Psoriasis

The oral phosphodiesterase-4 inhibitor apremilast significantly improves moderate to severe psoriasis with minimal side effects, according to data from a phase III, randomized controlled trial of 844 patients.

The drug had an excellent safety profile and resulted in significantly greater improvement in moderate to severe psoriasis than placebo after 16 weeks of treatment in the ESTEEM 1 trial.

The results were reported in a late-breaker session at the annual meeting of the American Academy of Dermatology.

Apremilast is "one of the new small molecules being developed for treatment of psoriasis," said Dr. Kristian Reich of SCIderm Research Institute and Dermatologikum, Hamburg, Germany.

"We believe it has anti-inflammatory properties, because by increasing the intracellular level of cyclic AMP (adenosine monophosphate), it actually activates protein kinase A to modulate the balance between proinflammatory and anti-inflammatory mediators released by a cell in a way that pro-inflammatory mediators are down-regulated and anti-inflammatory mediators are upregulated," he said.

Of 562 patients randomized to receive 30 mg of apremilast twice daily for 16 weeks, 33.1% achieved 75% improvement on the Psoriasis Area Severity Index (PASI-75) scale score, compared with only 5.3% of 282 patients who received placebo. Patients in the treatment group also showed significant improvement compared with the placebo group for secondary endpoints including physician global assessment (PGA) score, change in body surface area affected, and pruritus.

Improvements also were noted in difficult to treat areas such as the scalp and nails. For example, about 50% of affected patients achieved a 50% reduction in nail psoriasis severity, Dr. Reich said.

The study participants were adults with moderate to severe chronic plaque psoriasis, surface area involvement greater than 10%, and a PGA score of 3 or higher. All were candidates for phototherapy or systemic therapy, half had been treated previously with other systemic therapies, including biologics, and nearly 1 in 5 patients had been treated with tumor necrosis factor (TNF) blockers.

Patients initially receiving placebo switched over to active treatment after the first 16 weeks, and treatment in all patients continued at the 30-mg twice-daily dose for an additional 16 weeks, followed by a randomized withdrawal phase through week 52.

The treatment effects seen with apremilast at 16 weeks were slightly greater in patients who had not previously received conventional systemic or biologic therapy compared with the total patient population, but even those with prior failed TNF treatment achieved a PASI-75 response.

Onset of action occurred within 2-4 weeks, and clinically relevant improvement continued beyond 16 weeks. The mean percent change from baseline in PASI score was 54.9% at 16 weeks, and 61.9% at 32 weeks, Dr. Reich said. "It will be interesting to see, long-term, what happens beyond the 16-week endpoint," he added.

The 16-week outcomes in the apremilast group represent "significant moderate efficacy," but the safety profile of the drug is the real story of the data, Dr. Reich said.

"Safety is a major issue when it comes to systemic therapies for psoriasis," he emphasized.

A slightly higher rate of withdrawals in the apremilast group may have been due to gastrointestinal effects, a well-known side effect of TNF inhibitors.

Gastrointestinal side effects included diarrhea and nausea, but most cases were transient, and mild to moderate. Most side effects occurred and resolved within the first 15 days of treatment. In fact, more than 96% of patients reported experiencing either no adverse events or only mild to moderate adverse events. Reports of serious adverse events were similar in the treatment and placebo groups (2.1% v. 2.8%, respectively), as were reports of severe adverse events (3.6% vs. 3.2%, respectively).

No problems were noted with respect to lipid levels, liver enzymes, opportunistic infections, or cardiac abnormalities, and no cases of tuberculosis or lymphoma occurred during the study period.

"What stands out so far is an extremely good safety profile," Dr. Reich said.

ESTEEM 1 is the first of two phase III studies of apremilast for chronic plaque psoriasis. Statistical significance for the primary and major secondary endpoints of both ESTEEM 1 and ESTEEM 2 was announced previously by Celgene, the maker of apremilast.

"A NDA (New Drug Application) submission to the U.S. Food and Drug Administration, based on the combined ESTEEM 1 and 2 studies for psoriasis, is expected in the second half of 2013," according to a Celgene press release.

Celgene previously announced it would file a separate NDA for psoriatic arthritis in the first quarter of 2013, based on data from three other trials (PALACE-1, 2, and 3), which were released in 2012. Another phase III trial (POSTURE) began enrolling patients in April 2012 to evaluate apremilast in patients with ankylosing spondylitis.

Participants in the ESTEEM 1 trial will be enrolled in a 5-year extension study so researchers can collect long-term safety and efficacy data. However, based on the current findings, including data from psoriatic arthritis patients, the drug looks quite promising for the treatment of psoriasis, Dr. Reich said.

"I see this as a prime candidate for future management of psoriasis that allows us to treat a range of patients, including more moderate cases earlier on," he said. Such a treatment is needed, particularly in light of new disease concepts that characterize psoriasis as involving systemic inflammation that requires early control, he explained.

The study was sponsored by Celgene.

The oral phosphodiesterase-4 inhibitor apremilast significantly improves moderate to severe psoriasis with minimal side effects, according to data from a phase III, randomized controlled trial of 844 patients.

The drug had an excellent safety profile and resulted in significantly greater improvement in moderate to severe psoriasis than placebo after 16 weeks of treatment in the ESTEEM 1 trial.

The results were reported in a late-breaker session at the annual meeting of the American Academy of Dermatology.

Apremilast is "one of the new small molecules being developed for treatment of psoriasis," said Dr. Kristian Reich of SCIderm Research Institute and Dermatologikum, Hamburg, Germany.

"We believe it has anti-inflammatory properties, because by increasing the intracellular level of cyclic AMP (adenosine monophosphate), it actually activates protein kinase A to modulate the balance between proinflammatory and anti-inflammatory mediators released by a cell in a way that pro-inflammatory mediators are down-regulated and anti-inflammatory mediators are upregulated," he said.

Of 562 patients randomized to receive 30 mg of apremilast twice daily for 16 weeks, 33.1% achieved 75% improvement on the Psoriasis Area Severity Index (PASI-75) scale score, compared with only 5.3% of 282 patients who received placebo. Patients in the treatment group also showed significant improvement compared with the placebo group for secondary endpoints including physician global assessment (PGA) score, change in body surface area affected, and pruritus.

Improvements also were noted in difficult to treat areas such as the scalp and nails. For example, about 50% of affected patients achieved a 50% reduction in nail psoriasis severity, Dr. Reich said.

The study participants were adults with moderate to severe chronic plaque psoriasis, surface area involvement greater than 10%, and a PGA score of 3 or higher. All were candidates for phototherapy or systemic therapy, half had been treated previously with other systemic therapies, including biologics, and nearly 1 in 5 patients had been treated with tumor necrosis factor (TNF) blockers.

Patients initially receiving placebo switched over to active treatment after the first 16 weeks, and treatment in all patients continued at the 30-mg twice-daily dose for an additional 16 weeks, followed by a randomized withdrawal phase through week 52.

The treatment effects seen with apremilast at 16 weeks were slightly greater in patients who had not previously received conventional systemic or biologic therapy compared with the total patient population, but even those with prior failed TNF treatment achieved a PASI-75 response.

Onset of action occurred within 2-4 weeks, and clinically relevant improvement continued beyond 16 weeks. The mean percent change from baseline in PASI score was 54.9% at 16 weeks, and 61.9% at 32 weeks, Dr. Reich said. "It will be interesting to see, long-term, what happens beyond the 16-week endpoint," he added.

The 16-week outcomes in the apremilast group represent "significant moderate efficacy," but the safety profile of the drug is the real story of the data, Dr. Reich said.

"Safety is a major issue when it comes to systemic therapies for psoriasis," he emphasized.

A slightly higher rate of withdrawals in the apremilast group may have been due to gastrointestinal effects, a well-known side effect of TNF inhibitors.

Gastrointestinal side effects included diarrhea and nausea, but most cases were transient, and mild to moderate. Most side effects occurred and resolved within the first 15 days of treatment. In fact, more than 96% of patients reported experiencing either no adverse events or only mild to moderate adverse events. Reports of serious adverse events were similar in the treatment and placebo groups (2.1% v. 2.8%, respectively), as were reports of severe adverse events (3.6% vs. 3.2%, respectively).

No problems were noted with respect to lipid levels, liver enzymes, opportunistic infections, or cardiac abnormalities, and no cases of tuberculosis or lymphoma occurred during the study period.

"What stands out so far is an extremely good safety profile," Dr. Reich said.

ESTEEM 1 is the first of two phase III studies of apremilast for chronic plaque psoriasis. Statistical significance for the primary and major secondary endpoints of both ESTEEM 1 and ESTEEM 2 was announced previously by Celgene, the maker of apremilast.

"A NDA (New Drug Application) submission to the U.S. Food and Drug Administration, based on the combined ESTEEM 1 and 2 studies for psoriasis, is expected in the second half of 2013," according to a Celgene press release.

Celgene previously announced it would file a separate NDA for psoriatic arthritis in the first quarter of 2013, based on data from three other trials (PALACE-1, 2, and 3), which were released in 2012. Another phase III trial (POSTURE) began enrolling patients in April 2012 to evaluate apremilast in patients with ankylosing spondylitis.

Participants in the ESTEEM 1 trial will be enrolled in a 5-year extension study so researchers can collect long-term safety and efficacy data. However, based on the current findings, including data from psoriatic arthritis patients, the drug looks quite promising for the treatment of psoriasis, Dr. Reich said.

"I see this as a prime candidate for future management of psoriasis that allows us to treat a range of patients, including more moderate cases earlier on," he said. Such a treatment is needed, particularly in light of new disease concepts that characterize psoriasis as involving systemic inflammation that requires early control, he explained.

The study was sponsored by Celgene.

The oral phosphodiesterase-4 inhibitor apremilast significantly improves moderate to severe psoriasis with minimal side effects, according to data from a phase III, randomized controlled trial of 844 patients.

The drug had an excellent safety profile and resulted in significantly greater improvement in moderate to severe psoriasis than placebo after 16 weeks of treatment in the ESTEEM 1 trial.

The results were reported in a late-breaker session at the annual meeting of the American Academy of Dermatology.

Apremilast is "one of the new small molecules being developed for treatment of psoriasis," said Dr. Kristian Reich of SCIderm Research Institute and Dermatologikum, Hamburg, Germany.

