Psoriasis

PHILADELPHIA — Two studies showed an increased risk for nonmelanoma skin cancer in patients who take anti–tumor necrosis factor therapies, and should prompt physicians to evaluate the use of these drugs in patients who are at risk for skin cancer, according to the researchers.

Previous studies have been too small to show a definitive link between biologic therapy for rheumatoid arthritis (RA) and skin malignancy, although RA previously has been well established as a risk factor for skin cancer, according to Dr. Prahba Ranganathan.

She presented the results of her retrospective cohort study of RA patients in the Department of Veterans Affairs national database at the annual meeting of the American College of Rheumatology.

According to Dr. Ranganathan, among 16,829 patients with RA, 3,096 were treated with anti-TNFs at the VA between Oct. 1, 1998, and Sept. 30, 2006. The incidence of nonmelanoma skin cancer was 25.9 per 1,000 patient-years in this cohort, compared with 19.6 per 1,000 patient-years in the biologic-naive cohort, a 34% increased risk.

The incidence of melanoma also was increased by about 50%, with about 3.7 cases per 1,000 patient-years seen in the anti-TNF-treated group, vs. 2.6 cases per 1,000 patient-years in the biologic-naive cohort. Both results were significant.

A second study presented at the press conference confirmed these findings. Dr. Kimme Hyrich of the University of Manchester (England) looked at RA patients from the British Society for Rheumatology's biologics register, a prospective cohort study begun in 2001 to monitor the long-term safety of anti-TNFs.

Dr. Hyrich found that among 11,598 RA patients who were treated with anti-TNFs and had no prior nonmelanoma skin cancer, the incidence of a malignancy was 3.5 per 1,000 patient-years. In contrast, among 8,975 similar patients who were treated with nonbiologic therapies, the incidence of new nonmelanoma skin cancers was 2.4.

That was a 70% increased risk for the anti-TNF–treated patients, although the data were not significant, Dr. Hyrich reported.

Dr. Hyrich pointed out that patients treated with anti-TNF drugs typically have more contact with their physicians, which could have introduced a surveillance bias.

Dr. Ranganathan cautioned that even in patients with multiple skin cancer risks anti-TNFs are still a good choice for patients who've failed other treatments. “People with risk factors should be watched more closely and maybe have periodic skin exams,” she said.

Dr. Ranganathan, Dr. Hyrich, and their respective research teams did not report having any financial conflicts relative to their studies.

PHILADELPHIA — Two studies showed an increased risk for nonmelanoma skin cancer in patients who take anti–tumor necrosis factor therapies, and should prompt physicians to evaluate the use of these drugs in patients who are at risk for skin cancer, according to the researchers.

Previous studies have been too small to show a definitive link between biologic therapy for rheumatoid arthritis (RA) and skin malignancy, although RA previously has been well established as a risk factor for skin cancer, according to Dr. Prahba Ranganathan.

She presented the results of her retrospective cohort study of RA patients in the Department of Veterans Affairs national database at the annual meeting of the American College of Rheumatology.

According to Dr. Ranganathan, among 16,829 patients with RA, 3,096 were treated with anti-TNFs at the VA between Oct. 1, 1998, and Sept. 30, 2006. The incidence of nonmelanoma skin cancer was 25.9 per 1,000 patient-years in this cohort, compared with 19.6 per 1,000 patient-years in the biologic-naive cohort, a 34% increased risk.

The incidence of melanoma also was increased by about 50%, with about 3.7 cases per 1,000 patient-years seen in the anti-TNF-treated group, vs. 2.6 cases per 1,000 patient-years in the biologic-naive cohort. Both results were significant.

A second study presented at the press conference confirmed these findings. Dr. Kimme Hyrich of the University of Manchester (England) looked at RA patients from the British Society for Rheumatology's biologics register, a prospective cohort study begun in 2001 to monitor the long-term safety of anti-TNFs.

Dr. Hyrich found that among 11,598 RA patients who were treated with anti-TNFs and had no prior nonmelanoma skin cancer, the incidence of a malignancy was 3.5 per 1,000 patient-years. In contrast, among 8,975 similar patients who were treated with nonbiologic therapies, the incidence of new nonmelanoma skin cancers was 2.4.

That was a 70% increased risk for the anti-TNF–treated patients, although the data were not significant, Dr. Hyrich reported.

Dr. Hyrich pointed out that patients treated with anti-TNF drugs typically have more contact with their physicians, which could have introduced a surveillance bias.

Dr. Ranganathan cautioned that even in patients with multiple skin cancer risks anti-TNFs are still a good choice for patients who've failed other treatments. “People with risk factors should be watched more closely and maybe have periodic skin exams,” she said.

Dr. Ranganathan, Dr. Hyrich, and their respective research teams did not report having any financial conflicts relative to their studies.

PHILADELPHIA — Two studies showed an increased risk for nonmelanoma skin cancer in patients who take anti–tumor necrosis factor therapies, and should prompt physicians to evaluate the use of these drugs in patients who are at risk for skin cancer, according to the researchers.

Previous studies have been too small to show a definitive link between biologic therapy for rheumatoid arthritis (RA) and skin malignancy, although RA previously has been well established as a risk factor for skin cancer, according to Dr. Prahba Ranganathan.

She presented the results of her retrospective cohort study of RA patients in the Department of Veterans Affairs national database at the annual meeting of the American College of Rheumatology.

According to Dr. Ranganathan, among 16,829 patients with RA, 3,096 were treated with anti-TNFs at the VA between Oct. 1, 1998, and Sept. 30, 2006. The incidence of nonmelanoma skin cancer was 25.9 per 1,000 patient-years in this cohort, compared with 19.6 per 1,000 patient-years in the biologic-naive cohort, a 34% increased risk.

The incidence of melanoma also was increased by about 50%, with about 3.7 cases per 1,000 patient-years seen in the anti-TNF-treated group, vs. 2.6 cases per 1,000 patient-years in the biologic-naive cohort. Both results were significant.

A second study presented at the press conference confirmed these findings. Dr. Kimme Hyrich of the University of Manchester (England) looked at RA patients from the British Society for Rheumatology's biologics register, a prospective cohort study begun in 2001 to monitor the long-term safety of anti-TNFs.

Dr. Hyrich found that among 11,598 RA patients who were treated with anti-TNFs and had no prior nonmelanoma skin cancer, the incidence of a malignancy was 3.5 per 1,000 patient-years. In contrast, among 8,975 similar patients who were treated with nonbiologic therapies, the incidence of new nonmelanoma skin cancers was 2.4.

That was a 70% increased risk for the anti-TNF–treated patients, although the data were not significant, Dr. Hyrich reported.

Dr. Hyrich pointed out that patients treated with anti-TNF drugs typically have more contact with their physicians, which could have introduced a surveillance bias.

Dr. Ranganathan cautioned that even in patients with multiple skin cancer risks anti-TNFs are still a good choice for patients who've failed other treatments. “People with risk factors should be watched more closely and maybe have periodic skin exams,” she said.

Dr. Ranganathan, Dr. Hyrich, and their respective research teams did not report having any financial conflicts relative to their studies.

Significantly more lupus patients responded to belimumab than placebo in a randomized trial with more than 800 patients followed for a year, the second positive outcome from a pivotal trial of the investigational monoclonal antibody in lupus this year.

After successfully meeting the primary end point in two large, separate lupus-treatment trials, Human Genome Sciences and GlaxoSmithKline, the two companies jointly developing belimumab (Benlysta), plan to file a new drug application with the Food and Drug Administration during the first half of 2010, said H. Thomas Watkins, president of HGS, during a conference call for investors.

If approved, it would be the first drug to receive a labeled indication for lupus in more than 50 years. Belimumab acts by blunting B-cell activity.

Initial results for the more recent of the two pivotal trials, the Belimumab in Subjects with Systemic Lupus Erythematosus (BLISS)-76 study, were announced by HGS and GlaxoSmithKline in a press release, with a full report of the findings expected next summer. Initial results from the first pivotal trial, BLISS-52, were first released last July.

The primary outcome benefit from belimumab treatment was “solid,” said Dr. Joan T. Merrill, a specialist in treating systemic lupus erythematosus (SLE) who was a co-investigator on BLISS-76.

“The lupus community has waited decades for one positive phase III trial of an investigational drug developed for lupus. Now we have two.” Belimumab “may emerge as a significant new treatment for lupus,” said Dr. Merrill, professor of medicine at the University of Oklahoma Health Sciences Center in Oklahoma City. Dr. Merrill has served as a consultant to and has received research funding from HGS and GlaxoSmithKline as well as from several other drug companies.

BLISS-76 randomized 819 patients at 136 sites in 19 countries in North America and Europe. Enrollment criteria were not released for this study, but the similarly designed BLISS-52 trial included SLE patients with a score of 6 or more on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA SLEDAI). Patients also had to be seropositive for at least either antinuclear antibody at a level of 1:80 or greater or for anti–double stranded DNA at a level of 30 IU/mL or greater.

Patients were randomized to 1 mg/kg intravenous belimumab, 10 mg/kg intravenous belimumab, or placebo. Treatment occurred on days 0, 14, 28, and then every subsequent 28 days for 1 year. The study's primary end point was the percent of patients meeting the SLE Responder Index (SRI) after 52 weeks of treatment.

In BLISS-76 the SRI end point was reached by 43% of patients on the 10 mg/kg dosage, 41% of patients receiving 1 mg/kg, and 34% of patients on placebo. The difference in the outcome rate was statistically significant between the 10-mg/kg arm and placebo, but not between the 1-mg/kg arm and placebo. In BLISS-52, the rate of SRI responses at 52 weeks was 58% with the 10-mg/kg regimen compared with 44% in patients on placebo, also a statistically significant difference. The 10-mg/kg dosage is the one that HGS will pursue in its FDA filing, company officials said.

The safety profile of belimumab looked good in this study, as it had in BLISS-52, with no significant difference in the rates of malignancies, deaths, infections, serious infections, total adverse events, or serious adverse events among the treatment groups.

Significantly more lupus patients responded to belimumab than placebo in a randomized trial with more than 800 patients followed for a year, the second positive outcome from a pivotal trial of the investigational monoclonal antibody in lupus this year.

After successfully meeting the primary end point in two large, separate lupus-treatment trials, Human Genome Sciences and GlaxoSmithKline, the two companies jointly developing belimumab (Benlysta), plan to file a new drug application with the Food and Drug Administration during the first half of 2010, said H. Thomas Watkins, president of HGS, during a conference call for investors.

If approved, it would be the first drug to receive a labeled indication for lupus in more than 50 years. Belimumab acts by blunting B-cell activity.

Initial results for the more recent of the two pivotal trials, the Belimumab in Subjects with Systemic Lupus Erythematosus (BLISS)-76 study, were announced by HGS and GlaxoSmithKline in a press release, with a full report of the findings expected next summer. Initial results from the first pivotal trial, BLISS-52, were first released last July.

The primary outcome benefit from belimumab treatment was “solid,” said Dr. Joan T. Merrill, a specialist in treating systemic lupus erythematosus (SLE) who was a co-investigator on BLISS-76.

“The lupus community has waited decades for one positive phase III trial of an investigational drug developed for lupus. Now we have two.” Belimumab “may emerge as a significant new treatment for lupus,” said Dr. Merrill, professor of medicine at the University of Oklahoma Health Sciences Center in Oklahoma City. Dr. Merrill has served as a consultant to and has received research funding from HGS and GlaxoSmithKline as well as from several other drug companies.

BLISS-76 randomized 819 patients at 136 sites in 19 countries in North America and Europe. Enrollment criteria were not released for this study, but the similarly designed BLISS-52 trial included SLE patients with a score of 6 or more on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA SLEDAI). Patients also had to be seropositive for at least either antinuclear antibody at a level of 1:80 or greater or for anti–double stranded DNA at a level of 30 IU/mL or greater.

Patients were randomized to 1 mg/kg intravenous belimumab, 10 mg/kg intravenous belimumab, or placebo. Treatment occurred on days 0, 14, 28, and then every subsequent 28 days for 1 year. The study's primary end point was the percent of patients meeting the SLE Responder Index (SRI) after 52 weeks of treatment.

