastner said.

NIH investigators have talked with Dr. Peter Merkel, principal investigator and director of the Vasculitis Clinical Research Consortium, about conducting collaborative studies to look for variants of ADA2 in others who have nonfamilial PAN and did not have early-onset disease. "Even if they don’t [have variants in ADA2], it may still be the case that the pathway is somehow important and studies of biopsies from those patients would in some way allow us to connect that pathway to their disease. But that’s unknown," Dr. Kastner said.

When Dr. Kastner and his associates were looking for the mutations in other genetics databases, they found that whole-exome sequencing of 47 pairs of siblings with late-onset ischemic stroke in the Siblings With Ischemic Stroke Study had detected two brothers who each were heterozygous carriers of one of the mutations discovered in the study. Their ischemic strokes were similar in distribution to those seen in children with two mutations. "So it’s at least possible, although at this point it’s not formally proven, [that] that perhaps carrying one copy of this mutation, as opposed to having two as these kids have, could put you at some risk for having stroke later on in life. And it may be that, similarly, having one copy of a variant in this gene would predispose to other forms of vasculitis as well."

In three of the patients in the NIH study, treatment with low doses of fresh frozen plasma as a replacement therapy for ADA2 deficiency has appeared to be safe, but getting enough of it into patients and knowing whether it will last long enough are questions that the investigators are currently trying to answer, Dr. Kastner said. Initially, Dr. Kastner said his group was hesitant to use anti–tumor necrosis factor-alpha agents to treat patients because of the known, but small risk of demyelination with their use, which would not have been appropriate to try in patients who already had neurologic problems, because it would be very hard to tell if further lesions would be caused by underlying disease or the drug. However, when the Israeli group reported success with anti-TNF-alpha agents in their patients (and ultimately reported that 10 patients had a clinically significant therapeutic response), the NIH investigators decided to try them. Treatment with etanercept in five patients has reduced the occurrence of fevers in all and improved urticarial papules and plaques observed in three patients.

Pediatric rheumatologists who have patients with vasculitis or are suspected of having vasculitis should keep CECR1 mutations in mind now that the cause and some of the natural history and possible treatments for early-onset disease are known. Rheumatologists seeing adult patients with PAN could consider these mutations as a possible cause and at least note that some of these pathways may be important in their patients even if they don’t have mutations in CECR1, advised Dr. Kastner. He had no financial conflicts to disclose.

[email protected]

Autosomal recessive mutations in the gene CECR1 cause an inflammatory vasculopathy with a highly varied clinical presentation that often meets the criteria for polyarteritis nodosa and can occur with early-onset strokes, according to findings from two separate reports on families with several affected members as well as unrelated affected persons.

All but 2 of the combined total of 33 patients in both studies were younger than 18 years at the onset of disease, including 13 with a history of lacunar strokes and 12 who met criteria for polyarteritis nodosa (PAN) from the Paediatric Rheumatology European Society and the European League Against Rheumatism for those with an onset before 18 years of age or from the American College of Rheumatology at an onset of 18 years of age or older.

The studies identified 12 CECR1 (cat eye syndrome chromosome region, candidate 1) variants that encoded dysfunctional adenosine deaminase 2 (ADA2) proteins. In one report, Israeli and German researchers described individuals who presented primarily with features of polyarteritis nodosa. They identified mutations in 16 patients from five families of Georgian Jewish ancestry and four siblings from one family of German ancestry, as well as single cases in three unrelated patients of Georgian Jewish ancestry and 1 Turkish patient who had been referred to them (N. Engl. J. Med. 2014;370:921-31).

Maggie Bartlett, NHGRI

In the other report, researchers from the National Institutes of Health studied nine patients with pediatric onset of disease, including five patients from the United States, one from the United Kingdom, and three from Turkey, including one pair of siblings. Eight of the patients presented with a history of lacunar strokes (N. Engl. J. Med. 2014;370:911-20).

Both reports used whole-exome sequencing in most cases and candidate-gene sequencing in others to detect autosomally recessive mutations in CECR1 (cat’s eye syndrome chromosome region, candidate 1) that cause a deficiency in adenosine deaminase 2 (ADA2), including cases with heterozygous compound mutations. Cell culture experiments indicated that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and modeling of the mutations’ effects in zebrafish resulted in intracranial hemorrhages.

One of the main differences between the two studies was in the differing presentation of patients, with mainly strokes in the NIH study but more PAN-like disease and peripheral nervous system involvement in the Israeli and German study.

All of the patients in the Israeli and German study had highly variable disease severity, even within families. Of the 19 Georgian Jewish patients, 18 had cutaneous manifestation of the disease, mainly livedo reticularis, although some had ischemia and necrosis of the fingers and toes. Fever was present in 11, and myalgia and/or arthralgia occurred in 12. Ten had visceral features, six of which were gastrointestinal, and eight had neurologic disease, most of which occurred peripherally. Among the four German siblings, all had peripheral neuropathy, three had symptomatic or subclinical brain infarctions, three had cutaneous manifestations, and three had myalgia and/or arthralgia, but none had visceral involvement. The single Turkish patient had most of these clinical manifestations except for peripheral or central nervous system involvement. Not all of the 24 patients in the Israeli and German study were fully evaluated for PAN, but nearly all were suspected of having the disease.