"We believe it has anti-inflammatory properties, because by increasing the intracellular level of cyclic AMP (adenosine monophosphate), it actually activates protein kinase A to modulate the balance between proinflammatory and anti-inflammatory mediators released by a cell in a way that pro-inflammatory mediators are down-regulated and anti-inflammatory mediators are upregulated," he said.

Of 562 patients randomized to receive 30 mg of apremilast twice daily for 16 weeks, 33.1% achieved 75% improvement on the Psoriasis Area Severity Index (PASI-75) scale score, compared with only 5.3% of 282 patients who received placebo. Patients in the treatment group also showed significant improvement compared with the placebo group for secondary endpoints including physician global assessment (PGA) score, change in body surface area affected, and pruritus.

Improvements also were noted in difficult to treat areas such as the scalp and nails. For example, about 50% of affected patients achieved a 50% reduction in nail psoriasis severity, Dr. Reich said.

The study participants were adults with moderate to severe chronic plaque psoriasis, surface area involvement greater than 10%, and a PGA score of 3 or higher. All were candidates for phototherapy or systemic therapy, half had been treated previously with other systemic therapies, including biologics, and nearly 1 in 5 patients had been treated with tumor necrosis factor (TNF) blockers.

Patients initially receiving placebo switched over to active treatment after the first 16 weeks, and treatment in all patients continued at the 30-mg twice-daily dose for an additional 16 weeks, followed by a randomized withdrawal phase through week 52.

The treatment effects seen with apremilast at 16 weeks were slightly greater in patients who had not previously received conventional systemic or biologic therapy compared with the total patient population, but even those with prior failed TNF treatment achieved a PASI-75 response.

Onset of action occurred within 2-4 weeks, and clinically relevant improvement continued beyond 16 weeks. The mean percent change from baseline in PASI score was 54.9% at 16 weeks, and 61.9% at 32 weeks, Dr. Reich said. "It will be interesting to see, long-term, what happens beyond the 16-week endpoint," he added.

The 16-week outcomes in the apremilast group represent "significant moderate efficacy," but the safety profile of the drug is the real story of the data, Dr. Reich said.

"Safety is a major issue when it comes to systemic therapies for psoriasis," he emphasized.

A slightly higher rate of withdrawals in the apremilast group may have been due to gastrointestinal effects, a well-known side effect of TNF inhibitors.

Gastrointestinal side effects included diarrhea and nausea, but most cases were transient, and mild to moderate. Most side effects occurred and resolved within the first 15 days of treatment. In fact, more than 96% of patients reported experiencing either no adverse events or only mild to moderate adverse events. Reports of serious adverse events were similar in the treatment and placebo groups (2.1% v. 2.8%, respectively), as were reports of severe adverse events (3.6% vs. 3.2%, respectively).

No problems were noted with respect to lipid levels, liver enzymes, opportunistic infections, or cardiac abnormalities, and no cases of tuberculosis or lymphoma occurred during the study period.

"What stands out so far is an extremely good safety profile," Dr. Reich said.

ESTEEM 1 is the first of two phase III studies of apremilast for chronic plaque psoriasis. Statistical significance for the primary and major secondary endpoints of both ESTEEM 1 and ESTEEM 2 was announced previously by Celgene, the maker of apremilast.

"A NDA (New Drug Application) submission to the U.S. Food and Drug Administration, based on the combined ESTEEM 1 and 2 studies for psoriasis, is expected in the second half of 2013," according to a Celgene press release.

Celgene previously announced it would file a separate NDA for psoriatic arthritis in the first quarter of 2013, based on data from three other trials (PALACE-1, 2, and 3), which were released in 2012. Another phase III trial (POSTURE) began enrolling patients in April 2012 to evaluate apremilast in patients with ankylosing spondylitis.

Participants in the ESTEEM 1 trial will be enrolled in a 5-year extension study so researchers can collect long-term safety and efficacy data. However, based on the current findings, including data from psoriatic arthritis patients, the drug looks quite promising for the treatment of psoriasis, Dr. Reich said.

"I see this as a prime candidate for future management of psoriasis that allows us to treat a range of patients, including more moderate cases earlier on," he said. Such a treatment is needed, particularly in light of new disease concepts that characterize psoriasis as involving systemic inflammation that requires early control, he explained.

The study was sponsored by Celgene.

Patients who initiated anti-TNF therapy for inflammatory diseases had no higher risk of developing herpes zoster than did those who took other disease-modifying antirheumatic drugs.

However, a large database review did find a doubling of risk among those taking at least 10 mg/day of corticosteroids, according to Dr. Kevin Winthrop and colleagues. The report is in the March 6 issue of the JAMA.

These findings shed important light on the current mixed-results in literature on the topic, wrote Dr. Winthrop of Oregon Health and Science University, Portland, and his coauthors. The study is more than twice as large as any other on the subject and looked at a large number of patients with elevated herpes zoster risk (JAMA 2013;309:887-95).

It comprised more than 61,000 patients: 33,324 with newly initiated anti-TNF alpha treatment for rheumatoid arthritis and 25,742 who took other nonbiologic disease modifying anti-rheumatic medications. It was a subanalysis of the ongoing Safety Assessment of Biologic Therapy, a U.S. multi-institutional project evaluating the safety of biologic therapies.

Patients were drawn from five large databases spanning 1998-2008: the National Medicaid and Medicare database; Tennessee Medicaid; New Jersey’s Pharmaceutical Assistance to the Aged and Disabled, Pennsylvania’s Pharmaceutical Assistance for the Elderly; and Kaiser Permanente of Northern California. Database selection was important in this study, the investigators said, "Because it contained a large number of Medicare and Medicaid recipients who might have had higher baseline herpes zoster risk due to comorbidities and other unknown factors."

The regression analysis was based on a propensity matching score that took into account a number of baseline factors, including demographics, markers of comorbidity and disease severity, and other potential risk factors for herpes including cancer or diabetes.

Patients were grouped according to disease: rheumatoid arthritis (36,212), inflammatory bowel disease. (10,717) and psoriasis, psoriatic arthritis, or ankylosing spondylitis (12,137). Across all of the groups, there were 470 cases of herpes zoster; 310 among those taking anti-TNF drugs (crude incidence rate of 10/1,000) and 160 among those taking other DMARDs (crude incidence rate of 11/1,000).

After the investigators adjusted for baseline corticosteroid use and the propensity matching score, they found no significant between-group differences in the risk of herpes zoster (hazard ratio of 11 for anti-TNFs; HR, 10 for DMARDs).

Daily use of at least 10 mg corticosteroids was associated with a significantly increased risk of the disease in all of the patient groups (HR, 2).

Most herpes cases (356) occurred in the rheumatoid arthritis group; the investigators analyzed this group separately. These patients were a median of 60 years old; 266 were taking the anti-TNF drugs and 90 other DMARDs. The median follow-up was almost 1 year (294 days). Herpes caused hospitalization in 16 (6%) of those using the medications and in five of the DMARD group (5.5%) – not a significant difference.

Limiting follow-up to 3-6 months did not change the results. When the researchers extended follow-up in the Medicaid/Medicare groups until the end of 2008, they found similar herpes crude incidence rates in the anti-TNF and DMARD groups, and similar disease risk (HR, 12.6 and HR, 12.4, respectively).

When the authors looked at risk in anti-TNF subgroups, they found the highest crude incidence rate among infliximab users (14/1,000) and the lowest for adalimumab users (10/1,000). However, this significant between-group difference disappeared when examined with the propensity matching score. "Furthermore," they noted, "A higher proportion of infliximab users used concomitant methotrexate at baseline and after [the] index date compared with those using etanercept or adalimumab."

The high herpes rate among patients with rheumatoid arthritis supports widespread use of the live attenuated herpes zoster vaccine in those aged 50 years and older, the authors contended.

"Currently, vaccination during active use of anti-TNF therapy is contraindicated due to theoretical safety concerns of using a live vaccine during such therapy; however, it is unclear if such concerns are valid. Our data suggest that patients who develop herpes zoster while taking anti-TNF therapy are no more likely to be hospitalized than persons with herpes zoster using nonbiologic DMARDs ... Given these findings, the potential importance of this vaccine within the rheumatoid arthritis setting and the difficulty in vaccinating patients given the widespread use of anti-TNF therapy, we believe that a trial to evaluate the safety of this live virus vaccine among current anti-TNF users is warranted."

Dr. Winthrop has consulted for Genentec, Abbott Pfizer, UCB Pharma, and Amgen, and received research grants from Pfizer. Other authors reported relationships with numerous pharmaceutical companies.

michele.sullivan@elsevier.com

Patients who initiated anti-TNF therapy for inflammatory diseases had no higher risk of developing herpes zoster than did those who took other disease-modifying antirheumatic drugs.

However, a large database review did find a doubling of risk among those taking at least 10 mg/day of corticosteroids, according to Dr. Kevin Winthrop and colleagues. The report is in the March 6 issue of the JAMA.

These findings shed important light on the current mixed-results in literature on the topic, wrote Dr. Winthrop of Oregon Health and Science University, Portland, and his coauthors. The study is more than twice as large as any other on the subject and looked at a large number of patients with elevated herpes zoster risk (JAMA 2013;309:887-95).

It comprised more than 61,000 patients: 33,324 with newly initiated anti-TNF alpha treatment for rheumatoid arthritis and 25,742 who took other nonbiologic disease modifying anti-rheumatic medications. It was a subanalysis of the ongoing Safety Assessment of Biologic Therapy, a U.S. multi-institutional project evaluating the safety of biologic therapies.

Patients were drawn from five large databases spanning 1998-2008: the National Medicaid and Medicare database; Tennessee Medicaid; New Jersey’s Pharmaceutical Assistance to the Aged and Disabled, Pennsylvania’s Pharmaceutical Assistance for the Elderly; and Kaiser Permanente of Northern California. Database selection was important in this study, the investigators said, "Because it contained a large number of Medicare and Medicaid recipients who might have had higher baseline herpes zoster risk due to comorbidities and other unknown factors."

The regression analysis was based on a propensity matching score that took into account a number of baseline factors, including demographics, markers of comorbidity and disease severity, and other potential risk factors for herpes including cancer or diabetes.

Patients were grouped according to disease: rheumatoid arthritis (36,212), inflammatory bowel disease. (10,717) and psoriasis, psoriatic arthritis, or ankylosing spondylitis (12,137). Across all of the groups, there were 470 cases of herpes zoster; 310 among those taking anti-TNF drugs (crude incidence rate of 10/1,000) and 160 among those taking other DMARDs (crude incidence rate of 11/1,000).