In BLISS-76 the SRI end point was reached by 43% of patients on the 10 mg/kg dosage, 41% of patients receiving 1 mg/kg, and 34% of patients on placebo. The difference in the outcome rate was statistically significant between the 10-mg/kg arm and placebo, but not between the 1-mg/kg arm and placebo. In BLISS-52, the rate of SRI responses at 52 weeks was 58% with the 10-mg/kg regimen compared with 44% in patients on placebo, also a statistically significant difference. The 10-mg/kg dosage is the one that HGS will pursue in its FDA filing, company officials said.

The safety profile of belimumab looked good in this study, as it had in BLISS-52, with no significant difference in the rates of malignancies, deaths, infections, serious infections, total adverse events, or serious adverse events among the treatment groups.

Significantly more lupus patients responded to belimumab than placebo in a randomized trial with more than 800 patients followed for a year, the second positive outcome from a pivotal trial of the investigational monoclonal antibody in lupus this year.

After successfully meeting the primary end point in two large, separate lupus-treatment trials, Human Genome Sciences and GlaxoSmithKline, the two companies jointly developing belimumab (Benlysta), plan to file a new drug application with the Food and Drug Administration during the first half of 2010, said H. Thomas Watkins, president of HGS, during a conference call for investors.

If approved, it would be the first drug to receive a labeled indication for lupus in more than 50 years. Belimumab acts by blunting B-cell activity.

Initial results for the more recent of the two pivotal trials, the Belimumab in Subjects with Systemic Lupus Erythematosus (BLISS)-76 study, were announced by HGS and GlaxoSmithKline in a press release, with a full report of the findings expected next summer. Initial results from the first pivotal trial, BLISS-52, were first released last July.

The primary outcome benefit from belimumab treatment was “solid,” said Dr. Joan T. Merrill, a specialist in treating systemic lupus erythematosus (SLE) who was a co-investigator on BLISS-76.

“The lupus community has waited decades for one positive phase III trial of an investigational drug developed for lupus. Now we have two.” Belimumab “may emerge as a significant new treatment for lupus,” said Dr. Merrill, professor of medicine at the University of Oklahoma Health Sciences Center in Oklahoma City. Dr. Merrill has served as a consultant to and has received research funding from HGS and GlaxoSmithKline as well as from several other drug companies.

BLISS-76 randomized 819 patients at 136 sites in 19 countries in North America and Europe. Enrollment criteria were not released for this study, but the similarly designed BLISS-52 trial included SLE patients with a score of 6 or more on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA SLEDAI). Patients also had to be seropositive for at least either antinuclear antibody at a level of 1:80 or greater or for anti–double stranded DNA at a level of 30 IU/mL or greater.

Patients were randomized to 1 mg/kg intravenous belimumab, 10 mg/kg intravenous belimumab, or placebo. Treatment occurred on days 0, 14, 28, and then every subsequent 28 days for 1 year. The study's primary end point was the percent of patients meeting the SLE Responder Index (SRI) after 52 weeks of treatment.

In BLISS-76 the SRI end point was reached by 43% of patients on the 10 mg/kg dosage, 41% of patients receiving 1 mg/kg, and 34% of patients on placebo. The difference in the outcome rate was statistically significant between the 10-mg/kg arm and placebo, but not between the 1-mg/kg arm and placebo. In BLISS-52, the rate of SRI responses at 52 weeks was 58% with the 10-mg/kg regimen compared with 44% in patients on placebo, also a statistically significant difference. The 10-mg/kg dosage is the one that HGS will pursue in its FDA filing, company officials said.

The safety profile of belimumab looked good in this study, as it had in BLISS-52, with no significant difference in the rates of malignancies, deaths, infections, serious infections, total adverse events, or serious adverse events among the treatment groups.

BERLIN — Psoriasis patients who show less than a PASI-50 response to 20 mg/wk of methotrexate by week 12 are unlikely to benefit from dosage increases or longer therapy, according to a new analysis of the CHAMPION study.

Week 12 has been found to be a useful decision point for discontinuing methotrexate and moving on to a biologic agent, said Dr. Jean-Hilaire Saurat, professor of dermatology at the University of Geneva.

“With the data we've obtained with CHAMPION, our understanding of how the treatment should be conducted should be reconsidered. We know that probably by week 12 we should know if the patient will respond or not,” said Dr. Saurat.

CHAMPION (Comparative Study of Adalimumab vs. Methotrexate vs. Placebo in Patients With Psoriasis) was a phase III, 16-week, double-blind, randomized trial in patients with moderate to severe psoriasis (Br. J. Dermatol. 2008;158:558–66).

The study provides the only existent placebo-controlled methotrexate data, noted Dr. Suarat, who presented the post hoc subanalysis results at the annual congress of the European Academy of Dermatology and Venereology.

CHAMPION included 103 evaluable patients randomized to 7.5 mg of oral methotrexate once weekly for 2 weeks, 10 mg weekly for the next 2 weeks, and then 15 mg/wk for 4 weeks.

The 40 patients with at least a PASI-50 response after 8 weeks—that is, a 50% reduction from baseline in Psoriasis Area and Severity Index scores—were deemed early responders. They remained on methotrexate 15 mg/wk for the rest of the 16-week study.

Patients with less than a PASI-50 at week 8 had their dosage increased to 20 mg/wk for 4 weeks. If at week 12 they had achieved a PASI-50 response they stayed on 20 mg/wk for the final 4 weeks of the study; if not, their dosage was increased to 25 mg/wk.

The 22 participants who reached PASI-50 after 8 weeks at dosages greater than 15 mg were classified as late responders; the 41 who never attained PASI-50 were deemed late nonresponders.

The mean weekly methotrexate dosage at 16 weeks was 14.5 mg in early responders, 19.5 mg in late responders, and 23.2 mg in late nonresponders. After 16 weeks, 27% of subjects had a PASI-75 response on a maximum dose of 15 mg/wk.

“The good news is in the responders the response to methotrexate is as good as to a biologic like adalimumab [Humira]. There is a group of patients on methotrexate who are extremely happy, and you do not need high doses to reach this response,” Dr. Saurat said.

The new findings from CHAMPION will be particularly useful for European physicians because psoriasis patients who require systemic therapy have to be treated with methotrexate before biologics can be considered, he suggested.

Audience member Dr. Craig L. Leonardi pointed out that methotrexate is still widely prescribed in the United States as well.

“I use methotrexate a lot these days. I've got hundreds of patients on it…. There's clearly a group of patients who do very well with this drug at low doses. It would be spectacular if we could predict which ones,” said Dr. Leonardi of the department of dermatology at Saint Louis University.

Unfortunately, Dr. Saurat said, no baseline predictors of early response in CHAMPION could be identified. Of note, however, patients destined for early responder status at week 8 already had a mean 40% reduction in PASI scores after just 4 weeks on methotrexate at 15 mg/wk.

The CHAMPION trial was sponsored by Abbott, which manufactures adalimumab. Dr. Saurat is an adviser to the company. Dr. Leonardi has served as a consultant to manufacturers of biologic agents for psoriasis.

'The good news is in the responders the response to methotrexate is as good as to a biologic like adalimumab.'

Source Dr. Saurat

'There's clearly a group of patients who do very well with this drug [methotrexate] at low doses.'

Source Dr. Leonardi

Source Elsevier Global Medical News

BERLIN — Psoriasis patients who show less than a PASI-50 response to 20 mg/wk of methotrexate by week 12 are unlikely to benefit from dosage increases or longer therapy, according to a new analysis of the CHAMPION study.

Week 12 has been found to be a useful decision point for discontinuing methotrexate and moving on to a biologic agent, said Dr. Jean-Hilaire Saurat, professor of dermatology at the University of Geneva.

“With the data we've obtained with CHAMPION, our understanding of how the treatment should be conducted should be reconsidered. We know that probably by week 12 we should know if the patient will respond or not,” said Dr. Saurat.

CHAMPION (Comparative Study of Adalimumab vs. Methotrexate vs. Placebo in Patients With Psoriasis) was a phase III, 16-week, double-blind, randomized trial in patients with moderate to severe psoriasis (Br. J. Dermatol. 2008;158:558–66).

The study provides the only existent placebo-controlled methotrexate data, noted Dr. Suarat, who presented the post hoc subanalysis results at the annual congress of the European Academy of Dermatology and Venereology.

CHAMPION included 103 evaluable patients randomized to 7.5 mg of oral methotrexate once weekly for 2 weeks, 10 mg weekly for the next 2 weeks, and then 15 mg/wk for 4 weeks.

The 40 patients with at least a PASI-50 response after 8 weeks—that is, a 50% reduction from baseline in Psoriasis Area and Severity Index scores—were deemed early responders. They remained on methotrexate 15 mg/wk for the rest of the 16-week study.

Patients with less than a PASI-50 at week 8 had their dosage increased to 20 mg/wk for 4 weeks. If at week 12 they had achieved a PASI-50 response they stayed on 20 mg/wk for the final 4 weeks of the study; if not, their dosage was increased to 25 mg/wk.

The 22 participants who reached PASI-50 after 8 weeks at dosages greater than 15 mg were classified as late responders; the 41 who never attained PASI-50 were deemed late nonresponders.

The mean weekly methotrexate dosage at 16 weeks was 14.5 mg in early responders, 19.5 mg in late responders, and 23.2 mg in late nonresponders. After 16 weeks, 27% of subjects had a PASI-75 response on a maximum dose of 15 mg/wk.

“The good news is in the responders the response to methotrexate is as good as to a biologic like adalimumab [Humira]. There is a group of patients on methotrexate who are extremely happy, and you do not need high doses to reach this response,” Dr. Saurat said.

The new findings from CHAMPION will be particularly useful for European physicians because psoriasis patients who require systemic therapy have to be treated with methotrexate before biologics can be considered, he suggested.

Audience member Dr. Craig L. Leonardi pointed out that methotrexate is still widely prescribed in the United States as well.

“I use methotrexate a lot these days. I've got hundreds of patients on it…. There's clearly a group of patients who do very well with this drug at low doses. It would be spectacular if we could predict which ones,” said Dr. Leonardi of the department of dermatology at Saint Louis University.

Unfortunately, Dr. Saurat said, no baseline predictors of early response in CHAMPION could be identified. Of note, however, patients destined for early responder status at week 8 already had a mean 40% reduction in PASI scores after just 4 weeks on methotrexate at 15 mg/wk.

The CHAMPION trial was sponsored by Abbott, which manufactures adalimumab. Dr. Saurat is an adviser to the company. Dr. Leonardi has served as a consultant to manufacturers of biologic agents for psoriasis.

'The good news is in the responders the response to methotrexate is as good as to a biologic like adalimumab.'

Source Dr. Saurat

'There's clearly a group of patients who do very well with this drug [methotrexate] at low doses.'

Source Dr. Leonardi

Source Elsevier Global Medical News

BERLIN — Psoriasis patients who show less than a PASI-50 response to 20 mg/wk of methotrexate by week 12 are unlikely to benefit from dosage increases or longer therapy, according to a new analysis of the CHAMPION study.

Week 12 has been found to be a useful decision point for discontinuing methotrexate and moving on to a biologic agent, said Dr. Jean-Hilaire Saurat, professor of dermatology at the University of Geneva.

“With the data we've obtained with CHAMPION, our understanding of how the treatment should be conducted should be reconsidered. We know that probably by week 12 we should know if the patient will respond or not,” said Dr. Saurat.

CHAMPION (Comparative Study of Adalimumab vs. Methotrexate vs. Placebo in Patients With Psoriasis) was a phase III, 16-week, double-blind, randomized trial in patients with moderate to severe psoriasis (Br. J. Dermatol. 2008;158:558–66).

The study provides the only existent placebo-controlled methotrexate data, noted Dr. Suarat, who presented the post hoc subanalysis results at the annual congress of the European Academy of Dermatology and Venereology.

CHAMPION included 103 evaluable patients randomized to 7.5 mg of oral methotrexate once weekly for 2 weeks, 10 mg weekly for the next 2 weeks, and then 15 mg/wk for 4 weeks.

The 40 patients with at least a PASI-50 response after 8 weeks—that is, a 50% reduction from baseline in Psoriasis Area and Severity Index scores—were deemed early responders. They remained on methotrexate 15 mg/wk for the rest of the 16-week study.