The NIH team compiled cases that were most striking for the history of early-onset ischemic lacunar stroke in eight of the nine patients, including five from the United States who had strokes before the age of 5 years but showed no signs of cerebral vasculitis on MR angiography. Three patients also had hemorrhagic stroke or hemorrhagic transformation. All patients had recurrent fever, eight had livedo racemosa, and five had ophthalmologic involvement. Only the two Turkish siblings had a diagnosis of PAN.

The spectrum of disease observed in the studies could be related to what CECR1 mutation is present, with 12 overall reported in the two studies, according to one of the NIH study investigators, Dr. Daniel L. Kastner, a rheumatologist and scientific director of the National Human Genome Research Institute. He also is head of the inflammatory diseases section in the medical genetics branch of the Institute.

"It wouldn’t be surprising to me if certain mutations are associated with certain clinical presentations," he said in an interview.

The most common mutation reported among the Georgian Jewish patients – all of whom were diagnosed with PAN – was also found in the NIH study’s three Turkish patients, two of whom had a PAN diagnosis. This variant had a carrier frequency of about 10% in a control group of 246 unrelated Georgian Jewish controls, which would predict based on Mendelian genetic principles that 1 in 400 individuals in the Georgian Jewish population in Israel would carry two copies of the variant. The individuals who were homozygous for that variant in the Israeli and German study showed variability in phenotype, ranging from a diagnosis of diagnosed PAN to milder disease not meeting the full criteria for PAN. Given the relative commonality of the variant, ADA2-associated disease in Georgian Jewish people and other populations is likely underdiagnosed or being misdiagnosed for other conditions because of the clinical variability, Dr. Kastner said.

NIH investigators have talked with Dr. Peter Merkel, principal investigator and director of the Vasculitis Clinical Research Consortium, about conducting collaborative studies to look for variants of ADA2 in others who have nonfamilial PAN and did not have early-onset disease. "Even if they don’t [have variants in ADA2], it may still be the case that the pathway is somehow important and studies of biopsies from those patients would in some way allow us to connect that pathway to their disease. But that’s unknown," Dr. Kastner said.

When Dr. Kastner and his associates were looking for the mutations in other genetics databases, they found that whole-exome sequencing of 47 pairs of siblings with late-onset ischemic stroke in the Siblings With Ischemic Stroke Study had detected two brothers who each were heterozygous carriers of one of the mutations discovered in the study. Their ischemic strokes were similar in distribution to those seen in children with two mutations. "So it’s at least possible, although at this point it’s not formally proven, [that] that perhaps carrying one copy of this mutation, as opposed to having two as these kids have, could put you at some risk for having stroke later on in life. And it may be that, similarly, having one copy of a variant in this gene would predispose to other forms of vasculitis as well."

In three of the patients in the NIH study, treatment with low doses of fresh frozen plasma as a replacement therapy for ADA2 deficiency has appeared to be safe, but getting enough of it into patients and knowing whether it will last long enough are questions that the investigators are currently trying to answer, Dr. Kastner said. Initially, Dr. Kastner said his group was hesitant to use anti–tumor necrosis factor-alpha agents to treat patients because of the known, but small risk of demyelination with their use, which would not have been appropriate to try in patients who already had neurologic problems, because it would be very hard to tell if further lesions would be caused by underlying disease or the drug. However, when the Israeli group reported success with anti-TNF-alpha agents in their patients (and ultimately reported that 10 patients had a clinically significant therapeutic response), the NIH investigators decided to try them. Treatment with etanercept in five patients has reduced the occurrence of fevers in all and improved urticarial papules and plaques observed in three patients.

Pediatric rheumatologists who have patients with vasculitis or are suspected of having vasculitis should keep CECR1 mutations in mind now that the cause and some of the natural history and possible treatments for early-onset disease are known. Rheumatologists seeing adult patients with PAN could consider these mutations as a possible cause and at least note that some of these pathways may be important in their patients even if they don’t have mutations in CECR1, advised Dr. Kastner. He had no financial conflicts to disclose.

[email protected]

There is a growing amount of literature demonstrating that psoriasis is a chronic and debilitating inflammatory disease associated with serious comorbidities. Emerging comorbidities of psoriasis include cardiovascular disease and metabolic syndrome. Psoriasis patients have an increased prevalence of the core components of metabolic syndrome, including obesity, dyslipidemia, and insulin resistance.

According to van der Voort et al (J Am Acad Dermatol. 2014;70:517-524), prior case-controlled studies observed an increased prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with psoriasis, which they noted as a relevant factor in selecting optimal psoriasis treatment. Their study sought to compare the prevalence of NAFLD in participants with psoriasis and those without psoriasis. They conducted a large prospective population-based cohort study that enrolled elderly participants (>55 years). Nonalcoholic fatty liver disease was diagnosed as fatty liver on ultrasonography in the absence of other liver diseases. A multivariable logistic regression model was used to assess if psoriasis was associated with NAFLD after adjusting for demographic and lifestyle characteristics as well as laboratory findings.