After the investigators adjusted for baseline corticosteroid use and the propensity matching score, they found no significant between-group differences in the risk of herpes zoster (hazard ratio of 11 for anti-TNFs; HR, 10 for DMARDs).

Daily use of at least 10 mg corticosteroids was associated with a significantly increased risk of the disease in all of the patient groups (HR, 2).

Most herpes cases (356) occurred in the rheumatoid arthritis group; the investigators analyzed this group separately. These patients were a median of 60 years old; 266 were taking the anti-TNF drugs and 90 other DMARDs. The median follow-up was almost 1 year (294 days). Herpes caused hospitalization in 16 (6%) of those using the medications and in five of the DMARD group (5.5%) – not a significant difference.

Limiting follow-up to 3-6 months did not change the results. When the researchers extended follow-up in the Medicaid/Medicare groups until the end of 2008, they found similar herpes crude incidence rates in the anti-TNF and DMARD groups, and similar disease risk (HR, 12.6 and HR, 12.4, respectively).

When the authors looked at risk in anti-TNF subgroups, they found the highest crude incidence rate among infliximab users (14/1,000) and the lowest for adalimumab users (10/1,000). However, this significant between-group difference disappeared when examined with the propensity matching score. "Furthermore," they noted, "A higher proportion of infliximab users used concomitant methotrexate at baseline and after [the] index date compared with those using etanercept or adalimumab."

The high herpes rate among patients with rheumatoid arthritis supports widespread use of the live attenuated herpes zoster vaccine in those aged 50 years and older, the authors contended.

"Currently, vaccination during active use of anti-TNF therapy is contraindicated due to theoretical safety concerns of using a live vaccine during such therapy; however, it is unclear if such concerns are valid. Our data suggest that patients who develop herpes zoster while taking anti-TNF therapy are no more likely to be hospitalized than persons with herpes zoster using nonbiologic DMARDs ... Given these findings, the potential importance of this vaccine within the rheumatoid arthritis setting and the difficulty in vaccinating patients given the widespread use of anti-TNF therapy, we believe that a trial to evaluate the safety of this live virus vaccine among current anti-TNF users is warranted."

Dr. Winthrop has consulted for Genentec, Abbott Pfizer, UCB Pharma, and Amgen, and received research grants from Pfizer. Other authors reported relationships with numerous pharmaceutical companies.

michele.sullivan@elsevier.com

Patients who initiated anti-TNF therapy for inflammatory diseases had no higher risk of developing herpes zoster than did those who took other disease-modifying antirheumatic drugs.

However, a large database review did find a doubling of risk among those taking at least 10 mg/day of corticosteroids, according to Dr. Kevin Winthrop and colleagues. The report is in the March 6 issue of the JAMA.

These findings shed important light on the current mixed-results in literature on the topic, wrote Dr. Winthrop of Oregon Health and Science University, Portland, and his coauthors. The study is more than twice as large as any other on the subject and looked at a large number of patients with elevated herpes zoster risk (JAMA 2013;309:887-95).

It comprised more than 61,000 patients: 33,324 with newly initiated anti-TNF alpha treatment for rheumatoid arthritis and 25,742 who took other nonbiologic disease modifying anti-rheumatic medications. It was a subanalysis of the ongoing Safety Assessment of Biologic Therapy, a U.S. multi-institutional project evaluating the safety of biologic therapies.

Patients were drawn from five large databases spanning 1998-2008: the National Medicaid and Medicare database; Tennessee Medicaid; New Jersey’s Pharmaceutical Assistance to the Aged and Disabled, Pennsylvania’s Pharmaceutical Assistance for the Elderly; and Kaiser Permanente of Northern California. Database selection was important in this study, the investigators said, "Because it contained a large number of Medicare and Medicaid recipients who might have had higher baseline herpes zoster risk due to comorbidities and other unknown factors."

The regression analysis was based on a propensity matching score that took into account a number of baseline factors, including demographics, markers of comorbidity and disease severity, and other potential risk factors for herpes including cancer or diabetes.

Patients were grouped according to disease: rheumatoid arthritis (36,212), inflammatory bowel disease. (10,717) and psoriasis, psoriatic arthritis, or ankylosing spondylitis (12,137). Across all of the groups, there were 470 cases of herpes zoster; 310 among those taking anti-TNF drugs (crude incidence rate of 10/1,000) and 160 among those taking other DMARDs (crude incidence rate of 11/1,000).

After the investigators adjusted for baseline corticosteroid use and the propensity matching score, they found no significant between-group differences in the risk of herpes zoster (hazard ratio of 11 for anti-TNFs; HR, 10 for DMARDs).

Daily use of at least 10 mg corticosteroids was associated with a significantly increased risk of the disease in all of the patient groups (HR, 2).

Most herpes cases (356) occurred in the rheumatoid arthritis group; the investigators analyzed this group separately. These patients were a median of 60 years old; 266 were taking the anti-TNF drugs and 90 other DMARDs. The median follow-up was almost 1 year (294 days). Herpes caused hospitalization in 16 (6%) of those using the medications and in five of the DMARD group (5.5%) – not a significant difference.

Limiting follow-up to 3-6 months did not change the results. When the researchers extended follow-up in the Medicaid/Medicare groups until the end of 2008, they found similar herpes crude incidence rates in the anti-TNF and DMARD groups, and similar disease risk (HR, 12.6 and HR, 12.4, respectively).

When the authors looked at risk in anti-TNF subgroups, they found the highest crude incidence rate among infliximab users (14/1,000) and the lowest for adalimumab users (10/1,000). However, this significant between-group difference disappeared when examined with the propensity matching score. "Furthermore," they noted, "A higher proportion of infliximab users used concomitant methotrexate at baseline and after [the] index date compared with those using etanercept or adalimumab."

The high herpes rate among patients with rheumatoid arthritis supports widespread use of the live attenuated herpes zoster vaccine in those aged 50 years and older, the authors contended.

"Currently, vaccination during active use of anti-TNF therapy is contraindicated due to theoretical safety concerns of using a live vaccine during such therapy; however, it is unclear if such concerns are valid. Our data suggest that patients who develop herpes zoster while taking anti-TNF therapy are no more likely to be hospitalized than persons with herpes zoster using nonbiologic DMARDs ... Given these findings, the potential importance of this vaccine within the rheumatoid arthritis setting and the difficulty in vaccinating patients given the widespread use of anti-TNF therapy, we believe that a trial to evaluate the safety of this live virus vaccine among current anti-TNF users is warranted."

Dr. Winthrop has consulted for Genentec, Abbott Pfizer, UCB Pharma, and Amgen, and received research grants from Pfizer. Other authors reported relationships with numerous pharmaceutical companies.

michele.sullivan@elsevier.com

The risks of pregnancy loss and of preterm birth were higher in women who had vasculitis before they conceived than in women who were diagnosed as having vasculitis after conception in a retrospective cohort study.

Women who conceived before receiving a diagnosis of vasculitis had a rate of pregnancy loss similar to the general population, whereas women who conceived after they had received a diagnosis of vasculitis had a significantly higher rate of pregnancy loss, reported Dr. Megan E. B. Clowse of the division of rheumatology and immunology at Duke University, Durham, N.C., and her associates in the Vasculitis Clinical Research Consortium.

The investigators examined pregnancy outcomes among women with vasculitis, as well as the outcomes of pregnancies fathered by men with the disease, because so little is known about the subject. Such pregnancies were rare until recent improvements in treatments helped patients survive longer and lead fuller lives.

"Our goal was to identify pregnancies that occurred within a large cohort of women and men with vasculitis and assess whether such pregnancies were at greater risk for adverse outcomes and whether vasculitis activity increased during pregnancy," the researchers wrote.

They invited patients listed in a registry of rare diseases to complete an anonymous questionnaire regarding their reproductive health. A total of 329 women (who had 496 pregnancies) and 107 men (who fathered 156 pregnancies) were included in the analysis (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21983]).

Among the women, 140 had granulomatosis with polyangiitis, 22 had microscopic polyangiitis, 59 had Churg-Strauss syndrome, 18 had polyarteritis nodosa, 43 had Behcet’s disease, and 46 had Takayasu’s arteritis. The mean age at diagnosis was 39.7 years (range, 10-78 years). The mean age at the time of the study was 47 years.

The rate of pregnancy loss was significantly higher among the women who had vasculitis when they conceived (33.8%) than it was among women who conceived before they were diagnosed as having vasculitis (22.4%), giving a relative risk of 1.77 (CI 1.02-3.09; P = .04). This 22.4% rate of pregnancy loss is comparable with that reported in the general population (15%-20%), while the rate found in women who already had vasculitis was significantly higher than that in the general population, Dr. Clowse and her associates said.

Similarly, the rate of preterm birth was significantly higher in pregnancies that occurred after a diagnosis of vasculitis (23.3%) than in pregnancies that occurred before a diagnosis of vasculitis (11.4%), giving a relative risk of 2.35 (CI 1.07-5.16; P =.03).

However, the researchers said, it is important to note that the maternal age at conception was approximately 5 years older for women who became pregnant after they had vasculitis, which could have influenced the increased morbidity in this group.

Most (59%) of the women who had vasculitis when they conceived reported no change in their disease activity during pregnancy, and another 23% reported an improvement in vasculitis activity during pregnancy. Only 18% of women who had vasculitis when they conceived reported increased symptoms during pregnancy. Increased disease activity did not have a statistically significant effect on pregnancy loss or preterm delivery.

Exposure to cyclophosphamide or prednisone did not appear to affect pregnancy outcomes. However, the numbers of pregnancies among women taking these medications was small.

Among the men, 61 had granulomatosis with polyangitis, 8 had microscopic polyangiitis, 24 had Churg-Strauss syndrome, 9 had polyarteritis nodosa, 4 had Behcet’s disease, and 1 had Takayasu’s arteritis. The average age at diagnosis was 54.6 years (range, 23-86 years)

Six men fathered 18 pregnancies after they had been diagnosed as having vasculitis, and 48 men fathered 138 pregnancies before they were diagnosed as having vasculitis. The rate of pregnancy loss was 41.2% for fathers with vasculitis and 23.0% for fathers who did not yet have a diagnosis of vasculitis, a difference that did not reach statistical significance.

One man treated with cyclophosphamide fathered two pregnancies within a few years that resulted in live births without complications. However, two other men who had received cyclophosphamide at least 10 years before fathering a pregnancy reported a total of seven pregnancy losses (including one with anencephaly) and four live births.