Patients with less than a PASI-50 at week 8 had their dosage increased to 20 mg/wk for 4 weeks. If at week 12 they had achieved a PASI-50 response they stayed on 20 mg/wk for the final 4 weeks of the study; if not, their dosage was increased to 25 mg/wk.

The 22 participants who reached PASI-50 after 8 weeks at dosages greater than 15 mg were classified as late responders; the 41 who never attained PASI-50 were deemed late nonresponders.

The mean weekly methotrexate dosage at 16 weeks was 14.5 mg in early responders, 19.5 mg in late responders, and 23.2 mg in late nonresponders. After 16 weeks, 27% of subjects had a PASI-75 response on a maximum dose of 15 mg/wk.

“The good news is in the responders the response to methotrexate is as good as to a biologic like adalimumab [Humira]. There is a group of patients on methotrexate who are extremely happy, and you do not need high doses to reach this response,” Dr. Saurat said.

The new findings from CHAMPION will be particularly useful for European physicians because psoriasis patients who require systemic therapy have to be treated with methotrexate before biologics can be considered, he suggested.

Audience member Dr. Craig L. Leonardi pointed out that methotrexate is still widely prescribed in the United States as well.

“I use methotrexate a lot these days. I've got hundreds of patients on it…. There's clearly a group of patients who do very well with this drug at low doses. It would be spectacular if we could predict which ones,” said Dr. Leonardi of the department of dermatology at Saint Louis University.

Unfortunately, Dr. Saurat said, no baseline predictors of early response in CHAMPION could be identified. Of note, however, patients destined for early responder status at week 8 already had a mean 40% reduction in PASI scores after just 4 weeks on methotrexate at 15 mg/wk.

The CHAMPION trial was sponsored by Abbott, which manufactures adalimumab. Dr. Saurat is an adviser to the company. Dr. Leonardi has served as a consultant to manufacturers of biologic agents for psoriasis.

'The good news is in the responders the response to methotrexate is as good as to a biologic like adalimumab.'

Source Dr. Saurat

'There's clearly a group of patients who do very well with this drug [methotrexate] at low doses.'

Source Dr. Leonardi

Source Elsevier Global Medical News

BUDAPEST, HUNGARY — New European guidelines on high-dose intravenous immunoglobulin therapy in autoimmune dermatologic diseases restrict the first-line indications to toxic epidermal necrolysis, Kawasaki disease, and life-threatening, rapidly progressive cases of dermatomyositis.

With some exceptions, those recommended uses closely mirror standard practice in the United States, according to Dr. Eric Matteson, of the Mayo Clinic, Rochester, Minn.

“We use IVIG to manage Kawasaki disease and dermatomyositis. Beyond that, its use is generally limited to repletion therapy after plasma exchange, for example in patients with severe lupus or [antineutrophil cytoplasmic antibody]-associated vasculitis who develop pulmonary hemorrhage,” he said in an interview.

During his presentation at a satellite symposium that was devoted to the new guidelines and held in conjunction with the annual congress of the European Society for Dermatological Research, Dr. Alexander Enk said that the indications for IVIG as second-line therapy are broader. IVIG is deemed appropriate in the setting of an inadequate response or contraindications to conventional therapy in patients with any of the severe autoimmune blistering diseases, such as bullous pemphigoid, linear IgA dermatosis, and epidermolysis bullosa acquisita; for systemic vasculitic syndromes, including Wegener's granulomatosis and polyarteritis nodosa; and in severe forms of systemic lupus erythematosus.

Dr. Enk chaired the guideline panel on behalf of the European Academy of Dermatology and Venereology and the European Dermatology Forum.

IVIG should be given as an adjunct to continued use of standard first-line corticosteroids and other immunosuppressive agents, barring contraindications.

The guidelines list several other diseases for which IVIG can be considered an option on the basis of case reports. These include atopic dermatitis, scleromyxedema, autoimmune urticaria, and pyoderma gangrenosum.

Dr. Enk was quick to concede that the evidence base for IVIG in autoimmune dermatologic diseases is limited. It consists overwhelmingly of small case series.

But in the absence of high-level clinical trial evidence, recommendations based upon expert consensus are the next-best option, said Dr. Enk, professor and chair of the department of dermatology at the University of Heidelberg (Germany). These are uncommon diseases with which most physicians have limited experience, and it is all off-label therapy, he noted.

The guidelines were created to provide the medical community with the best practices of European experts, to provide physicians with protection against lawsuits, and to serve as a basis for attaining reimbursement, he said.

Speaking of reimbursement, Dr. Enk noted that although IVIG is quite expensive, it is relatively free of side effects and often induces prolonged remission.

An economic analysis conducted in Massachusetts concluded that when the cost of treating corticosteroid-induced osteoporotic fractures and other side effects of conventional chronic immunosuppressive therapy for autoimmune mucocutaneous blistering diseases was factored in, IVIG was a clear winner (Int. Immunopharmacol. 2006;6:600–6).

The guidelines spell out the recommended dosing, duration of therapy per cycle, and time interval between cycles (J. Dtsch. Dermatol. Ges. 2009;7:806–12).

The guidelines recommend dosing IVIG for all of the indicated disorders, except toxic epidermal necrolysis (TEN), at 2 g/kg of body weight given over 2–5 consecutive days to avoid adverse reactions. It should initially be given every 4 weeks, gradually extending the interval between infusions to 6 weeks if the response is good. If there is no response after six cycles, the recommendation is to halt IVIG therapy. Treatment for longer than 12 months is rarely warranted.

For TEN, the recommendation is 3 g/kg given over 3 days. As in Kawasaki disease, this is a one-time therapy.

Practice guidelines unsupported by clinical evidence leave much to be desired, noted guideline panelist Dr. Lars French. The chief obstacle to conducting randomized trials of IVIG has been a financial one. “The companies sell every gram of IVIG they make and have no incentive to fund a trial,” said Dr. French, professor of dermatology at the University of Zurich.

However, the European regulatory agency recently announced that IVIG manufacturers who fund clinical trials establishing efficacy in autoimmune diseases can win an indication for their product, Dr. French said.

In the meantime, he added that he has no qualms in recommending early administration of IVIG in patients with confirmed TEN. “There are numerous case reports in which it has proven potentially lifesaving,” he said.

Dr. Enk disclosed receiving grant support from IVIG manufacturer Biotest Pharmaceuticals Corp., which sponsored the satellite symposium. Dr. French and Dr. Matteson reported having no relevant financial conflicts of interest.

Practice guidelines unsupported by clinical evidence leave much to be desired.

Source DR. FRENCH

IVIG is appropriate when there is inadequate response to conventional therapy for auto-immune blistering.

Source DR. ENK

BUDAPEST, HUNGARY — New European guidelines on high-dose intravenous immunoglobulin therapy in autoimmune dermatologic diseases restrict the first-line indications to toxic epidermal necrolysis, Kawasaki disease, and life-threatening, rapidly progressive cases of dermatomyositis.

With some exceptions, those recommended uses closely mirror standard practice in the United States, according to Dr. Eric Matteson, of the Mayo Clinic, Rochester, Minn.

“We use IVIG to manage Kawasaki disease and dermatomyositis. Beyond that, its use is generally limited to repletion therapy after plasma exchange, for example in patients with severe lupus or [antineutrophil cytoplasmic antibody]-associated vasculitis who develop pulmonary hemorrhage,” he said in an interview.

During his presentation at a satellite symposium that was devoted to the new guidelines and held in conjunction with the annual congress of the European Society for Dermatological Research, Dr. Alexander Enk said that the indications for IVIG as second-line therapy are broader. IVIG is deemed appropriate in the setting of an inadequate response or contraindications to conventional therapy in patients with any of the severe autoimmune blistering diseases, such as bullous pemphigoid, linear IgA dermatosis, and epidermolysis bullosa acquisita; for systemic vasculitic syndromes, including Wegener's granulomatosis and polyarteritis nodosa; and in severe forms of systemic lupus erythematosus.

Dr. Enk chaired the guideline panel on behalf of the European Academy of Dermatology and Venereology and the European Dermatology Forum.

IVIG should be given as an adjunct to continued use of standard first-line corticosteroids and other immunosuppressive agents, barring contraindications.

The guidelines list several other diseases for which IVIG can be considered an option on the basis of case reports. These include atopic dermatitis, scleromyxedema, autoimmune urticaria, and pyoderma gangrenosum.

Dr. Enk was quick to concede that the evidence base for IVIG in autoimmune dermatologic diseases is limited. It consists overwhelmingly of small case series.

But in the absence of high-level clinical trial evidence, recommendations based upon expert consensus are the next-best option, said Dr. Enk, professor and chair of the department of dermatology at the University of Heidelberg (Germany). These are uncommon diseases with which most physicians have limited experience, and it is all off-label therapy, he noted.

The guidelines were created to provide the medical community with the best practices of European experts, to provide physicians with protection against lawsuits, and to serve as a basis for attaining reimbursement, he said.

Speaking of reimbursement, Dr. Enk noted that although IVIG is quite expensive, it is relatively free of side effects and often induces prolonged remission.

An economic analysis conducted in Massachusetts concluded that when the cost of treating corticosteroid-induced osteoporotic fractures and other side effects of conventional chronic immunosuppressive therapy for autoimmune mucocutaneous blistering diseases was factored in, IVIG was a clear winner (Int. Immunopharmacol. 2006;6:600–6).

The guidelines spell out the recommended dosing, duration of therapy per cycle, and time interval between cycles (J. Dtsch. Dermatol. Ges. 2009;7:806–12).

The guidelines recommend dosing IVIG for all of the indicated disorders, except toxic epidermal necrolysis (TEN), at 2 g/kg of body weight given over 2–5 consecutive days to avoid adverse reactions. It should initially be given every 4 weeks, gradually extending the interval between infusions to 6 weeks if the response is good. If there is no response after six cycles, the recommendation is to halt IVIG therapy. Treatment for longer than 12 months is rarely warranted.

For TEN, the recommendation is 3 g/kg given over 3 days. As in Kawasaki disease, this is a one-time therapy.

Practice guidelines unsupported by clinical evidence leave much to be desired, noted guideline panelist Dr. Lars French. The chief obstacle to conducting randomized trials of IVIG has been a financial one. “The companies sell every gram of IVIG they make and have no incentive to fund a trial,” said Dr. French, professor of dermatology at the University of Zurich.

However, the European regulatory agency recently announced that IVIG manufacturers who fund clinical trials establishing efficacy in autoimmune diseases can win an indication for their product, Dr. French said.

In the meantime, he added that he has no qualms in recommending early administration of IVIG in patients with confirmed TEN. “There are numerous case reports in which it has proven potentially lifesaving,” he said.

Dr. Enk disclosed receiving grant support from IVIG manufacturer Biotest Pharmaceuticals Corp., which sponsored the satellite symposium. Dr. French and Dr. Matteson reported having no relevant financial conflicts of interest.

Practice guidelines unsupported by clinical evidence leave much to be desired.

Source DR. FRENCH

IVIG is appropriate when there is inadequate response to conventional therapy for auto-immune blistering.

Source DR. ENK

BUDAPEST, HUNGARY — New European guidelines on high-dose intravenous immunoglobulin therapy in autoimmune dermatologic diseases restrict the first-line indications to toxic epidermal necrolysis, Kawasaki disease, and life-threatening, rapidly progressive cases of dermatomyositis.

With some exceptions, those recommended uses closely mirror standard practice in the United States, according to Dr. Eric Matteson, of the Mayo Clinic, Rochester, Minn.

“We use IVIG to manage Kawasaki disease and dermatomyositis. Beyond that, its use is generally limited to repletion therapy after plasma exchange, for example in patients with severe lupus or [antineutrophil cytoplasmic antibody]-associated vasculitis who develop pulmonary hemorrhage,” he said in an interview.

During his presentation at a satellite symposium that was devoted to the new guidelines and held in conjunction with the annual congress of the European Society for Dermatological Research, Dr. Alexander Enk said that the indications for IVIG as second-line therapy are broader. IVIG is deemed appropriate in the setting of an inadequate response or contraindications to conventional therapy in patients with any of the severe autoimmune blistering diseases, such as bullous pemphigoid, linear IgA dermatosis, and epidermolysis bullosa acquisita; for systemic vasculitic syndromes, including Wegener's granulomatosis and polyarteritis nodosa; and in severe forms of systemic lupus erythematosus.