In total, 2292 participants were included in the study; 118 (5.1%) participants had psoriasis. The prevalence of NAFLD was 46.2% in participants with psoriasis compared to 33.3% in those without psoriasis (P=.005); psoriasis was significantly associated with NAFLD. After the authors adjusted for alcohol consumption, pack-years and smoking status, presence of metabolic syndrome, and alanine aminotransferase levels, psoriasis remained a significant predictor of NAFLD (adjusted odds ratio, 1.7; 95% confidence interval, 1.1-2.6). The authors concluded that elderly participants with psoriasis were 70% more likely to have NAFLD than those without psoriasis independent of common NAFLD risk factors.

What’s the issue?

This study gives us a new comorbidity to be aware of and monitor. In considering therapy in this population, it also is important to consider the risk for NAFLD when selecting treatments that may have hepatic toxicity or are metabolized by the liver. How will this study change your approach to patients with psoriasis?

We want to know your views! Tell us what you think.

There is a growing amount of literature demonstrating that psoriasis is a chronic and debilitating inflammatory disease associated with serious comorbidities. Emerging comorbidities of psoriasis include cardiovascular disease and metabolic syndrome. Psoriasis patients have an increased prevalence of the core components of metabolic syndrome, including obesity, dyslipidemia, and insulin resistance.

According to van der Voort et al (J Am Acad Dermatol. 2014;70:517-524), prior case-controlled studies observed an increased prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with psoriasis, which they noted as a relevant factor in selecting optimal psoriasis treatment. Their study sought to compare the prevalence of NAFLD in participants with psoriasis and those without psoriasis. They conducted a large prospective population-based cohort study that enrolled elderly participants (>55 years). Nonalcoholic fatty liver disease was diagnosed as fatty liver on ultrasonography in the absence of other liver diseases. A multivariable logistic regression model was used to assess if psoriasis was associated with NAFLD after adjusting for demographic and lifestyle characteristics as well as laboratory findings.

In total, 2292 participants were included in the study; 118 (5.1%) participants had psoriasis. The prevalence of NAFLD was 46.2% in participants with psoriasis compared to 33.3% in those without psoriasis (P=.005); psoriasis was significantly associated with NAFLD. After the authors adjusted for alcohol consumption, pack-years and smoking status, presence of metabolic syndrome, and alanine aminotransferase levels, psoriasis remained a significant predictor of NAFLD (adjusted odds ratio, 1.7; 95% confidence interval, 1.1-2.6). The authors concluded that elderly participants with psoriasis were 70% more likely to have NAFLD than those without psoriasis independent of common NAFLD risk factors.

What’s the issue?

This study gives us a new comorbidity to be aware of and monitor. In considering therapy in this population, it also is important to consider the risk for NAFLD when selecting treatments that may have hepatic toxicity or are metabolized by the liver. How will this study change your approach to patients with psoriasis?

We want to know your views! Tell us what you think.

There is a growing amount of literature demonstrating that psoriasis is a chronic and debilitating inflammatory disease associated with serious comorbidities. Emerging comorbidities of psoriasis include cardiovascular disease and metabolic syndrome. Psoriasis patients have an increased prevalence of the core components of metabolic syndrome, including obesity, dyslipidemia, and insulin resistance.

According to van der Voort et al (J Am Acad Dermatol. 2014;70:517-524), prior case-controlled studies observed an increased prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with psoriasis, which they noted as a relevant factor in selecting optimal psoriasis treatment. Their study sought to compare the prevalence of NAFLD in participants with psoriasis and those without psoriasis. They conducted a large prospective population-based cohort study that enrolled elderly participants (>55 years). Nonalcoholic fatty liver disease was diagnosed as fatty liver on ultrasonography in the absence of other liver diseases. A multivariable logistic regression model was used to assess if psoriasis was associated with NAFLD after adjusting for demographic and lifestyle characteristics as well as laboratory findings.

In total, 2292 participants were included in the study; 118 (5.1%) participants had psoriasis. The prevalence of NAFLD was 46.2% in participants with psoriasis compared to 33.3% in those without psoriasis (P=.005); psoriasis was significantly associated with NAFLD. After the authors adjusted for alcohol consumption, pack-years and smoking status, presence of metabolic syndrome, and alanine aminotransferase levels, psoriasis remained a significant predictor of NAFLD (adjusted odds ratio, 1.7; 95% confidence interval, 1.1-2.6). The authors concluded that elderly participants with psoriasis were 70% more likely to have NAFLD than those without psoriasis independent of common NAFLD risk factors.

What’s the issue?

This study gives us a new comorbidity to be aware of and monitor. In considering therapy in this population, it also is important to consider the risk for NAFLD when selecting treatments that may have hepatic toxicity or are metabolized by the liver. How will this study change your approach to patients with psoriasis?

We want to know your views! Tell us what you think.