This study was limited in that it relied on retrospective self-report for diagnosis and was not powered to ascertain the role of confounding factors such as maternal age at the time of conception, prior pregnancy complications, and tobacco use. It also may have been biased because patients who had pregnancy difficulties may have been more likely than those who did not to complete a long questionnaire on that topic.

In addition, the number of men in the cohort was low, and a high proportion of them reported multiple pregnancy losses. It remains unclear whether this reflects a true increase in pregnancy loss rate for fathers with vasculitis or "simply reflects the greater interest that these particular men might have in responding to such a survey," Dr. Clowse and her colleagues said.

This study was supported by the Vasculitis Foundation and the Vasculitis Clinical Research Consortium, which receives support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Research Resources, and the Office of Rare Diseases Research. No financial conflicts of interest were reported.

rhnews@elsevier.com

The risks of pregnancy loss and of preterm birth were higher in women who had vasculitis before they conceived than in women who were diagnosed as having vasculitis after conception in a retrospective cohort study.

Women who conceived before receiving a diagnosis of vasculitis had a rate of pregnancy loss similar to the general population, whereas women who conceived after they had received a diagnosis of vasculitis had a significantly higher rate of pregnancy loss, reported Dr. Megan E. B. Clowse of the division of rheumatology and immunology at Duke University, Durham, N.C., and her associates in the Vasculitis Clinical Research Consortium.

The investigators examined pregnancy outcomes among women with vasculitis, as well as the outcomes of pregnancies fathered by men with the disease, because so little is known about the subject. Such pregnancies were rare until recent improvements in treatments helped patients survive longer and lead fuller lives.

"Our goal was to identify pregnancies that occurred within a large cohort of women and men with vasculitis and assess whether such pregnancies were at greater risk for adverse outcomes and whether vasculitis activity increased during pregnancy," the researchers wrote.

They invited patients listed in a registry of rare diseases to complete an anonymous questionnaire regarding their reproductive health. A total of 329 women (who had 496 pregnancies) and 107 men (who fathered 156 pregnancies) were included in the analysis (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21983]).

Among the women, 140 had granulomatosis with polyangiitis, 22 had microscopic polyangiitis, 59 had Churg-Strauss syndrome, 18 had polyarteritis nodosa, 43 had Behcet’s disease, and 46 had Takayasu’s arteritis. The mean age at diagnosis was 39.7 years (range, 10-78 years). The mean age at the time of the study was 47 years.

The rate of pregnancy loss was significantly higher among the women who had vasculitis when they conceived (33.8%) than it was among women who conceived before they were diagnosed as having vasculitis (22.4%), giving a relative risk of 1.77 (CI 1.02-3.09; P = .04). This 22.4% rate of pregnancy loss is comparable with that reported in the general population (15%-20%), while the rate found in women who already had vasculitis was significantly higher than that in the general population, Dr. Clowse and her associates said.

Similarly, the rate of preterm birth was significantly higher in pregnancies that occurred after a diagnosis of vasculitis (23.3%) than in pregnancies that occurred before a diagnosis of vasculitis (11.4%), giving a relative risk of 2.35 (CI 1.07-5.16; P =.03).

However, the researchers said, it is important to note that the maternal age at conception was approximately 5 years older for women who became pregnant after they had vasculitis, which could have influenced the increased morbidity in this group.

Most (59%) of the women who had vasculitis when they conceived reported no change in their disease activity during pregnancy, and another 23% reported an improvement in vasculitis activity during pregnancy. Only 18% of women who had vasculitis when they conceived reported increased symptoms during pregnancy. Increased disease activity did not have a statistically significant effect on pregnancy loss or preterm delivery.

Exposure to cyclophosphamide or prednisone did not appear to affect pregnancy outcomes. However, the numbers of pregnancies among women taking these medications was small.

Among the men, 61 had granulomatosis with polyangitis, 8 had microscopic polyangiitis, 24 had Churg-Strauss syndrome, 9 had polyarteritis nodosa, 4 had Behcet’s disease, and 1 had Takayasu’s arteritis. The average age at diagnosis was 54.6 years (range, 23-86 years)

Six men fathered 18 pregnancies after they had been diagnosed as having vasculitis, and 48 men fathered 138 pregnancies before they were diagnosed as having vasculitis. The rate of pregnancy loss was 41.2% for fathers with vasculitis and 23.0% for fathers who did not yet have a diagnosis of vasculitis, a difference that did not reach statistical significance.

One man treated with cyclophosphamide fathered two pregnancies within a few years that resulted in live births without complications. However, two other men who had received cyclophosphamide at least 10 years before fathering a pregnancy reported a total of seven pregnancy losses (including one with anencephaly) and four live births.

This study was limited in that it relied on retrospective self-report for diagnosis and was not powered to ascertain the role of confounding factors such as maternal age at the time of conception, prior pregnancy complications, and tobacco use. It also may have been biased because patients who had pregnancy difficulties may have been more likely than those who did not to complete a long questionnaire on that topic.

In addition, the number of men in the cohort was low, and a high proportion of them reported multiple pregnancy losses. It remains unclear whether this reflects a true increase in pregnancy loss rate for fathers with vasculitis or "simply reflects the greater interest that these particular men might have in responding to such a survey," Dr. Clowse and her colleagues said.

This study was supported by the Vasculitis Foundation and the Vasculitis Clinical Research Consortium, which receives support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Research Resources, and the Office of Rare Diseases Research. No financial conflicts of interest were reported.

rhnews@elsevier.com

The risks of pregnancy loss and of preterm birth were higher in women who had vasculitis before they conceived than in women who were diagnosed as having vasculitis after conception in a retrospective cohort study.

Women who conceived before receiving a diagnosis of vasculitis had a rate of pregnancy loss similar to the general population, whereas women who conceived after they had received a diagnosis of vasculitis had a significantly higher rate of pregnancy loss, reported Dr. Megan E. B. Clowse of the division of rheumatology and immunology at Duke University, Durham, N.C., and her associates in the Vasculitis Clinical Research Consortium.

The investigators examined pregnancy outcomes among women with vasculitis, as well as the outcomes of pregnancies fathered by men with the disease, because so little is known about the subject. Such pregnancies were rare until recent improvements in treatments helped patients survive longer and lead fuller lives.

"Our goal was to identify pregnancies that occurred within a large cohort of women and men with vasculitis and assess whether such pregnancies were at greater risk for adverse outcomes and whether vasculitis activity increased during pregnancy," the researchers wrote.

They invited patients listed in a registry of rare diseases to complete an anonymous questionnaire regarding their reproductive health. A total of 329 women (who had 496 pregnancies) and 107 men (who fathered 156 pregnancies) were included in the analysis (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21983]).

Among the women, 140 had granulomatosis with polyangiitis, 22 had microscopic polyangiitis, 59 had Churg-Strauss syndrome, 18 had polyarteritis nodosa, 43 had Behcet’s disease, and 46 had Takayasu’s arteritis. The mean age at diagnosis was 39.7 years (range, 10-78 years). The mean age at the time of the study was 47 years.

The rate of pregnancy loss was significantly higher among the women who had vasculitis when they conceived (33.8%) than it was among women who conceived before they were diagnosed as having vasculitis (22.4%), giving a relative risk of 1.77 (CI 1.02-3.09; P = .04). This 22.4% rate of pregnancy loss is comparable with that reported in the general population (15%-20%), while the rate found in women who already had vasculitis was significantly higher than that in the general population, Dr. Clowse and her associates said.

Similarly, the rate of preterm birth was significantly higher in pregnancies that occurred after a diagnosis of vasculitis (23.3%) than in pregnancies that occurred before a diagnosis of vasculitis (11.4%), giving a relative risk of 2.35 (CI 1.07-5.16; P =.03).

However, the researchers said, it is important to note that the maternal age at conception was approximately 5 years older for women who became pregnant after they had vasculitis, which could have influenced the increased morbidity in this group.

Most (59%) of the women who had vasculitis when they conceived reported no change in their disease activity during pregnancy, and another 23% reported an improvement in vasculitis activity during pregnancy. Only 18% of women who had vasculitis when they conceived reported increased symptoms during pregnancy. Increased disease activity did not have a statistically significant effect on pregnancy loss or preterm delivery.

Exposure to cyclophosphamide or prednisone did not appear to affect pregnancy outcomes. However, the numbers of pregnancies among women taking these medications was small.

Among the men, 61 had granulomatosis with polyangitis, 8 had microscopic polyangiitis, 24 had Churg-Strauss syndrome, 9 had polyarteritis nodosa, 4 had Behcet’s disease, and 1 had Takayasu’s arteritis. The average age at diagnosis was 54.6 years (range, 23-86 years)

Six men fathered 18 pregnancies after they had been diagnosed as having vasculitis, and 48 men fathered 138 pregnancies before they were diagnosed as having vasculitis. The rate of pregnancy loss was 41.2% for fathers with vasculitis and 23.0% for fathers who did not yet have a diagnosis of vasculitis, a difference that did not reach statistical significance.

One man treated with cyclophosphamide fathered two pregnancies within a few years that resulted in live births without complications. However, two other men who had received cyclophosphamide at least 10 years before fathering a pregnancy reported a total of seven pregnancy losses (including one with anencephaly) and four live births.

This study was limited in that it relied on retrospective self-report for diagnosis and was not powered to ascertain the role of confounding factors such as maternal age at the time of conception, prior pregnancy complications, and tobacco use. It also may have been biased because patients who had pregnancy difficulties may have been more likely than those who did not to complete a long questionnaire on that topic.

In addition, the number of men in the cohort was low, and a high proportion of them reported multiple pregnancy losses. It remains unclear whether this reflects a true increase in pregnancy loss rate for fathers with vasculitis or "simply reflects the greater interest that these particular men might have in responding to such a survey," Dr. Clowse and her colleagues said.

This study was supported by the Vasculitis Foundation and the Vasculitis Clinical Research Consortium, which receives support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Research Resources, and the Office of Rare Diseases Research. No financial conflicts of interest were reported.

rhnews@elsevier.com

MIAMI BEACH -- Patients with chronic plaque psoriasis showed significant improvement after 16 weeks of treatment with the humanized monoclonal antibody MK-3222, based on early data from an ongoing randomized, controlled, dose-ranging study of 355 adults. The findings were presented in a late-breaker session at the annual meeting of the American Academy of Dermatology.