Dr. Enk chaired the guideline panel on behalf of the European Academy of Dermatology and Venereology and the European Dermatology Forum.

IVIG should be given as an adjunct to continued use of standard first-line corticosteroids and other immunosuppressive agents, barring contraindications.

The guidelines list several other diseases for which IVIG can be considered an option on the basis of case reports. These include atopic dermatitis, scleromyxedema, autoimmune urticaria, and pyoderma gangrenosum.

Dr. Enk was quick to concede that the evidence base for IVIG in autoimmune dermatologic diseases is limited. It consists overwhelmingly of small case series.

But in the absence of high-level clinical trial evidence, recommendations based upon expert consensus are the next-best option, said Dr. Enk, professor and chair of the department of dermatology at the University of Heidelberg (Germany). These are uncommon diseases with which most physicians have limited experience, and it is all off-label therapy, he noted.

The guidelines were created to provide the medical community with the best practices of European experts, to provide physicians with protection against lawsuits, and to serve as a basis for attaining reimbursement, he said.

Speaking of reimbursement, Dr. Enk noted that although IVIG is quite expensive, it is relatively free of side effects and often induces prolonged remission.

An economic analysis conducted in Massachusetts concluded that when the cost of treating corticosteroid-induced osteoporotic fractures and other side effects of conventional chronic immunosuppressive therapy for autoimmune mucocutaneous blistering diseases was factored in, IVIG was a clear winner (Int. Immunopharmacol. 2006;6:600–6).

The guidelines spell out the recommended dosing, duration of therapy per cycle, and time interval between cycles (J. Dtsch. Dermatol. Ges. 2009;7:806–12).

The guidelines recommend dosing IVIG for all of the indicated disorders, except toxic epidermal necrolysis (TEN), at 2 g/kg of body weight given over 2–5 consecutive days to avoid adverse reactions. It should initially be given every 4 weeks, gradually extending the interval between infusions to 6 weeks if the response is good. If there is no response after six cycles, the recommendation is to halt IVIG therapy. Treatment for longer than 12 months is rarely warranted.

For TEN, the recommendation is 3 g/kg given over 3 days. As in Kawasaki disease, this is a one-time therapy.

Practice guidelines unsupported by clinical evidence leave much to be desired, noted guideline panelist Dr. Lars French. The chief obstacle to conducting randomized trials of IVIG has been a financial one. “The companies sell every gram of IVIG they make and have no incentive to fund a trial,” said Dr. French, professor of dermatology at the University of Zurich.

However, the European regulatory agency recently announced that IVIG manufacturers who fund clinical trials establishing efficacy in autoimmune diseases can win an indication for their product, Dr. French said.

In the meantime, he added that he has no qualms in recommending early administration of IVIG in patients with confirmed TEN. “There are numerous case reports in which it has proven potentially lifesaving,” he said.

Dr. Enk disclosed receiving grant support from IVIG manufacturer Biotest Pharmaceuticals Corp., which sponsored the satellite symposium. Dr. French and Dr. Matteson reported having no relevant financial conflicts of interest.

Practice guidelines unsupported by clinical evidence leave much to be desired.

Source DR. FRENCH

IVIG is appropriate when there is inadequate response to conventional therapy for auto-immune blistering.

Source DR. ENK

BERLIN — Selective inhibition of the proinflammatory cytokine interleukin-17A using a novel fully human monoclonal antibody showed considerable early promise for treatment of psoriasis in a phase II double-blind randomized trial.

This was a proof-of-concept study, and what it proved is that the interleukin 17A–producing T helper 17 cells are an entirely new and attractive therapeutic target in moderate to severe chronic plaque psoriasis, Dr. Zoe Draelos reported at the annual congress of the European Academy of Dermatology and Venereology.

Based upon the phase II results, it's full speed ahead for development of the fully human IgG monoclonal antibody known for now as AIN457. The next round of clinical trials will be considerably larger, longer term, and aimed at identifying optimal dosing, according to Dr. Draelos, a dermatologist in High Point, N.C.

AIN457 is also in clinical trials for the treatment of other immune-mediated disorders, most notably rheumatoid arthritis and noninfectious uveitis. It is also being studied for the treatment of Chrohn's disease.

The phase II study involved 36 patients with chronic plaque psoriasis covering at least 10% of their body surface area and an Investigator's Global Assessment (IGA) severity score of 3 or more, according to Dr. Draelos.

Participants were randomized to a single intravenous infusion of AIN457 at 3 mg/kg or placebo and then followed for 12 weeks.

The study had two primary end points: change in Psoriasis Area and Severity Index (PASI) score at 4 weeks and reduction in IGA score.

The mean decrease in PASI score 4 weeks after the infusion was 58% in the AIN457-treated patients and 4% with placebo, she said.

The response was fast, with a significant difference from placebo emerging within 2 weeks of infusion.

At 12 weeks, the mean reduction in PASI was 63% in patients who received the IL-17A blocker and 9% in controls. A 50% decrease in PASI score (PASI 50) was recorded by 72% of AIN457-treated patients, a PASI 75 by 44%, and a PASI 90 by 11%.

Eighty-three percent of AIN457-treated patients had at least a one-point improvement in IGA score at week 4, compared with 11% of controls. By week 12, 28% of patients in the active-treatment arm had an IGA score of 1, indicative of being almost clear, compared with 6% of controls.

AIN457 exhibited a favorable side effect profile in this small study. No serious adverse events were attributed to the study drug.

Five AIN457-treated patients and three controls developed sinusitis or another infection during the follow-up period. Importantly, no one who received AIN457 developed anti-AIN457 antibodies.

IL-17A, which is upregulated in psoriatic lesional skin, has been called the master regulator of innate defense protein synthesis in keratinocytes.

Dr. Thomas A. Luger, president of the EADV congress, who wasn't involved in the AIN457 study, singled it out as a highlight of the meeting.

“I think this is exciting. It's early data, but it is proof of the concept that this antibody offers a new way to treat psoriasis,” said Dr. Luger, professor and chair of the department of dermatology at the University of Münster (Germany).

Other anti-IL-17A antibodies are also in the developmental pipeline, but AIN457 is furthest along, he noted.

The phase II trial for AIN457 was funded by Novartis.

Mean decrease in PASI 4 weeks after the infusion was 58% in the AIN457-treated patients and 4% with placebo.

Source DR. DRAELOS

BERLIN — Selective inhibition of the proinflammatory cytokine interleukin-17A using a novel fully human monoclonal antibody showed considerable early promise for treatment of psoriasis in a phase II double-blind randomized trial.

This was a proof-of-concept study, and what it proved is that the interleukin 17A–producing T helper 17 cells are an entirely new and attractive therapeutic target in moderate to severe chronic plaque psoriasis, Dr. Zoe Draelos reported at the annual congress of the European Academy of Dermatology and Venereology.

Based upon the phase II results, it's full speed ahead for development of the fully human IgG monoclonal antibody known for now as AIN457. The next round of clinical trials will be considerably larger, longer term, and aimed at identifying optimal dosing, according to Dr. Draelos, a dermatologist in High Point, N.C.

AIN457 is also in clinical trials for the treatment of other immune-mediated disorders, most notably rheumatoid arthritis and noninfectious uveitis. It is also being studied for the treatment of Chrohn's disease.

The phase II study involved 36 patients with chronic plaque psoriasis covering at least 10% of their body surface area and an Investigator's Global Assessment (IGA) severity score of 3 or more, according to Dr. Draelos.

Participants were randomized to a single intravenous infusion of AIN457 at 3 mg/kg or placebo and then followed for 12 weeks.

The study had two primary end points: change in Psoriasis Area and Severity Index (PASI) score at 4 weeks and reduction in IGA score.

The mean decrease in PASI score 4 weeks after the infusion was 58% in the AIN457-treated patients and 4% with placebo, she said.

The response was fast, with a significant difference from placebo emerging within 2 weeks of infusion.

At 12 weeks, the mean reduction in PASI was 63% in patients who received the IL-17A blocker and 9% in controls. A 50% decrease in PASI score (PASI 50) was recorded by 72% of AIN457-treated patients, a PASI 75 by 44%, and a PASI 90 by 11%.

Eighty-three percent of AIN457-treated patients had at least a one-point improvement in IGA score at week 4, compared with 11% of controls. By week 12, 28% of patients in the active-treatment arm had an IGA score of 1, indicative of being almost clear, compared with 6% of controls.

AIN457 exhibited a favorable side effect profile in this small study. No serious adverse events were attributed to the study drug.

Five AIN457-treated patients and three controls developed sinusitis or another infection during the follow-up period. Importantly, no one who received AIN457 developed anti-AIN457 antibodies.

IL-17A, which is upregulated in psoriatic lesional skin, has been called the master regulator of innate defense protein synthesis in keratinocytes.

Dr. Thomas A. Luger, president of the EADV congress, who wasn't involved in the AIN457 study, singled it out as a highlight of the meeting.

“I think this is exciting. It's early data, but it is proof of the concept that this antibody offers a new way to treat psoriasis,” said Dr. Luger, professor and chair of the department of dermatology at the University of Münster (Germany).

Other anti-IL-17A antibodies are also in the developmental pipeline, but AIN457 is furthest along, he noted.

The phase II trial for AIN457 was funded by Novartis.

Mean decrease in PASI 4 weeks after the infusion was 58% in the AIN457-treated patients and 4% with placebo.

Source DR. DRAELOS

BERLIN — Selective inhibition of the proinflammatory cytokine interleukin-17A using a novel fully human monoclonal antibody showed considerable early promise for treatment of psoriasis in a phase II double-blind randomized trial.

This was a proof-of-concept study, and what it proved is that the interleukin 17A–producing T helper 17 cells are an entirely new and attractive therapeutic target in moderate to severe chronic plaque psoriasis, Dr. Zoe Draelos reported at the annual congress of the European Academy of Dermatology and Venereology.

Based upon the phase II results, it's full speed ahead for development of the fully human IgG monoclonal antibody known for now as AIN457. The next round of clinical trials will be considerably larger, longer term, and aimed at identifying optimal dosing, according to Dr. Draelos, a dermatologist in High Point, N.C.

AIN457 is also in clinical trials for the treatment of other immune-mediated disorders, most notably rheumatoid arthritis and noninfectious uveitis. It is also being studied for the treatment of Chrohn's disease.

The phase II study involved 36 patients with chronic plaque psoriasis covering at least 10% of their body surface area and an Investigator's Global Assessment (IGA) severity score of 3 or more, according to Dr. Draelos.

Participants were randomized to a single intravenous infusion of AIN457 at 3 mg/kg or placebo and then followed for 12 weeks.

The study had two primary end points: change in Psoriasis Area and Severity Index (PASI) score at 4 weeks and reduction in IGA score.

The mean decrease in PASI score 4 weeks after the infusion was 58% in the AIN457-treated patients and 4% with placebo, she said.

The response was fast, with a significant difference from placebo emerging within 2 weeks of infusion.

At 12 weeks, the mean reduction in PASI was 63% in patients who received the IL-17A blocker and 9% in controls. A 50% decrease in PASI score (PASI 50) was recorded by 72% of AIN457-treated patients, a PASI 75 by 44%, and a PASI 90 by 11%.

Eighty-three percent of AIN457-treated patients had at least a one-point improvement in IGA score at week 4, compared with 11% of controls. By week 12, 28% of patients in the active-treatment arm had an IGA score of 1, indicative of being almost clear, compared with 6% of controls.

AIN457 exhibited a favorable side effect profile in this small study. No serious adverse events were attributed to the study drug.

Five AIN457-treated patients and three controls developed sinusitis or another infection during the follow-up period. Importantly, no one who received AIN457 developed anti-AIN457 antibodies.

IL-17A, which is upregulated in psoriatic lesional skin, has been called the master regulator of innate defense protein synthesis in keratinocytes.

Dr. Thomas A. Luger, president of the EADV congress, who wasn't involved in the AIN457 study, singled it out as a highlight of the meeting.

“I think this is exciting. It's early data, but it is proof of the concept that this antibody offers a new way to treat psoriasis,” said Dr. Luger, professor and chair of the department of dermatology at the University of Münster (Germany).