The patients were randomized to receive MK-3222 doses of 5 mg, 25 mg, 100 mg, 200 mg, or a placebo, injected subcutaneously at weeks 0 and 4, then every 12 weeks thereafter until week 52. The mean baseline Psoriasis Area and Severity (PASI) index score of the patients was 12, and all patients had greater than 10% body surface area involvement and at least a moderate Physician Global Assessment (PGA) scale score.

Responses at 16 weeks were dose-dependent; PASI 75 responses occurred in 33%, 64%, 66%, 74%, and 4.4% in the 5-mg, 25-mg, 100-mg, 200-mg and placebo groups respectively, said Dr. Kim Papp of Probity Medical Research, Waterloo, Ontario, Canada. PGA responses were 33%, 58%, 62%, 74%, and 2%, respectively. The differences were statistically significant for each dose compared with placebo for both PASI 75 responses and PGA responses.

MK-3222 is a high-affinity humanized anti-IL-23p19 monoclonal antibody that doesn't bind human IL-12 (subunit p40), Dr. Papp said. "We know from results of previous studies that blockade of IL-23 is, in fact, an effective route to treating psoriasis," he said.

Dr. Papp noted that safety signals have been linked with IL-12 blockade, but not with IL-23 blockade, which provides support for further research of this agent.

In this study, MK-3222 was generally safe and well-tolerated, with a low drop-out rate. Adverse events were similar across all treatment groups. Four serious adverse events were reported within the first 16 weeks of treatment, including one case of bacterial arthritis possibly related to treatment, and one death that was unrelated to treatment.

"Those of us who see these patients know that there is an exquisite need for additional therapies," Dr. Papp said. The findings are encouraging, and MK-3222, which is currently in phase III development, "certainly deserves further exploration as a therapy for psoriasis," he said.

MIAMI BEACH -- Patients with chronic plaque psoriasis showed significant improvement after 16 weeks of treatment with the humanized monoclonal antibody MK-3222, based on early data from an ongoing randomized, controlled, dose-ranging study of 355 adults. The findings were presented in a late-breaker session at the annual meeting of the American Academy of Dermatology.

The patients were randomized to receive MK-3222 doses of 5 mg, 25 mg, 100 mg, 200 mg, or a placebo, injected subcutaneously at weeks 0 and 4, then every 12 weeks thereafter until week 52. The mean baseline Psoriasis Area and Severity (PASI) index score of the patients was 12, and all patients had greater than 10% body surface area involvement and at least a moderate Physician Global Assessment (PGA) scale score.

Responses at 16 weeks were dose-dependent; PASI 75 responses occurred in 33%, 64%, 66%, 74%, and 4.4% in the 5-mg, 25-mg, 100-mg, 200-mg and placebo groups respectively, said Dr. Kim Papp of Probity Medical Research, Waterloo, Ontario, Canada. PGA responses were 33%, 58%, 62%, 74%, and 2%, respectively. The differences were statistically significant for each dose compared with placebo for both PASI 75 responses and PGA responses.

MK-3222 is a high-affinity humanized anti-IL-23p19 monoclonal antibody that doesn't bind human IL-12 (subunit p40), Dr. Papp said. "We know from results of previous studies that blockade of IL-23 is, in fact, an effective route to treating psoriasis," he said.

Dr. Papp noted that safety signals have been linked with IL-12 blockade, but not with IL-23 blockade, which provides support for further research of this agent.

In this study, MK-3222 was generally safe and well-tolerated, with a low drop-out rate. Adverse events were similar across all treatment groups. Four serious adverse events were reported within the first 16 weeks of treatment, including one case of bacterial arthritis possibly related to treatment, and one death that was unrelated to treatment.

"Those of us who see these patients know that there is an exquisite need for additional therapies," Dr. Papp said. The findings are encouraging, and MK-3222, which is currently in phase III development, "certainly deserves further exploration as a therapy for psoriasis," he said.

MIAMI BEACH -- Patients with chronic plaque psoriasis showed significant improvement after 16 weeks of treatment with the humanized monoclonal antibody MK-3222, based on early data from an ongoing randomized, controlled, dose-ranging study of 355 adults. The findings were presented in a late-breaker session at the annual meeting of the American Academy of Dermatology.

The patients were randomized to receive MK-3222 doses of 5 mg, 25 mg, 100 mg, 200 mg, or a placebo, injected subcutaneously at weeks 0 and 4, then every 12 weeks thereafter until week 52. The mean baseline Psoriasis Area and Severity (PASI) index score of the patients was 12, and all patients had greater than 10% body surface area involvement and at least a moderate Physician Global Assessment (PGA) scale score.

Responses at 16 weeks were dose-dependent; PASI 75 responses occurred in 33%, 64%, 66%, 74%, and 4.4% in the 5-mg, 25-mg, 100-mg, 200-mg and placebo groups respectively, said Dr. Kim Papp of Probity Medical Research, Waterloo, Ontario, Canada. PGA responses were 33%, 58%, 62%, 74%, and 2%, respectively. The differences were statistically significant for each dose compared with placebo for both PASI 75 responses and PGA responses.

MK-3222 is a high-affinity humanized anti-IL-23p19 monoclonal antibody that doesn't bind human IL-12 (subunit p40), Dr. Papp said. "We know from results of previous studies that blockade of IL-23 is, in fact, an effective route to treating psoriasis," he said.

Dr. Papp noted that safety signals have been linked with IL-12 blockade, but not with IL-23 blockade, which provides support for further research of this agent.

In this study, MK-3222 was generally safe and well-tolerated, with a low drop-out rate. Adverse events were similar across all treatment groups. Four serious adverse events were reported within the first 16 weeks of treatment, including one case of bacterial arthritis possibly related to treatment, and one death that was unrelated to treatment.

"Those of us who see these patients know that there is an exquisite need for additional therapies," Dr. Papp said. The findings are encouraging, and MK-3222, which is currently in phase III development, "certainly deserves further exploration as a therapy for psoriasis," he said.

Phosphodiesterase-5 inhibitors appear to reduce the daily frequency of ischemic attacks in secondary Raynaud’s phenomenon to a significant degree, amounting to a decrease of nearly 0.5 attacks per day, according to a meta-analysis of trials.

The study also revealed significant but moderate effects of the phosphodiesterase-5 (PDE-5) inhibitors on the Raynaud’s Condition Score (RCS) and attack duration, but the class effect of PDE-5 inhibitors in secondary Raynaud’s phenomenon (RP) needs to be clarified through additional studies because differences between the trials made it difficult to come to clear conclusions, according to Matthieu Roustit, Pharm.D., Ph.D., of Joseph Fourier University, Grenoble, France, and his colleagues.

The investigators searched the Cochrane, Medline, Embase, and Web of Sciences databases for double-blind, randomized, controlled trials of PDE-5 inhibitors in secondary RP (Ann. Rheum. Dis. 2013 Feb. 20 [doi:10.1136/annrheumdis-2012-202836]).

They also looked for these trials in abstracts from meetings of the European League Against Rheumatism and the American College of Rheumatology, as well as in listings at the clinicaltrials.gov site.

In the final analysis, the investigators included six double-blind, randomized, placebo-controlled trials involving 244 patients – one with sildenafil (Viagra), one with modified-release sildenafil, three with tadalafil (Cialis), and one with vardenafil (Levitra). They excluded patients with primary Raynaud’s.

Most patients (91.8%) had RP secondary to systemic sclerosis; the remainder had mixed or undifferentiated connective tissue disease.

Only two trials allowed the use of other vasodilators, both of which tested tadalafil as an add-on to calcium channel blockers, although another study that tested tadalafil monotherapy for RP allowed seven patients to take calcium channel blockers and eight patients to take angiotensin-converting enzyme inhibitors for other indications.

Dr. Roustit and his associates found that the use of PDE-5 inhibitors significantly reduced the mean RCS by -0.46 (95% confidence interval -0.74 to -0.17; P = .002).

The drugs also reduced the frequency of attacks by -0.49 per day (95% CI, -0.71 to -0.28; P less than .0001), although this improvement fell beneath the minimally significant difference on the RCS, which is estimated to be 1.4-1.5 attacks per day.

PDE-5 inhibitors lessened the daily duration of attacks by 14.62 minutes (95% CI, -20.25 to -9.00; P less than .0001).

According to the authors, the decrease in number of attacks per day echoes the finding of another study assessing the efficacy of calcium channel blockers in secondary RP, which calculated a reduction of roughly 0.6 attacks per day (Arthritis Rheum. 2001;44:1841-7).

They added, however, that some data have also found PDE-5 inhibitors to be associated with reduction of digital ischemic ulcers in secondary Raynaud’s, although "data are scarce, and larger RCTs are ongoing to address this issue."

Dr. Roustit and another investigator disclosed receiving research grants from Pfizer (which markets sildenafil), Actelion, GlaxoSmithKline (which markets vardenafil) and Bioprojet for other studies. A third investigator disclosed receiving research grants and honoraria from Pfizer and Actelion for other studies.

rhnews@elsevier.com

Phosphodiesterase-5 inhibitors appear to reduce the daily frequency of ischemic attacks in secondary Raynaud’s phenomenon to a significant degree, amounting to a decrease of nearly 0.5 attacks per day, according to a meta-analysis of trials.

The study also revealed significant but moderate effects of the phosphodiesterase-5 (PDE-5) inhibitors on the Raynaud’s Condition Score (RCS) and attack duration, but the class effect of PDE-5 inhibitors in secondary Raynaud’s phenomenon (RP) needs to be clarified through additional studies because differences between the trials made it difficult to come to clear conclusions, according to Matthieu Roustit, Pharm.D., Ph.D., of Joseph Fourier University, Grenoble, France, and his colleagues.

The investigators searched the Cochrane, Medline, Embase, and Web of Sciences databases for double-blind, randomized, controlled trials of PDE-5 inhibitors in secondary RP (Ann. Rheum. Dis. 2013 Feb. 20 [doi:10.1136/annrheumdis-2012-202836]).

They also looked for these trials in abstracts from meetings of the European League Against Rheumatism and the American College of Rheumatology, as well as in listings at the clinicaltrials.gov site.

In the final analysis, the investigators included six double-blind, randomized, placebo-controlled trials involving 244 patients – one with sildenafil (Viagra), one with modified-release sildenafil, three with tadalafil (Cialis), and one with vardenafil (Levitra). They excluded patients with primary Raynaud’s.

Most patients (91.8%) had RP secondary to systemic sclerosis; the remainder had mixed or undifferentiated connective tissue disease.

Only two trials allowed the use of other vasodilators, both of which tested tadalafil as an add-on to calcium channel blockers, although another study that tested tadalafil monotherapy for RP allowed seven patients to take calcium channel blockers and eight patients to take angiotensin-converting enzyme inhibitors for other indications.

Dr. Roustit and his associates found that the use of PDE-5 inhibitors significantly reduced the mean RCS by -0.46 (95% confidence interval -0.74 to -0.17; P = .002).

The drugs also reduced the frequency of attacks by -0.49 per day (95% CI, -0.71 to -0.28; P less than .0001), although this improvement fell beneath the minimally significant difference on the RCS, which is estimated to be 1.4-1.5 attacks per day.

PDE-5 inhibitors lessened the daily duration of attacks by 14.62 minutes (95% CI, -20.25 to -9.00; P less than .0001).

According to the authors, the decrease in number of attacks per day echoes the finding of another study assessing the efficacy of calcium channel blockers in secondary RP, which calculated a reduction of roughly 0.6 attacks per day (Arthritis Rheum. 2001;44:1841-7).

They added, however, that some data have also found PDE-5 inhibitors to be associated with reduction of digital ischemic ulcers in secondary Raynaud’s, although "data are scarce, and larger RCTs are ongoing to address this issue."

Dr. Roustit and another investigator disclosed receiving research grants from Pfizer (which markets sildenafil), Actelion, GlaxoSmithKline (which markets vardenafil) and Bioprojet for other studies. A third investigator disclosed receiving research grants and honoraria from Pfizer and Actelion for other studies.

rhnews@elsevier.com

Phosphodiesterase-5 inhibitors appear to reduce the daily frequency of ischemic attacks in secondary Raynaud’s phenomenon to a significant degree, amounting to a decrease of nearly 0.5 attacks per day, according to a meta-analysis of trials.

The study also revealed significant but moderate effects of the phosphodiesterase-5 (PDE-5) inhibitors on the Raynaud’s Condition Score (RCS) and attack duration, but the class effect of PDE-5 inhibitors in secondary Raynaud’s phenomenon (RP) needs to be clarified through additional studies because differences between the trials made it difficult to come to clear conclusions, according to Matthieu Roustit, Pharm.D., Ph.D., of Joseph Fourier University, Grenoble, France, and his colleagues.

The investigators searched the Cochrane, Medline, Embase, and Web of Sciences databases for double-blind, randomized, controlled trials of PDE-5 inhibitors in secondary RP (Ann. Rheum. Dis. 2013 Feb. 20 [doi:10.1136/annrheumdis-2012-202836]).

They also looked for these trials in abstracts from meetings of the European League Against Rheumatism and the American College of Rheumatology, as well as in listings at the clinicaltrials.gov site.

In the final analysis, the investigators included six double-blind, randomized, placebo-controlled trials involving 244 patients – one with sildenafil (Viagra), one with modified-release sildenafil, three with tadalafil (Cialis), and one with vardenafil (Levitra). They excluded patients with primary Raynaud’s.

Most patients (91.8%) had RP secondary to systemic sclerosis; the remainder had mixed or undifferentiated connective tissue disease.

Only two trials allowed the use of other vasodilators, both of which tested tadalafil as an add-on to calcium channel blockers, although another study that tested tadalafil monotherapy for RP allowed seven patients to take calcium channel blockers and eight patients to take angiotensin-converting enzyme inhibitors for other indications.

Dr. Roustit and his associates found that the use of PDE-5 inhibitors significantly reduced the mean RCS by -0.46 (95% confidence interval -0.74 to -0.17; P = .002).

The drugs also reduced the frequency of attacks by -0.49 per day (95% CI, -0.71 to -0.28; P less than .0001), although this improvement fell beneath the minimally significant difference on the RCS, which is estimated to be 1.4-1.5 attacks per day.

PDE-5 inhibitors lessened the daily duration of attacks by 14.62 minutes (95% CI, -20.25 to -9.00; P less than .0001).

According to the authors, the decrease in number of attacks per day echoes the finding of another study assessing the efficacy of calcium channel blockers in secondary RP, which calculated a reduction of roughly 0.6 attacks per day (Arthritis Rheum. 2001;44:1841-7).

They added, however, that some data have also found PDE-5 inhibitors to be associated with reduction of digital ischemic ulcers in secondary Raynaud’s, although "data are scarce, and larger RCTs are ongoing to address this issue."

Dr. Roustit and another investigator disclosed receiving research grants from Pfizer (which markets sildenafil), Actelion, GlaxoSmithKline (which markets vardenafil) and Bioprojet for other studies. A third investigator disclosed receiving research grants and honoraria from Pfizer and Actelion for other studies.

rhnews@elsevier.com

Smoking significantly raises the risk that patients with systemic lupus erythematosus will develop active cutaneous manifestations of the disease, based on data from a multicenter cohort study of 1,346 patients.

Overall, current smokers were 63% more likely than former or never smokers to have an active SLE rash after controlling for multiple variables. In addition, patients who had ever smoked were more than twice as likely to meet the American College of Rheumatology criteria for discoid rash (odds ratio, 2.36) and photosensitivity (odds ratio, 1.47).

©pmphoto/iStockphoto.com

The study is the largest to date examining the effect of smoking on cutaneous outcomes in systemic lupus erythematosus (SLE), said Dr. Josiane Bourré-Tessier of the University of Montreal and her associates.

The researchers examined a possible association between smoking status and skin activity using data from the 1000 Faces of Lupus Cohort, a cohort of SLE patients who presented for care at 14 participating specialty clinics across Canada. The study population included 1,346 participants aged 16 years and older who enrolled between 2005 and 2009 (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21966]).

The patients were assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K), which focuses on rash and alopecia; the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI), which focuses on alopecia, extensive scarring, and skin ulceration; and the American College of Rheumatology (ACR) revised criteria for SLE, which focus on discoid rash, malar rash, and photosensitivity.

More than 90% of the study subjects were women, and 63% were white. The mean age was 47 years; mean disease duration was 13 years. Approximately 14% of the patients were current smokers and 27% were past smokers.

Most patients (70%) were taking antimalarials at the time of the study – 64% taking hydroxychloroquine and 6% taking chloroquine. Another 35% were taking immunosuppressants.

According to the SLEDAI-2K, 28% of patients had some mucocutaneous disease activity: 15% had rash, 13% had alopecia, 8% had mucosal ulcers, and 8% had at least two of these symptoms. According to the SDI, 12% had alopecia, including 4% with extensive scarring and 0.2% with skin ulceration. According to ACR criteria, 60% of patients had ever experienced malar rash; 17% had experienced discoid rash; 56%, photosensitivity; and 56%, ulcerations.

No association was found between past smoking and active skin manifestations, based on the SLEDAI-2K.

Based on the SDI, there was no association between smoking and cutaneous damage. This finding, however, may be due to the small number of patients with cutaneous damage, the researchers said. Alternatively, it may suggest that a longer observation period is needed to show a relationship between smoking and long-term cutaneous damage.

Both current and past smoking were associated with discoid rash and photosensitivity, based on the ACR criteria. Since ACR criteria are cumulative, this finding suggests that past smoking "may have triggered the prior emergence of cutaneous criteria," Dr. Bourré-Tessier and her associates said.

The association between smoking and skin manifestations of SLE "is not surprising, as cigarettes contain multiple chemical factors that may generate free radicals and alter inflammatory cell function and extracellular matrix turnover," the researchers wrote.

"These chemical factors may also interact with DNA and promote the production of autoantibodies directed against altered DNA," they suggested.

It was encouraging to find that current, but not past, smoking was associated with skin activity because that suggests the adverse effect may be reversible if patients stop smoking, the researchers noted.

The findings support the results of previous investigations showing that smoking promotes disease activity in a variety of autoimmune conditions. The data also give clinicians added incentive to encourage SLE patients to quit smoking, Dr. Bourré-Tessier and her associates said.

The study was limited by an inability to account for potential confounders such as medication adherence and sun exposure, they added.

The 1000 Faces of Lupus Cohort was funded by the Arthritis Society and the Lupus Society of Manitoba. No financial conflicts of interest were reported.

rhnews@elsevier.com

Smoking significantly raises the risk that patients with systemic lupus erythematosus will develop active cutaneous manifestations of the disease, based on data from a multicenter cohort study of 1,346 patients.

Overall, current smokers were 63% more likely than former or never smokers to have an active SLE rash after controlling for multiple variables. In addition, patients who had ever smoked were more than twice as likely to meet the American College of Rheumatology criteria for discoid rash (odds ratio, 2.36) and photosensitivity (odds ratio, 1.47).

©pmphoto/iStockphoto.com

The study is the largest to date examining the effect of smoking on cutaneous outcomes in systemic lupus erythematosus (SLE), said Dr. Josiane Bourré-Tessier of the University of Montreal and her associates.

The researchers examined a possible association between smoking status and skin activity using data from the 1000 Faces of Lupus Cohort, a cohort of SLE patients who presented for care at 14 participating specialty clinics across Canada. The study population included 1,346 participants aged 16 years and older who enrolled between 2005 and 2009 (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21966]).

The patients were assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K), which focuses on rash and alopecia; the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI), which focuses on alopecia, extensive scarring, and skin ulceration; and the American College of Rheumatology (ACR) revised criteria for SLE, which focus on discoid rash, malar rash, and photosensitivity.

More than 90% of the study subjects were women, and 63% were white. The mean age was 47 years; mean disease duration was 13 years. Approximately 14% of the patients were current smokers and 27% were past smokers.

Most patients (70%) were taking antimalarials at the time of the study – 64% taking hydroxychloroquine and 6% taking chloroquine. Another 35% were taking immunosuppressants.

According to the SLEDAI-2K, 28% of patients had some mucocutaneous disease activity: 15% had rash, 13% had alopecia, 8% had mucosal ulcers, and 8% had at least two of these symptoms. According to the SDI, 12% had alopecia, including 4% with extensive scarring and 0.2% with skin ulceration. According to ACR criteria, 60% of patients had ever experienced malar rash; 17% had experienced discoid rash; 56%, photosensitivity; and 56%, ulcerations.

No association was found between past smoking and active skin manifestations, based on the SLEDAI-2K.

Based on the SDI, there was no association between smoking and cutaneous damage. This finding, however, may be due to the small number of patients with cutaneous damage, the researchers said. Alternatively, it may suggest that a longer observation period is needed to show a relationship between smoking and long-term cutaneous damage.