Other anti-IL-17A antibodies are also in the developmental pipeline, but AIN457 is furthest along, he noted.

The phase II trial for AIN457 was funded by Novartis.

Mean decrease in PASI 4 weeks after the infusion was 58% in the AIN457-treated patients and 4% with placebo.

Source DR. DRAELOS

BERLIN — Impaired sexual function is extremely common in the setting of moderate to severe psoriasis, and ustekinumab therapy reduces these problems by 10-fold.

That's a key quality of life finding from the ongoing randomized double-blind phase III PHOENIX-1 and −2 clinical trials of this human monoclonal antibody directed against the proinflammatory cytokines interkeukin-12 and −23, Dr. Lyn Guenther reported at the annual congress of the European Academy of Dermatology and Venereology.

The marked reduction in sexual difficulties was paralleled by a sharp improvement in overall quality of life in the ustekinumab-treated patients in the PHOENIX studies. Their mean baseline score on the Dermatology Life Quality Index (DLQI) was 12, reflecting a very large negative impact on quality of life. Twelve weeks into the studies, the average DLQI had dropped by 9.1 points for ustekinumab patients, compared with a 0.5-point dip in the placebo arm, according to Dr. Guenther, medical director of the Guenther Dermatology Research Centre and professor of dermatology at the University of Western Ontario, London.

The DLQI is scored on a 0–30 scale. A 5-point or greater improvement is considered clinically significant.

The PHOENIX trials include 1,996 adults with moderate to severe psoriasis who were randomized 2:1 to ustekinumab (Stelara) at 45 mg or 90 mg at weeks 0, 4, 12, and every 12 weeks thereafter or to placebo. After 12 weeks, patients in the placebo group were crossed over to ustekinumab.

The mean age of participants at entry was 46 years. Sixty-nine percent are men. Their average baseline Psoriasis Area and Severity Index (PASI) score was 20, with 26% of their body surface area being affected and an average disease duration of 20 years. Twenty-eight percent had psoriatic arthritis.

Question 9 on the DLQI is designed to explore sexual problems. Here's the phrasing: “Over the last week, how much has your skin caused any sexual difficulties?”

The response options are “not at all,” “a little,” “a lot,” “very much,” or “not relevant.” A reply of “a lot” or “very much” was interpreted as indicating sexual difficulties.

The prevalence of impaired sexual function by this measure went from 22.4% at baseline—27.1% in women and 20.8% in men—to 2.7% after 12 weeks on ustekinumab. There was no change in the placebo group, but they showed markedly improved overall quality of life and sexual function upon repeat DLQI testing at 24–28 weeks—3 months or more after having been switched to ustekinumab. There was no significant difference between patients on 90 mg as opposed to 45 mg.

The studies are funded by Centocor. Dr. Guenther is a consultant to the company.

BERLIN — Impaired sexual function is extremely common in the setting of moderate to severe psoriasis, and ustekinumab therapy reduces these problems by 10-fold.

That's a key quality of life finding from the ongoing randomized double-blind phase III PHOENIX-1 and −2 clinical trials of this human monoclonal antibody directed against the proinflammatory cytokines interkeukin-12 and −23, Dr. Lyn Guenther reported at the annual congress of the European Academy of Dermatology and Venereology.

The marked reduction in sexual difficulties was paralleled by a sharp improvement in overall quality of life in the ustekinumab-treated patients in the PHOENIX studies. Their mean baseline score on the Dermatology Life Quality Index (DLQI) was 12, reflecting a very large negative impact on quality of life. Twelve weeks into the studies, the average DLQI had dropped by 9.1 points for ustekinumab patients, compared with a 0.5-point dip in the placebo arm, according to Dr. Guenther, medical director of the Guenther Dermatology Research Centre and professor of dermatology at the University of Western Ontario, London.

The DLQI is scored on a 0–30 scale. A 5-point or greater improvement is considered clinically significant.

The PHOENIX trials include 1,996 adults with moderate to severe psoriasis who were randomized 2:1 to ustekinumab (Stelara) at 45 mg or 90 mg at weeks 0, 4, 12, and every 12 weeks thereafter or to placebo. After 12 weeks, patients in the placebo group were crossed over to ustekinumab.

The mean age of participants at entry was 46 years. Sixty-nine percent are men. Their average baseline Psoriasis Area and Severity Index (PASI) score was 20, with 26% of their body surface area being affected and an average disease duration of 20 years. Twenty-eight percent had psoriatic arthritis.

Question 9 on the DLQI is designed to explore sexual problems. Here's the phrasing: “Over the last week, how much has your skin caused any sexual difficulties?”

The response options are “not at all,” “a little,” “a lot,” “very much,” or “not relevant.” A reply of “a lot” or “very much” was interpreted as indicating sexual difficulties.

The prevalence of impaired sexual function by this measure went from 22.4% at baseline—27.1% in women and 20.8% in men—to 2.7% after 12 weeks on ustekinumab. There was no change in the placebo group, but they showed markedly improved overall quality of life and sexual function upon repeat DLQI testing at 24–28 weeks—3 months or more after having been switched to ustekinumab. There was no significant difference between patients on 90 mg as opposed to 45 mg.

The studies are funded by Centocor. Dr. Guenther is a consultant to the company.

BERLIN — Impaired sexual function is extremely common in the setting of moderate to severe psoriasis, and ustekinumab therapy reduces these problems by 10-fold.

That's a key quality of life finding from the ongoing randomized double-blind phase III PHOENIX-1 and −2 clinical trials of this human monoclonal antibody directed against the proinflammatory cytokines interkeukin-12 and −23, Dr. Lyn Guenther reported at the annual congress of the European Academy of Dermatology and Venereology.

The marked reduction in sexual difficulties was paralleled by a sharp improvement in overall quality of life in the ustekinumab-treated patients in the PHOENIX studies. Their mean baseline score on the Dermatology Life Quality Index (DLQI) was 12, reflecting a very large negative impact on quality of life. Twelve weeks into the studies, the average DLQI had dropped by 9.1 points for ustekinumab patients, compared with a 0.5-point dip in the placebo arm, according to Dr. Guenther, medical director of the Guenther Dermatology Research Centre and professor of dermatology at the University of Western Ontario, London.

The DLQI is scored on a 0–30 scale. A 5-point or greater improvement is considered clinically significant.

The PHOENIX trials include 1,996 adults with moderate to severe psoriasis who were randomized 2:1 to ustekinumab (Stelara) at 45 mg or 90 mg at weeks 0, 4, 12, and every 12 weeks thereafter or to placebo. After 12 weeks, patients in the placebo group were crossed over to ustekinumab.

The mean age of participants at entry was 46 years. Sixty-nine percent are men. Their average baseline Psoriasis Area and Severity Index (PASI) score was 20, with 26% of their body surface area being affected and an average disease duration of 20 years. Twenty-eight percent had psoriatic arthritis.

Question 9 on the DLQI is designed to explore sexual problems. Here's the phrasing: “Over the last week, how much has your skin caused any sexual difficulties?”

The response options are “not at all,” “a little,” “a lot,” “very much,” or “not relevant.” A reply of “a lot” or “very much” was interpreted as indicating sexual difficulties.

The prevalence of impaired sexual function by this measure went from 22.4% at baseline—27.1% in women and 20.8% in men—to 2.7% after 12 weeks on ustekinumab. There was no change in the placebo group, but they showed markedly improved overall quality of life and sexual function upon repeat DLQI testing at 24–28 weeks—3 months or more after having been switched to ustekinumab. There was no significant difference between patients on 90 mg as opposed to 45 mg.

The studies are funded by Centocor. Dr. Guenther is a consultant to the company.

BUDAPEST, HUNGARY — Topical or oral antiangiogenic therapy may offer a novel avenue of treatment in inflammatory skin diseases such as psoriasis and rosacea.

In what he described as the first proof-of-concept study to show that blocking the vascular endothelial growth factor (VEGF) receptor may provide an entirely new approach to treating chronic inflammatory skin conditions, Dr. Michael Detmar presented highlights of his research during a satellite symposium held in conjunction with the annual meeting of the European Society for Dermatological Research.

Antiangiogenesis therapy is a hot research area in oncology, as exemplified by the clinical and commercial success of bevacizumab (Avastin), a monoclonal antibody directed against VEGF-A signaling, but this approach has received surprisingly little attention for the treatment of chronic inflammatory skin diseases, noted Dr. Detmar, professor of pharmacogenomics and chair of the Institute of Pharmaceutical Sciences at the Swiss Federal Institute of Technology Zurich.

In studying potential dermatologic applications of VEGF inhibition, Dr. Detmar and his colleagues at the Swiss institute and Novartis opted to eschew the monoclonal antibodies favored in oncology, selecting instead a Novartis small-molecule VEGF receptor tyrosine-kinase inhibitor, NVP-BAW2881.

The production costs for a small molecule are vastly less than for biologic monoclonal antibodies, and the small molecule can be formulated as an oral or topical agent, noted Dr. Detmar.

Using a realistic transgenic mouse model of psoriasis, the investigators showed that topical application of NVP-BAW2881 addressed all three major inflammatory components of psoriasis pathogenesis: It inhibited leukocyte infiltration into the skin, reduced the abnormally large number of cutaneous blood and lymphatic vessels, and normalized epithelial architecture, curbing the keratinocyte hyperproliferation and abnormal differentiation. In effect, the VEGF receptor tyrosine kinase inhibitor essentially resolved the psoriatic phenotype, said Dr. Detmar.

In other studies using domestic pig skin, the topical agent reduced VEGF-A–induced vascular permeability, and it inhibited contact hypersensitivity reactions and UVB-induced inflammation.

“We know the lymphatic vessels are activated in inflammation,” Dr. Detmar said. “They are greatly enlarged in psoriasis and in mouse models of various chronic inflammatory conditions. The question is, what is the role of the lymphatic vessels in skin inflammation: Do they promote it, or do they try to inhibit it?”

His initial hypothesis was that lymphatic vessels promote inflammation. He and his coinvestigators put this notion to the test in laboratory mice by inhibiting lymphatic vessel function via blockade of VEGF receptor-3. This resulted in enhanced inflammation. Their hypothesis was wrong.

More recently, the investigators demonstrated that stimulation of the lymphatic vessels by chronic activation of the pathway involving VEGF receptor-3 resulted in greatly reduced skin inflammation. The mice did not develop the chronic severe psoriasislike disease for which they were genetically programmed (J. Invest. Dermatol. 2009;129:1292–8).

The satellite symposium was sponsored by Galderma SA.

Dr. Detmar reported no financial conflicts of interest in connection with his work.

'What is the role of the lymphatic vessels in skin inflammation: Do they promote it, or do they try to inhibit it?'

Source DR. DETMAR

BUDAPEST, HUNGARY — Topical or oral antiangiogenic therapy may offer a novel avenue of treatment in inflammatory skin diseases such as psoriasis and rosacea.

In what he described as the first proof-of-concept study to show that blocking the vascular endothelial growth factor (VEGF) receptor may provide an entirely new approach to treating chronic inflammatory skin conditions, Dr. Michael Detmar presented highlights of his research during a satellite symposium held in conjunction with the annual meeting of the European Society for Dermatological Research.

Antiangiogenesis therapy is a hot research area in oncology, as exemplified by the clinical and commercial success of bevacizumab (Avastin), a monoclonal antibody directed against VEGF-A signaling, but this approach has received surprisingly little attention for the treatment of chronic inflammatory skin diseases, noted Dr. Detmar, professor of pharmacogenomics and chair of the Institute of Pharmaceutical Sciences at the Swiss Federal Institute of Technology Zurich.

In studying potential dermatologic applications of VEGF inhibition, Dr. Detmar and his colleagues at the Swiss institute and Novartis opted to eschew the monoclonal antibodies favored in oncology, selecting instead a Novartis small-molecule VEGF receptor tyrosine-kinase inhibitor, NVP-BAW2881.

The production costs for a small molecule are vastly less than for biologic monoclonal antibodies, and the small molecule can be formulated as an oral or topical agent, noted Dr. Detmar.