Both current and past smoking were associated with discoid rash and photosensitivity, based on the ACR criteria. Since ACR criteria are cumulative, this finding suggests that past smoking "may have triggered the prior emergence of cutaneous criteria," Dr. Bourré-Tessier and her associates said.

The association between smoking and skin manifestations of SLE "is not surprising, as cigarettes contain multiple chemical factors that may generate free radicals and alter inflammatory cell function and extracellular matrix turnover," the researchers wrote.

"These chemical factors may also interact with DNA and promote the production of autoantibodies directed against altered DNA," they suggested.

It was encouraging to find that current, but not past, smoking was associated with skin activity because that suggests the adverse effect may be reversible if patients stop smoking, the researchers noted.

The findings support the results of previous investigations showing that smoking promotes disease activity in a variety of autoimmune conditions. The data also give clinicians added incentive to encourage SLE patients to quit smoking, Dr. Bourré-Tessier and her associates said.

The study was limited by an inability to account for potential confounders such as medication adherence and sun exposure, they added.

The 1000 Faces of Lupus Cohort was funded by the Arthritis Society and the Lupus Society of Manitoba. No financial conflicts of interest were reported.

rhnews@elsevier.com

Smoking significantly raises the risk that patients with systemic lupus erythematosus will develop active cutaneous manifestations of the disease, based on data from a multicenter cohort study of 1,346 patients.

Overall, current smokers were 63% more likely than former or never smokers to have an active SLE rash after controlling for multiple variables. In addition, patients who had ever smoked were more than twice as likely to meet the American College of Rheumatology criteria for discoid rash (odds ratio, 2.36) and photosensitivity (odds ratio, 1.47).

©pmphoto/iStockphoto.com

The study is the largest to date examining the effect of smoking on cutaneous outcomes in systemic lupus erythematosus (SLE), said Dr. Josiane Bourré-Tessier of the University of Montreal and her associates.

The researchers examined a possible association between smoking status and skin activity using data from the 1000 Faces of Lupus Cohort, a cohort of SLE patients who presented for care at 14 participating specialty clinics across Canada. The study population included 1,346 participants aged 16 years and older who enrolled between 2005 and 2009 (Arthritis Care Res. 2013 Feb. 11 [doi:10.1002/acr.21966]).

The patients were assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K), which focuses on rash and alopecia; the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI), which focuses on alopecia, extensive scarring, and skin ulceration; and the American College of Rheumatology (ACR) revised criteria for SLE, which focus on discoid rash, malar rash, and photosensitivity.

More than 90% of the study subjects were women, and 63% were white. The mean age was 47 years; mean disease duration was 13 years. Approximately 14% of the patients were current smokers and 27% were past smokers.

Most patients (70%) were taking antimalarials at the time of the study – 64% taking hydroxychloroquine and 6% taking chloroquine. Another 35% were taking immunosuppressants.

According to the SLEDAI-2K, 28% of patients had some mucocutaneous disease activity: 15% had rash, 13% had alopecia, 8% had mucosal ulcers, and 8% had at least two of these symptoms. According to the SDI, 12% had alopecia, including 4% with extensive scarring and 0.2% with skin ulceration. According to ACR criteria, 60% of patients had ever experienced malar rash; 17% had experienced discoid rash; 56%, photosensitivity; and 56%, ulcerations.

No association was found between past smoking and active skin manifestations, based on the SLEDAI-2K.

Based on the SDI, there was no association between smoking and cutaneous damage. This finding, however, may be due to the small number of patients with cutaneous damage, the researchers said. Alternatively, it may suggest that a longer observation period is needed to show a relationship between smoking and long-term cutaneous damage.

Both current and past smoking were associated with discoid rash and photosensitivity, based on the ACR criteria. Since ACR criteria are cumulative, this finding suggests that past smoking "may have triggered the prior emergence of cutaneous criteria," Dr. Bourré-Tessier and her associates said.

The association between smoking and skin manifestations of SLE "is not surprising, as cigarettes contain multiple chemical factors that may generate free radicals and alter inflammatory cell function and extracellular matrix turnover," the researchers wrote.

"These chemical factors may also interact with DNA and promote the production of autoantibodies directed against altered DNA," they suggested.

It was encouraging to find that current, but not past, smoking was associated with skin activity because that suggests the adverse effect may be reversible if patients stop smoking, the researchers noted.

The findings support the results of previous investigations showing that smoking promotes disease activity in a variety of autoimmune conditions. The data also give clinicians added incentive to encourage SLE patients to quit smoking, Dr. Bourré-Tessier and her associates said.

The study was limited by an inability to account for potential confounders such as medication adherence and sun exposure, they added.

The 1000 Faces of Lupus Cohort was funded by the Arthritis Society and the Lupus Society of Manitoba. No financial conflicts of interest were reported.

rhnews@elsevier.com

The postpartum period is often a time when women with moderate to severe psoriasis experience a significant disease flare – and if they’re breastfeeding, treatment options are limited, according to Dr. Alan Menter.

This postpartum major flare of psoriasis is an underappreciated phenomenon that catches many dermatologists and most ob.gyns. off guard, he said.

"Fifty to 60% of psoriasis patients have genital involvement. A woman with genital psoriasis in the postpartum period or during delivery really needs help, and I think we in dermatology should be addressing these issues because most of the obstetricians are not sure how to treat these patients," said Dr. Menter, chief of the division of dermatology at Baylor University Medical Center, Dallas, and chair of the American Academy of Dermatology psoriasis guidelines committee.

Psoriasis is equally common in men and women, and two-thirds of affected individuals present before age 40 – for women, the childbearing years. Thorny psoriasis management issues in pregnancy and postpartum are common.

Psoriasis slowly improves during pregnancy in roughly two-thirds of patients, as is true for other immune-mediated diseases. But for that other third, many of the mainstay therapies for tough psoriasis are off limits during pregnancy and/or post partum. UVB is a good, safe option, albeit inconvenient. Retinoids and cyclosporine are out because of teratogenicity.

Cyclosporine probably should be considered the go-to drug for significant disease during pregnancy. Its strengths are its fast onset of action and the safety reassurance provided by vast patient registries started back in the 1980s when the drug was first used in transplant recipients.

"We’re all comfortable using cyclosporine," Dr. Menter said. "Our AAD guidelines state it is appropriate for 1 year of continuous use. The European guidelines say, ‘2 years of continuous use.’ But I think most of us use it as an interventional therapy for 3-6 months. I actually think we should be using it a little more frequently as an interventional therapy."

Cyclosporine must be stopped in month 8 of pregnancy to allow the drug to clear from the patient’s system before delivery, since it is secreted in breast milk.

For the breastfeeding woman experiencing a major disease flare, the options are basically potent topical steroids, which physicians should feel comfortable in prescribing according to the standard dosing schedule used in nonpregnant patients, or – when topical therapy won’t get the job done – the biologic agents, listed by the Food and Drug Administration as category B.

The most forward-thinking approach to take with young women who require systemic therapy for psoriasis is to discuss pregnancy-related issues before pregnancy occurs. In particular, a prospective case-control study from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project concluded that women with psoriasis were significantly more likely to smoke, carry a diagnosis of depression, and be overweight or obese before pregnancy – factors that increase their risk for adverse pregnancy outcomes (Br. J. Dermatol. 2010;163:334-9).

Moreover, other studies have shown that psoriasis patients, men as well as women, have an increased prevalence of the metabolic syndrome, which increases their long-term risk of cardiovascular disease. Women with an adverse cardiovascular risk profile who are considering pregnancy and parenthood may be in a teachable moment where they are more amenable to lifestyle changes that reduce the risks both to their baby and themselves, Dr. Menter said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

Of course, half of pregnancies in the United States are unplanned, so the potential for unintended first-trimester fetal exposure to a teratogenic drug is substantial. While methotrexate is rated by the FDA as category X in pregnancy, dermatologists can derive some comfort from a well-executed review of 101 methotrexate-exposed pregnancies in rheumatology patients (Clin. Exp. Rheumatol. 2009;27:678-84). The 23% miscarriage rate wasn’t significantly different from that seen in pregnant psoriasis patients not on systemic agents. The live birth rate was 66%, with a 5% rate of neonatal malformations, all minor.

"The outcomes were actually better than any of us would have anticipated," Dr. Menter commented.

Psoriasis appears to have an inherent adverse impact upon pregnancy, he continued, pointing to an Israeli study of 68 deliveries in 35 women with moderate to severe psoriasis and 237 deliveries in 236 controls without psoriasis matched for age, parity, and gestational age.

"I think this is something we have to very gently discuss with our female patients who are considering pregnancy. We should tell them to be cautious in pregnancy because of this link between psoriasis and a slightly increased risk of spontaneous abortions. And I also discuss it with our ob.gyn. colleagues, who really are not aware of this link," the dermatologist said.

Dr. Menter reported receiving research support and/or consultant or lecture fees from roughly 20 pharmaceutical companies. SDEF and this news organization are owned by the same parent company.

b.jancin@elsevier.com

*This story was updated March 1, 2013.

The postpartum period is often a time when women with moderate to severe psoriasis experience a significant disease flare – and if they’re breastfeeding, treatment options are limited, according to Dr. Alan Menter.

This postpartum major flare of psoriasis is an underappreciated phenomenon that catches many dermatologists and most ob.gyns. off guard, he said.

"Fifty to 60% of psoriasis patients have genital involvement. A woman with genital psoriasis in the postpartum period or during delivery really needs help, and I think we in dermatology should be addressing these issues because most of the obstetricians are not sure how to treat these patients," said Dr. Menter, chief of the division of dermatology at Baylor University Medical Center, Dallas, and chair of the American Academy of Dermatology psoriasis guidelines committee.

Psoriasis is equally common in men and women, and two-thirds of affected individuals present before age 40 – for women, the childbearing years. Thorny psoriasis management issues in pregnancy and postpartum are common.

Psoriasis slowly improves during pregnancy in roughly two-thirds of patients, as is true for other immune-mediated diseases. But for that other third, many of the mainstay therapies for tough psoriasis are off limits during pregnancy and/or post partum. UVB is a good, safe option, albeit inconvenient. Retinoids and cyclosporine are out because of teratogenicity.

Cyclosporine probably should be considered the go-to drug for significant disease during pregnancy. Its strengths are its fast onset of action and the safety reassurance provided by vast patient registries started back in the 1980s when the drug was first used in transplant recipients.