Using a realistic transgenic mouse model of psoriasis, the investigators showed that topical application of NVP-BAW2881 addressed all three major inflammatory components of psoriasis pathogenesis: It inhibited leukocyte infiltration into the skin, reduced the abnormally large number of cutaneous blood and lymphatic vessels, and normalized epithelial architecture, curbing the keratinocyte hyperproliferation and abnormal differentiation. In effect, the VEGF receptor tyrosine kinase inhibitor essentially resolved the psoriatic phenotype, said Dr. Detmar.

In other studies using domestic pig skin, the topical agent reduced VEGF-A–induced vascular permeability, and it inhibited contact hypersensitivity reactions and UVB-induced inflammation.

“We know the lymphatic vessels are activated in inflammation,” Dr. Detmar said. “They are greatly enlarged in psoriasis and in mouse models of various chronic inflammatory conditions. The question is, what is the role of the lymphatic vessels in skin inflammation: Do they promote it, or do they try to inhibit it?”

His initial hypothesis was that lymphatic vessels promote inflammation. He and his coinvestigators put this notion to the test in laboratory mice by inhibiting lymphatic vessel function via blockade of VEGF receptor-3. This resulted in enhanced inflammation. Their hypothesis was wrong.

More recently, the investigators demonstrated that stimulation of the lymphatic vessels by chronic activation of the pathway involving VEGF receptor-3 resulted in greatly reduced skin inflammation. The mice did not develop the chronic severe psoriasislike disease for which they were genetically programmed (J. Invest. Dermatol. 2009;129:1292–8).

The satellite symposium was sponsored by Galderma SA.

Dr. Detmar reported no financial conflicts of interest in connection with his work.

'What is the role of the lymphatic vessels in skin inflammation: Do they promote it, or do they try to inhibit it?'

Source DR. DETMAR

BUDAPEST, HUNGARY — Topical or oral antiangiogenic therapy may offer a novel avenue of treatment in inflammatory skin diseases such as psoriasis and rosacea.

In what he described as the first proof-of-concept study to show that blocking the vascular endothelial growth factor (VEGF) receptor may provide an entirely new approach to treating chronic inflammatory skin conditions, Dr. Michael Detmar presented highlights of his research during a satellite symposium held in conjunction with the annual meeting of the European Society for Dermatological Research.

Antiangiogenesis therapy is a hot research area in oncology, as exemplified by the clinical and commercial success of bevacizumab (Avastin), a monoclonal antibody directed against VEGF-A signaling, but this approach has received surprisingly little attention for the treatment of chronic inflammatory skin diseases, noted Dr. Detmar, professor of pharmacogenomics and chair of the Institute of Pharmaceutical Sciences at the Swiss Federal Institute of Technology Zurich.

In studying potential dermatologic applications of VEGF inhibition, Dr. Detmar and his colleagues at the Swiss institute and Novartis opted to eschew the monoclonal antibodies favored in oncology, selecting instead a Novartis small-molecule VEGF receptor tyrosine-kinase inhibitor, NVP-BAW2881.

The production costs for a small molecule are vastly less than for biologic monoclonal antibodies, and the small molecule can be formulated as an oral or topical agent, noted Dr. Detmar.

Using a realistic transgenic mouse model of psoriasis, the investigators showed that topical application of NVP-BAW2881 addressed all three major inflammatory components of psoriasis pathogenesis: It inhibited leukocyte infiltration into the skin, reduced the abnormally large number of cutaneous blood and lymphatic vessels, and normalized epithelial architecture, curbing the keratinocyte hyperproliferation and abnormal differentiation. In effect, the VEGF receptor tyrosine kinase inhibitor essentially resolved the psoriatic phenotype, said Dr. Detmar.

In other studies using domestic pig skin, the topical agent reduced VEGF-A–induced vascular permeability, and it inhibited contact hypersensitivity reactions and UVB-induced inflammation.

“We know the lymphatic vessels are activated in inflammation,” Dr. Detmar said. “They are greatly enlarged in psoriasis and in mouse models of various chronic inflammatory conditions. The question is, what is the role of the lymphatic vessels in skin inflammation: Do they promote it, or do they try to inhibit it?”

His initial hypothesis was that lymphatic vessels promote inflammation. He and his coinvestigators put this notion to the test in laboratory mice by inhibiting lymphatic vessel function via blockade of VEGF receptor-3. This resulted in enhanced inflammation. Their hypothesis was wrong.

More recently, the investigators demonstrated that stimulation of the lymphatic vessels by chronic activation of the pathway involving VEGF receptor-3 resulted in greatly reduced skin inflammation. The mice did not develop the chronic severe psoriasislike disease for which they were genetically programmed (J. Invest. Dermatol. 2009;129:1292–8).

The satellite symposium was sponsored by Galderma SA.

Dr. Detmar reported no financial conflicts of interest in connection with his work.

'What is the role of the lymphatic vessels in skin inflammation: Do they promote it, or do they try to inhibit it?'

Source DR. DETMAR

The Food and Drug Administration's approval of ustekinumab for moderate to severe plaque psoriasis—the first interleukin-12 and −23 antagonist to be approved in the United States—is accompanied by requirements for a risk management plan and postmarketing studies that address uncertainties about the long-term safety of the biologic drug.

Ustekinumab was approved for the treatment of moderate to severe plaque psoriasis in adult patients (aged 18 and older) who are candidates for phototherapy or systemic therapy. Ustekinumab will be marketed by Centocor Inc. as Stelara.

Because of concerns over potential long-term risks of ustekinumab, which delayed approval, the FDA is requiring a risk evaluation and mitigation strategy (REMS) and postmarketing requirements that include a 5-year follow-up of patients in the clinical trials for malignancies, serious infections, and other serious adverse events; the enrollment of treated patients in a registry that will follow them for 8 years; and the establishment of a U.S.-based pregnancy registry.

Elements of the REMS include a communication plan targeted to health care providers, as well as a patient medication guide that explains the risks of treatment and will be distributed to patients with each prescription, including refills. The company is also required to provide the FDA with assessments of how well the REMS is working; such assessment will include evaluations of prescriber and patient understanding of the risks of treatment. Prescribers will also be evaluated in how well they select appropriate patients for treatment, according to the FDA's approval letter.

Ustekinumab “is the first drug that's based truly on a genetic defect recognized in psoriasis,” Dr. Alan Menter, chairman of the division of dermatology at Baylor University Medical Center in Dallas, said in an interview.

Although precisely how IL-12 and −23 contribute to the pathophysiology of psoriasis is not entirely understood, “the fact is that the shared protein between them has a key role in the inflammatory aspect of psoriasis … and we now have a drug that specifically targets that,” he noted.

The most attractive features of this drug are rapid efficacy; “maintenance, if not improvement” of efficacy in most patients with continued treatment, especially through week 24 and beyond; and the convenient dosing schedule, which is every 12 weeks after the first two doses given 4 weeks apart, Dr. Menter said. Long-term safety is the “big unknown,” so 5-year follow-up data are needed, he said.

Risk is a particular concern because of what happened to the biologic efalizumab (Raptiva), which was taken off the market after three cases of progressive multifocal leukoencephalopathy (PML), a progressive and often fatal brain infection, were reported in patients who were treated with the drug for psoriasis, including two fatal cases.

Another concern is that a significant proportion of psoriasis patients weigh more than 220 pounds and thus need the higher dose, which could be financially difficult for some patients, he added.

Dr. Menter was an investigator in clinical trials of ustekinumab, and is an investigator in phase III clinical trials of ABT-874, another IL-12 and −23 antagonist for psoriasis that is being manufactured by Abbott. He said he has no financial ties to Centocor or Abbott.

The first two doses of ustekinumab are administered subcutaneously, 4 weeks apart, after which it is administered every 12 weeks; a 45-mg dose is recommended for those weighing 220 pounds or less, and 90 mg for those heavier than 220 pounds. Ustekinumab must be administered under the supervision of a physician.

At a June 2008 meeting of the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee, which backed the approval of ustekinumab, most of the panel favored office-based administration because it would provide an opportunity for clinicians to evaluate patients for responses and side effects every 3 months, and would help collect postmarketing data.

The wholesaler's acquisition cost or list price for a 45-mg vial of ustekinumab is $4,663, according to Brian Kenney, a spokesperson for Centocor.

FDA approval was based primarily on two pivotal studies (PHOENIX I and PHOENIX II) of almost 2,000 patients, aged 18 years and older, who had plaque psoriasis and a PASI (Psoriasis Area and Severity Index) score of 12 or greater, with at least 10% surface body involvement. At 12 weeks, 67% of those on the 45-mg dose and 66%-76% of those on the 90-mg dose had achieved a least a 75% reduction in psoriasis as measured by their PASI 75 response, compared with 4% of those on placebo. Response rates among those who weighed less than 220 pounds showed similar response to both doses, but those who were heavier than 220 pounds had better response rates with the higher dose.

Dr. Menter described the efficacy data as “very compelling,” noting that at week 24 (8 weeks after the third injection), almost 50% of patients achieved a PASI 90.

As with the tumor necrosis factor blockers, the ustekinumab label includes warnings and precautions about the risk of serious infections and the possible increased risk of malignancies. Serious infections—including some that required hospitalization—have been reported in patients on ustekinumab. There has been one report of reversible posterior leukoencephalopathy syndrome (RPLS), a rare, potentially fatal neurologic disorder that is not caused by demyelination or a known infectious agent, according to the ustekinumab label. If RPLS is suspected, ustekinumab should be discontinued immediately and the patient should be treated.

Among the manufacturer's other postmarketing requirements is to enroll 4,000 ustekinumab-treated patients in the Psoriasis Longitudinal Assessment and Registry (PSOLAR), and follow them for 8 years for serious infections, tuberculosis, opportunistic infections, malignancy, hypersensitivity reactions, autoimmune diseases, and neurologic or demyelinating diseases.

Dr. Menter is cochair of PSOLAR.

Ustekinumab 'is the first drug that's based truly on a genetic defect recognized in psoriasis.'

Source DR. MENTER

The Food and Drug Administration's approval of ustekinumab for moderate to severe plaque psoriasis—the first interleukin-12 and −23 antagonist to be approved in the United States—is accompanied by requirements for a risk management plan and postmarketing studies that address uncertainties about the long-term safety of the biologic drug.

Ustekinumab was approved for the treatment of moderate to severe plaque psoriasis in adult patients (aged 18 and older) who are candidates for phototherapy or systemic therapy. Ustekinumab will be marketed by Centocor Inc. as Stelara.

Because of concerns over potential long-term risks of ustekinumab, which delayed approval, the FDA is requiring a risk evaluation and mitigation strategy (REMS) and postmarketing requirements that include a 5-year follow-up of patients in the clinical trials for malignancies, serious infections, and other serious adverse events; the enrollment of treated patients in a registry that will follow them for 8 years; and the establishment of a U.S.-based pregnancy registry.

Elements of the REMS include a communication plan targeted to health care providers, as well as a patient medication guide that explains the risks of treatment and will be distributed to patients with each prescription, including refills. The company is also required to provide the FDA with assessments of how well the REMS is working; such assessment will include evaluations of prescriber and patient understanding of the risks of treatment. Prescribers will also be evaluated in how well they select appropriate patients for treatment, according to the FDA's approval letter.

Ustekinumab “is the first drug that's based truly on a genetic defect recognized in psoriasis,” Dr. Alan Menter, chairman of the division of dermatology at Baylor University Medical Center in Dallas, said in an interview.

Although precisely how IL-12 and −23 contribute to the pathophysiology of psoriasis is not entirely understood, “the fact is that the shared protein between them has a key role in the inflammatory aspect of psoriasis … and we now have a drug that specifically targets that,” he noted.

The most attractive features of this drug are rapid efficacy; “maintenance, if not improvement” of efficacy in most patients with continued treatment, especially through week 24 and beyond; and the convenient dosing schedule, which is every 12 weeks after the first two doses given 4 weeks apart, Dr. Menter said. Long-term safety is the “big unknown,” so 5-year follow-up data are needed, he said.

Risk is a particular concern because of what happened to the biologic efalizumab (Raptiva), which was taken off the market after three cases of progressive multifocal leukoencephalopathy (PML), a progressive and often fatal brain infection, were reported in patients who were treated with the drug for psoriasis, including two fatal cases.

Another concern is that a significant proportion of psoriasis patients weigh more than 220 pounds and thus need the higher dose, which could be financially difficult for some patients, he added.

Dr. Menter was an investigator in clinical trials of ustekinumab, and is an investigator in phase III clinical trials of ABT-874, another IL-12 and −23 antagonist for psoriasis that is being manufactured by Abbott. He said he has no financial ties to Centocor or Abbott.

The first two doses of ustekinumab are administered subcutaneously, 4 weeks apart, after which it is administered every 12 weeks; a 45-mg dose is recommended for those weighing 220 pounds or less, and 90 mg for those heavier than 220 pounds. Ustekinumab must be administered under the supervision of a physician.

At a June 2008 meeting of the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee, which backed the approval of ustekinumab, most of the panel favored office-based administration because it would provide an opportunity for clinicians to evaluate patients for responses and side effects every 3 months, and would help collect postmarketing data.

The wholesaler's acquisition cost or list price for a 45-mg vial of ustekinumab is $4,663, according to Brian Kenney, a spokesperson for Centocor.

FDA approval was based primarily on two pivotal studies (PHOENIX I and PHOENIX II) of almost 2,000 patients, aged 18 years and older, who had plaque psoriasis and a PASI (Psoriasis Area and Severity Index) score of 12 or greater, with at least 10% surface body involvement. At 12 weeks, 67% of those on the 45-mg dose and 66%-76% of those on the 90-mg dose had achieved a least a 75% reduction in psoriasis as measured by their PASI 75 response, compared with 4% of those on placebo. Response rates among those who weighed less than 220 pounds showed similar response to both doses, but those who were heavier than 220 pounds had better response rates with the higher dose.

Dr. Menter described the efficacy data as “very compelling,” noting that at week 24 (8 weeks after the third injection), almost 50% of patients achieved a PASI 90.

As with the tumor necrosis factor blockers, the ustekinumab label includes warnings and precautions about the risk of serious infections and the possible increased risk of malignancies. Serious infections—including some that required hospitalization—have been reported in patients on ustekinumab. There has been one report of reversible posterior leukoencephalopathy syndrome (RPLS), a rare, potentially fatal neurologic disorder that is not caused by demyelination or a known infectious agent, according to the ustekinumab label. If RPLS is suspected, ustekinumab should be discontinued immediately and the patient should be treated.

Among the manufacturer's other postmarketing requirements is to enroll 4,000 ustekinumab-treated patients in the Psoriasis Longitudinal Assessment and Registry (PSOLAR), and follow them for 8 years for serious infections, tuberculosis, opportunistic infections, malignancy, hypersensitivity reactions, autoimmune diseases, and neurologic or demyelinating diseases.

Dr. Menter is cochair of PSOLAR.

Ustekinumab 'is the first drug that's based truly on a genetic defect recognized in psoriasis.'

Source DR. MENTER

The Food and Drug Administration's approval of ustekinumab for moderate to severe plaque psoriasis—the first interleukin-12 and −23 antagonist to be approved in the United States—is accompanied by requirements for a risk management plan and postmarketing studies that address uncertainties about the long-term safety of the biologic drug.

Ustekinumab was approved for the treatment of moderate to severe plaque psoriasis in adult patients (aged 18 and older) who are candidates for phototherapy or systemic therapy. Ustekinumab will be marketed by Centocor Inc. as Stelara.

Because of concerns over potential long-term risks of ustekinumab, which delayed approval, the FDA is requiring a risk evaluation and mitigation strategy (REMS) and postmarketing requirements that include a 5-year follow-up of patients in the clinical trials for malignancies, serious infections, and other serious adverse events; the enrollment of treated patients in a registry that will follow them for 8 years; and the establishment of a U.S.-based pregnancy registry.

Elements of the REMS include a communication plan targeted to health care providers, as well as a patient medication guide that explains the risks of treatment and will be distributed to patients with each prescription, including refills. The company is also required to provide the FDA with assessments of how well the REMS is working; such assessment will include evaluations of prescriber and patient understanding of the risks of treatment. Prescribers will also be evaluated in how well they select appropriate patients for treatment, according to the FDA's approval letter.

Ustekinumab “is the first drug that's based truly on a genetic defect recognized in psoriasis,” Dr. Alan Menter, chairman of the division of dermatology at Baylor University Medical Center in Dallas, said in an interview.

Although precisely how IL-12 and −23 contribute to the pathophysiology of psoriasis is not entirely understood, “the fact is that the shared protein between them has a key role in the inflammatory aspect of psoriasis … and we now have a drug that specifically targets that,” he noted.

The most attractive features of this drug are rapid efficacy; “maintenance, if not improvement” of efficacy in most patients with continued treatment, especially through week 24 and beyond; and the convenient dosing schedule, which is every 12 weeks after the first two doses given 4 weeks apart, Dr. Menter said. Long-term safety is the “big unknown,” so 5-year follow-up data are needed, he said.

Risk is a particular concern because of what happened to the biologic efalizumab (Raptiva), which was taken off the market after three cases of progressive multifocal leukoencephalopathy (PML), a progressive and often fatal brain infection, were reported in patients who were treated with the drug for psoriasis, including two fatal cases.

Another concern is that a significant proportion of psoriasis patients weigh more than 220 pounds and thus need the higher dose, which could be financially difficult for some patients, he added.

Dr. Menter was an investigator in clinical trials of ustekinumab, and is an investigator in phase III clinical trials of ABT-874, another IL-12 and −23 antagonist for psoriasis that is being manufactured by Abbott. He said he has no financial ties to Centocor or Abbott.

The first two doses of ustekinumab are administered subcutaneously, 4 weeks apart, after which it is administered every 12 weeks; a 45-mg dose is recommended for those weighing 220 pounds or less, and 90 mg for those heavier than 220 pounds. Ustekinumab must be administered under the supervision of a physician.

At a June 2008 meeting of the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee, which backed the approval of ustekinumab, most of the panel favored office-based administration because it would provide an opportunity for clinicians to evaluate patients for responses and side effects every 3 months, and would help collect postmarketing data.

The wholesaler's acquisition cost or list price for a 45-mg vial of ustekinumab is $4,663, according to Brian Kenney, a spokesperson for Centocor.

FDA approval was based primarily on two pivotal studies (PHOENIX I and PHOENIX II) of almost 2,000 patients, aged 18 years and older, who had plaque psoriasis and a PASI (Psoriasis Area and Severity Index) score of 12 or greater, with at least 10% surface body involvement. At 12 weeks, 67% of those on the 45-mg dose and 66%-76% of those on the 90-mg dose had achieved a least a 75% reduction in psoriasis as measured by their PASI 75 response, compared with 4% of those on placebo. Response rates among those who weighed less than 220 pounds showed similar response to both doses, but those who were heavier than 220 pounds had better response rates with the higher dose.

Dr. Menter described the efficacy data as “very compelling,” noting that at week 24 (8 weeks after the third injection), almost 50% of patients achieved a PASI 90.

As with the tumor necrosis factor blockers, the ustekinumab label includes warnings and precautions about the risk of serious infections and the possible increased risk of malignancies. Serious infections—including some that required hospitalization—have been reported in patients on ustekinumab. There has been one report of reversible posterior leukoencephalopathy syndrome (RPLS), a rare, potentially fatal neurologic disorder that is not caused by demyelination or a known infectious agent, according to the ustekinumab label. If RPLS is suspected, ustekinumab should be discontinued immediately and the patient should be treated.

Among the manufacturer's other postmarketing requirements is to enroll 4,000 ustekinumab-treated patients in the Psoriasis Longitudinal Assessment and Registry (PSOLAR), and follow them for 8 years for serious infections, tuberculosis, opportunistic infections, malignancy, hypersensitivity reactions, autoimmune diseases, and neurologic or demyelinating diseases.

Dr. Menter is cochair of PSOLAR.

Ustekinumab 'is the first drug that's based truly on a genetic defect recognized in psoriasis.'

Source DR. MENTER

BUDAPEST, HUNGARY — More than 100 psoriasis patients treated with adalimumab, etanercept, or infliximab experienced marked clinical improvement for every patient who developed a serious adverse event, according to a risk-benefit analysis of the major randomized trials of the tumor necrosis factor antagonists.

In the resultant rank ordering of TNF blockers in terms of efficacy, infliximab came out on top. The number of patients with moderate to severe chronic plaque psoriasis who needed to be treated (NNT) with infliximab instead of placebo in order for one additional patient to achieve at least a 75% reduction in their Psoriasis Area and Severity Index (PASI 75) score was 1.4, Dr. Stephen J. Rozzo said at the annual meeting of the European Society for Dermatological Research.

The NNT for a PASI 75 with adalimumab at 40 mg every other week was 1.6. Etanercept brought up the rear in terms of efficacy, with a NNT of 2.3 when dosed at 50 mg twice weekly and 3.2 with 50 mg once weekly. Infliximab was dosed at 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks.

If the efficacy data from the trials and their open-label extensions are viewed from another angle, 74% of infliximab-treated patients achieved PASI 75, as did 64% on adalimumab, 44% on twice-weekly etanercept, and 31% on once-weekly etanercept, according to Dr. Rozzo of Abbott Laboratories in Abbott Park, Ill.

The safety analysis was more complex. No agent had a consistently better safety profile than did the others, and there was a good deal of overlap in terms of adverse event rates.

“There was no consistent pattern to these rates,” according to Dr. Rozzo.

As a generalization, however, the numbers needed to harm (NNH) were more than 100-fold greater than the NNTs for all three TNF antagonists.

Infliximab had the highest associated risk of nonmelanoma skin cancer, with an NNH of 99 for this end point in the placebo-controlled trials. In contrast, the NNH for nonmelanoma skin cancer was 270 with once-weekly etanercept, 324 with twice-weekly etanercept, and 470 with adalimumab.

The NNH for one additional serious infectious adverse event was 99 for infliximab, 148 for once-weekly etanercept, 183 for twice-weekly etanercept, and 291 for adalimumab, he said.

There were no cases of tuberculosis, other opportunistic infections, or demyelinating disorders for any of the TNF antagonists during the placebo-controlled portion of the clinical trials.

The long-term safety analysis was based upon nearly 7,400 psoriasis patients who were exposed to one of the TNF antagonists for an average duration of almost 11 months. This analysis concluded that the risk of serious infections was 0.015 cases per patient-year of exposure to adalimumab, 0.014 per patient-year for various dosages of etanercept, and 0.018 per patient-year for infliximab. The risk of nonmelanoma skin cancer was 0.007 per patient-year for adalimumab, 0.010 per patient-year for etanercept, and 0.017 per patient-year for infliximab.

Mean baseline body weights of participants ranged from 88.9 kg to 92.7 kg, suggesting a high prevalence of obesity.

Dr. Rozzo indicated that the NNTs and NNHs generated in this evidence-based assessment need to be taken with a grain of salt, as they were obtained from clinical trials that did not involve head-to-head comparisons among biologics. Moreover, the duration of the placebo-controlled portions varied from study to study. For these reasons, he did not perform any tests of statistical significance for the differences in results. The assessment was sponsored by Abbott.

BUDAPEST, HUNGARY — More than 100 psoriasis patients treated with adalimumab, etanercept, or infliximab experienced marked clinical improvement for every patient who developed a serious adverse event, according to a risk-benefit analysis of the major randomized trials of the tumor necrosis factor antagonists.

In the resultant rank ordering of TNF blockers in terms of efficacy, infliximab came out on top. The number of patients with moderate to severe chronic plaque psoriasis who needed to be treated (NNT) with infliximab instead of placebo in order for one additional patient to achieve at least a 75% reduction in their Psoriasis Area and Severity Index (PASI 75) score was 1.4, Dr. Stephen J. Rozzo said at the annual meeting of the European Society for Dermatological Research.

The NNT for a PASI 75 with adalimumab at 40 mg every other week was 1.6. Etanercept brought up the rear in terms of efficacy, with a NNT of 2.3 when dosed at 50 mg twice weekly and 3.2 with 50 mg once weekly. Infliximab was dosed at 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks.

If the efficacy data from the trials and their open-label extensions are viewed from another angle, 74% of infliximab-treated patients achieved PASI 75, as did 64% on adalimumab, 44% on twice-weekly etanercept, and 31% on once-weekly etanercept, according to Dr. Rozzo of Abbott Laboratories in Abbott Park, Ill.

The safety analysis was more complex. No agent had a consistently better safety profile than did the others, and there was a good deal of overlap in terms of adverse event rates.

“There was no consistent pattern to these rates,” according to Dr. Rozzo.

As a generalization, however, the numbers needed to harm (NNH) were more than 100-fold greater than the NNTs for all three TNF antagonists.

Infliximab had the highest associated risk of nonmelanoma skin cancer, with an NNH of 99 for this end point in the placebo-controlled trials. In contrast, the NNH for nonmelanoma skin cancer was 270 with once-weekly etanercept, 324 with twice-weekly etanercept, and 470 with adalimumab.

The NNH for one additional serious infectious adverse event was 99 for infliximab, 148 for once-weekly etanercept, 183 for twice-weekly etanercept, and 291 for adalimumab, he said.

There were no cases of tuberculosis, other opportunistic infections, or demyelinating disorders for any of the TNF antagonists during the placebo-controlled portion of the clinical trials.

The long-term safety analysis was based upon nearly 7,400 psoriasis patients who were exposed to one of the TNF antagonists for an average duration of almost 11 months. This analysis concluded that the risk of serious infections was 0.015 cases per patient-year of exposure to adalimumab, 0.014 per patient-year for various dosages of etanercept, and 0.018 per patient-year for infliximab. The risk of nonmelanoma skin cancer was 0.007 per patient-year for adalimumab, 0.010 per patient-year for etanercept, and 0.017 per patient-year for infliximab.

Mean baseline body weights of participants ranged from 88.9 kg to 92.7 kg, suggesting a high prevalence of obesity.

Dr. Rozzo indicated that the NNTs and NNHs generated in this evidence-based assessment need to be taken with a grain of salt, as they were obtained from clinical trials that did not involve head-to-head comparisons among biologics. Moreover, the duration of the placebo-controlled portions varied from study to study. For these reasons, he did not perform any tests of statistical significance for the differences in results. The assessment was sponsored by Abbott.

BUDAPEST, HUNGARY — More than 100 psoriasis patients treated with adalimumab, etanercept, or infliximab experienced marked clinical improvement for every patient who developed a serious adverse event, according to a risk-benefit analysis of the major randomized trials of the tumor necrosis factor antagonists.

In the resultant rank ordering of TNF blockers in terms of efficacy, infliximab came out on top. The number of patients with moderate to severe chronic plaque psoriasis who needed to be treated (NNT) with infliximab instead of placebo in order for one additional patient to achieve at least a 75% reduction in their Psoriasis Area and Severity Index (PASI 75) score was 1.4, Dr. Stephen J. Rozzo said at the annual meeting of the European Society for Dermatological Research.

The NNT for a PASI 75 with adalimumab at 40 mg every other week was 1.6. Etanercept brought up the rear in terms of efficacy, with a NNT of 2.3 when dosed at 50 mg twice weekly and 3.2 with 50 mg once weekly. Infliximab was dosed at 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks.

If the efficacy data from the trials and their open-label extensions are viewed from another angle, 74% of infliximab-treated patients achieved PASI 75, as did 64% on adalimumab, 44% on twice-weekly etanercept, and 31% on once-weekly etanercept, according to Dr. Rozzo of Abbott Laboratories in Abbott Park, Ill.

The safety analysis was more complex. No agent had a consistently better safety profile than did the others, and there was a good deal of overlap in terms of adverse event rates.

“There was no consistent pattern to these rates,” according to Dr. Rozzo.

As a generalization, however, the numbers needed to harm (NNH) were more than 100-fold greater than the NNTs for all three TNF antagonists.

Infliximab had the highest associated risk of nonmelanoma skin cancer, with an NNH of 99 for this end point in the placebo-controlled trials. In contrast, the NNH for nonmelanoma skin cancer was 270 with once-weekly etanercept, 324 with twice-weekly etanercept, and 470 with adalimumab.

The NNH for one additional serious infectious adverse event was 99 for infliximab, 148 for once-weekly etanercept, 183 for twice-weekly etanercept, and 291 for adalimumab, he said.

There were no cases of tuberculosis, other opportunistic infections, or demyelinating disorders for any of the TNF antagonists during the placebo-controlled portion of the clinical trials.

The long-term safety analysis was based upon nearly 7,400 psoriasis patients who were exposed to one of the TNF antagonists for an average duration of almost 11 months. This analysis concluded that the risk of serious infections was 0.015 cases per patient-year of exposure to adalimumab, 0.014 per patient-year for various dosages of etanercept, and 0.018 per patient-year for infliximab. The risk of nonmelanoma skin cancer was 0.007 per patient-year for adalimumab, 0.010 per patient-year for etanercept, and 0.017 per patient-year for infliximab.

Mean baseline body weights of participants ranged from 88.9 kg to 92.7 kg, suggesting a high prevalence of obesity.

Dr. Rozzo indicated that the NNTs and NNHs generated in this evidence-based assessment need to be taken with a grain of salt, as they were obtained from clinical trials that did not involve head-to-head comparisons among biologics. Moreover, the duration of the placebo-controlled portions varied from study to study. For these reasons, he did not perform any tests of statistical significance for the differences in results. The assessment was sponsored by Abbott.

The intensity of exposure to ambient ultraviolet radiation appears to determine the prevalence of dermatomyositis and an autoantibody specific to the disease in women, based on a recent study.

The UV Index across geographical regions of the United States also significantly correlated with the presence of an autoantibody unique to dermatomyositis (DM)—known as anti-Mi-2—and not to autoantibodies more commonly found in polymyositis (PM). The association between UV radiation and DM was strongest in a collective group of European, Hispanic, and Asian American women, but it also was significant among black women.

This is the first study to show evidence of the influence of sex on the association between UV radiation and autoimmune disorders, commented Dr. Victoria P. Werth, professor of dermatology at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center.

The study brings up many “intriguing kinds of things that we don't totally understand,” such as differences in risk factors and responses to UV radiation between men and women and between PM and DM. These types of “interesting epidemiologic observations” may help in the future to understand more about the differences in pathogenesis, Dr. Werth said in an interview.

In the cross-sectional, retrospective study, Dr. Lori A. Love of the National Institute of Environmental Health Sciences and her coinvestigators gathered clinical data and serum samples from 202 PM and 178 DM patients at referral centers across the United States.

The investigators detected myositis-specific autoantibodies in 172 patients (45%), some of which were found in both PM and DM patients, whereas others were found only in each particular phenotypic type of myositis, such as anti-SRP in 21 PM patients and anti-Mi-2 in 23 DM patients.

PM occurred in a significantly greater proportion of black patients (66%) than among nonblack patients (48%). Most (86%) of the patients with anti-SRP antibodies were black, Dr. Love and her associates reported (Arthritis Rheum. 2009;60:2499-504).

The proportion of patients in the study who had anti-Mi-2 autoantibodies was significantly associated with the UV Index for the seven regions (comprising 37 states) that the investigators categorized according to shared geoclimatic factors. However, the UV Index was not associated with the proportion of patients with DM. Both of these comparisons proved to be significant for women but not for men.

The investigators noted that the study may be limited by the following: referral bias; the use of state-level UV radiation intensities; the lack of accounting for individual-level exposure; differences in UV radiation exposure at different locations over time; and the use of personal photoprotective measures.

The study was funded in part by the intramural research programs of the National Institute of Environmental Health Sciences. Dr. Werth said she had no relevant disclosures.

The intensity of UV radiation exposure may be tied to the prevalence of dermatomyositis in women, shown here.

Source Courtesy Dr. Victoria P. Werth

The intensity of exposure to ambient ultraviolet radiation appears to determine the prevalence of dermatomyositis and an autoantibody specific to the disease in women, based on a recent study.

The UV Index across geographical regions of the United States also significantly correlated with the presence of an autoantibody unique to dermatomyositis (DM)—known as anti-Mi-2—and not to autoantibodies more commonly found in polymyositis (PM). The association between UV radiation and DM was strongest in a collective group of European, Hispanic, and Asian American women, but it also was significant among black women.

This is the first study to show evidence of the influence of sex on the association between UV radiation and autoimmune disorders, commented Dr. Victoria P. Werth, professor of dermatology at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center.

The study brings up many “intriguing kinds of things that we don't totally understand,” such as differences in risk factors and responses to UV radiation between men and women and between PM and DM. These types of “interesting epidemiologic observations” may help in the future to understand more about the differences in pathogenesis, Dr. Werth said in an interview.

In the cross-sectional, retrospective study, Dr. Lori A. Love of the National Institute of Environmental Health Sciences and her coinvestigators gathered clinical data and serum samples from 202 PM and 178 DM patients at referral centers across the United States.

The investigators detected myositis-specific autoantibodies in 172 patients (45%), some of which were found in both PM and DM patients, whereas others were found only in each particular phenotypic type of myositis, such as anti-SRP in 21 PM patients and anti-Mi-2 in 23 DM patients.

PM occurred in a significantly greater proportion of black patients (66%) than among nonblack patients (48%). Most (86%) of the patients with anti-SRP antibodies were black, Dr. Love and her associates reported (Arthritis Rheum. 2009;60:2499-504).

The proportion of patients in the study who had anti-Mi-2 autoantibodies was significantly associated with the UV Index for the seven regions (comprising 37 states) that the investigators categorized according to shared geoclimatic factors. However, the UV Index was not associated with the proportion of patients with DM. Both of these comparisons proved to be significant for women but not for men.

The investigators noted that the study may be limited by the following: referral bias; the use of state-level UV radiation intensities; the lack of accounting for individual-level exposure; differences in UV radiation exposure at different locations over time; and the use of personal photoprotective measures.

The study was funded in part by the intramural research programs of the National Institute of Environmental Health Sciences. Dr. Werth said she had no relevant disclosures.

The intensity of UV radiation exposure may be tied to the prevalence of dermatomyositis in women, shown here.

Source Courtesy Dr. Victoria P. Werth

The intensity of exposure to ambient ultraviolet radiation appears to determine the prevalence of dermatomyositis and an autoantibody specific to the disease in women, based on a recent study.

The UV Index across geographical regions of the United States also significantly correlated with the presence of an autoantibody unique to dermatomyositis (DM)—known as anti-Mi-2—and not to autoantibodies more commonly found in polymyositis (PM). The association between UV radiation and DM was strongest in a collective group of European, Hispanic, and Asian American women, but it also was significant among black women.

This is the first study to show evidence of the influence of sex on the association between UV radiation and autoimmune disorders, commented Dr. Victoria P. Werth, professor of dermatology at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center.

The study brings up many “intriguing kinds of things that we don't totally understand,” such as differences in risk factors and responses to UV radiation between men and women and between PM and DM. These types of “interesting epidemiologic observations” may help in the future to understand more about the differences in pathogenesis, Dr. Werth said in an interview.

In the cross-sectional, retrospective study, Dr. Lori A. Love of the National Institute of Environmental Health Sciences and her coinvestigators gathered clinical data and serum samples from 202 PM and 178 DM patients at referral centers across the United States.

The investigators detected myositis-specific autoantibodies in 172 patients (45%), some of which were found in both PM and DM patients, whereas others were found only in each particular phenotypic type of myositis, such as anti-SRP in 21 PM patients and anti-Mi-2 in 23 DM patients.

PM occurred in a significantly greater proportion of black patients (66%) than among nonblack patients (48%). Most (86%) of the patients with anti-SRP antibodies were black, Dr. Love and her associates reported (Arthritis Rheum. 2009;60:2499-504).

The proportion of patients in the study who had anti-Mi-2 autoantibodies was significantly associated with the UV Index for the seven regions (comprising 37 states) that the investigators categorized according to shared geoclimatic factors. However, the UV Index was not associated with the proportion of patients with DM. Both of these comparisons proved to be significant for women but not for men.

The investigators noted that the study may be limited by the following: referral bias; the use of state-level UV radiation intensities; the lack of accounting for individual-level exposure; differences in UV radiation exposure at different locations over time; and the use of personal photoprotective measures.

The study was funded in part by the intramural research programs of the National Institute of Environmental Health Sciences. Dr. Werth said she had no relevant disclosures.

The intensity of UV radiation exposure may be tied to the prevalence of dermatomyositis in women, shown here.

Source Courtesy Dr. Victoria P. Werth