"We’re all comfortable using cyclosporine," Dr. Menter said. "Our AAD guidelines state it is appropriate for 1 year of continuous use. The European guidelines say, ‘2 years of continuous use.’ But I think most of us use it as an interventional therapy for 3-6 months. I actually think we should be using it a little more frequently as an interventional therapy."

Cyclosporine must be stopped in month 8 of pregnancy to allow the drug to clear from the patient’s system before delivery, since it is secreted in breast milk.

For the breastfeeding woman experiencing a major disease flare, the options are basically potent topical steroids, which physicians should feel comfortable in prescribing according to the standard dosing schedule used in nonpregnant patients, or – when topical therapy won’t get the job done – the biologic agents, listed by the Food and Drug Administration as category B.

The most forward-thinking approach to take with young women who require systemic therapy for psoriasis is to discuss pregnancy-related issues before pregnancy occurs. In particular, a prospective case-control study from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project concluded that women with psoriasis were significantly more likely to smoke, carry a diagnosis of depression, and be overweight or obese before pregnancy – factors that increase their risk for adverse pregnancy outcomes (Br. J. Dermatol. 2010;163:334-9).

Moreover, other studies have shown that psoriasis patients, men as well as women, have an increased prevalence of the metabolic syndrome, which increases their long-term risk of cardiovascular disease. Women with an adverse cardiovascular risk profile who are considering pregnancy and parenthood may be in a teachable moment where they are more amenable to lifestyle changes that reduce the risks both to their baby and themselves, Dr. Menter said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

Of course, half of pregnancies in the United States are unplanned, so the potential for unintended first-trimester fetal exposure to a teratogenic drug is substantial. While methotrexate is rated by the FDA as category X in pregnancy, dermatologists can derive some comfort from a well-executed review of 101 methotrexate-exposed pregnancies in rheumatology patients (Clin. Exp. Rheumatol. 2009;27:678-84). The 23% miscarriage rate wasn’t significantly different from that seen in pregnant psoriasis patients not on systemic agents. The live birth rate was 66%, with a 5% rate of neonatal malformations, all minor.

"The outcomes were actually better than any of us would have anticipated," Dr. Menter commented.

Psoriasis appears to have an inherent adverse impact upon pregnancy, he continued, pointing to an Israeli study of 68 deliveries in 35 women with moderate to severe psoriasis and 237 deliveries in 236 controls without psoriasis matched for age, parity, and gestational age.

"I think this is something we have to very gently discuss with our female patients who are considering pregnancy. We should tell them to be cautious in pregnancy because of this link between psoriasis and a slightly increased risk of spontaneous abortions. And I also discuss it with our ob.gyn. colleagues, who really are not aware of this link," the dermatologist said.

Dr. Menter reported receiving research support and/or consultant or lecture fees from roughly 20 pharmaceutical companies. SDEF and this news organization are owned by the same parent company.

b.jancin@elsevier.com

*This story was updated March 1, 2013.

The postpartum period is often a time when women with moderate to severe psoriasis experience a significant disease flare – and if they’re breastfeeding, treatment options are limited, according to Dr. Alan Menter.

This postpartum major flare of psoriasis is an underappreciated phenomenon that catches many dermatologists and most ob.gyns. off guard, he said.

"Fifty to 60% of psoriasis patients have genital involvement. A woman with genital psoriasis in the postpartum period or during delivery really needs help, and I think we in dermatology should be addressing these issues because most of the obstetricians are not sure how to treat these patients," said Dr. Menter, chief of the division of dermatology at Baylor University Medical Center, Dallas, and chair of the American Academy of Dermatology psoriasis guidelines committee.

Psoriasis is equally common in men and women, and two-thirds of affected individuals present before age 40 – for women, the childbearing years. Thorny psoriasis management issues in pregnancy and postpartum are common.

Psoriasis slowly improves during pregnancy in roughly two-thirds of patients, as is true for other immune-mediated diseases. But for that other third, many of the mainstay therapies for tough psoriasis are off limits during pregnancy and/or post partum. UVB is a good, safe option, albeit inconvenient. Retinoids and cyclosporine are out because of teratogenicity.

Cyclosporine probably should be considered the go-to drug for significant disease during pregnancy. Its strengths are its fast onset of action and the safety reassurance provided by vast patient registries started back in the 1980s when the drug was first used in transplant recipients.

"We’re all comfortable using cyclosporine," Dr. Menter said. "Our AAD guidelines state it is appropriate for 1 year of continuous use. The European guidelines say, ‘2 years of continuous use.’ But I think most of us use it as an interventional therapy for 3-6 months. I actually think we should be using it a little more frequently as an interventional therapy."

Cyclosporine must be stopped in month 8 of pregnancy to allow the drug to clear from the patient’s system before delivery, since it is secreted in breast milk.

For the breastfeeding woman experiencing a major disease flare, the options are basically potent topical steroids, which physicians should feel comfortable in prescribing according to the standard dosing schedule used in nonpregnant patients, or – when topical therapy won’t get the job done – the biologic agents, listed by the Food and Drug Administration as category B.

The most forward-thinking approach to take with young women who require systemic therapy for psoriasis is to discuss pregnancy-related issues before pregnancy occurs. In particular, a prospective case-control study from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project concluded that women with psoriasis were significantly more likely to smoke, carry a diagnosis of depression, and be overweight or obese before pregnancy – factors that increase their risk for adverse pregnancy outcomes (Br. J. Dermatol. 2010;163:334-9).

Moreover, other studies have shown that psoriasis patients, men as well as women, have an increased prevalence of the metabolic syndrome, which increases their long-term risk of cardiovascular disease. Women with an adverse cardiovascular risk profile who are considering pregnancy and parenthood may be in a teachable moment where they are more amenable to lifestyle changes that reduce the risks both to their baby and themselves, Dr. Menter said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

Of course, half of pregnancies in the United States are unplanned, so the potential for unintended first-trimester fetal exposure to a teratogenic drug is substantial. While methotrexate is rated by the FDA as category X in pregnancy, dermatologists can derive some comfort from a well-executed review of 101 methotrexate-exposed pregnancies in rheumatology patients (Clin. Exp. Rheumatol. 2009;27:678-84). The 23% miscarriage rate wasn’t significantly different from that seen in pregnant psoriasis patients not on systemic agents. The live birth rate was 66%, with a 5% rate of neonatal malformations, all minor.

"The outcomes were actually better than any of us would have anticipated," Dr. Menter commented.

Psoriasis appears to have an inherent adverse impact upon pregnancy, he continued, pointing to an Israeli study of 68 deliveries in 35 women with moderate to severe psoriasis and 237 deliveries in 236 controls without psoriasis matched for age, parity, and gestational age.

"I think this is something we have to very gently discuss with our female patients who are considering pregnancy. We should tell them to be cautious in pregnancy because of this link between psoriasis and a slightly increased risk of spontaneous abortions. And I also discuss it with our ob.gyn. colleagues, who really are not aware of this link," the dermatologist said.

Dr. Menter reported receiving research support and/or consultant or lecture fees from roughly 20 pharmaceutical companies. SDEF and this news organization are owned by the same parent company.

b.jancin@elsevier.com

*This story was updated March 1, 2013.

At the SDEF Hawaii Dermatology Seminar, Dr. Alan Menter of Baylor University discussed the particular challenges women with psoriasis face in the peripartum period. Many patients – and many ob.gyns.– are not well informed about postpartum psoriasis flare or what to do if genital psoriasis is present at delivery. The SDEF Hawaii Dermatology Seminar is presented by the Skin Disease Education Foundation/Global Academy for Medical Education and is owned by the same parent company as this news organization.

At the SDEF Hawaii Dermatology Seminar, Dr. Alan Menter of Baylor University discussed the particular challenges women with psoriasis face in the peripartum period. Many patients – and many ob.gyns.– are not well informed about postpartum psoriasis flare or what to do if genital psoriasis is present at delivery. The SDEF Hawaii Dermatology Seminar is presented by the Skin Disease Education Foundation/Global Academy for Medical Education and is owned by the same parent company as this news organization.

At the SDEF Hawaii Dermatology Seminar, Dr. Alan Menter of Baylor University discussed the particular challenges women with psoriasis face in the peripartum period. Many patients – and many ob.gyns.– are not well informed about postpartum psoriasis flare or what to do if genital psoriasis is present at delivery. The SDEF Hawaii Dermatology Seminar is presented by the Skin Disease Education Foundation/Global Academy for Medical Education and is owned by the same parent company as this news organization.

PRAGUE – The major role that the Janus kinases play in the pathogenesis of psoriasis is confirmed, based on the results of a phase II study of the investigational oral agent ASP015K, according to Dr. Bernhardt Zeiher.

ASP015K inhibits Janus kinase (JAK) 1 and 3, with relative sparing of JAK 2. In a 6-week dose-ranging study of 124 patients with moderate to severe psoriasis, all tested doses – 10, 25, 60, and 100 mg twice daily as well as 50 mg once daily – significantly outperformed placebo in terms of improvement in Psoriasis Area and Severity Index (PASI) scores.

Moreover, immunohistochemistry of skin biopsies gathered at baseline and at days 14 and 42 after initiation of ASP015K showed the drug reduced epidermal thickness, epidermal proliferation as measured by Ki67, and infiltration of CD3 T cells and CD11c dendritic cells. The greatest changes at the cellular level were seen at the highest dose, 100 mg twice daily.

"Although treatment was only for 6 weeks, the defining pathology of psoriasis was reversed in 62% of patients in the 100-mg b.i.d. cohort. In these patients, epidermal thickness was normalized and was comparable with nonlesional skin after treatment, parakeratosis was eliminated, and a granular layer was restored. Keratinocyte proliferation, judged by Ki67 staining, was reversed to levels of nonlesional skin. Major reductions in the number of T cells and inflammatory CD11c-positive dendritic cells were also measured in day 42 biopsies, along with elimination of organized lymphoid structures," according to Dr. Zeiher of Astellas Pharma, Deerfield, Ill., which is developing the JAK 1/3 inhibitor.

Improvements in cellular findings and PASI scores were largely dose-dependent.

Mean PASI scores fell by 12 points over a 6-week period in patients assigned to ASP015K at 100 mg b.i.d.; a 4-point drop in mean PASI scores was seen in placebo-treated controls.

Yet histologic improvements associated with the 50-mg once-daily dose were second in magnitude only to those seen with the 100-mg b.i.d. dose.

"When you look at the kinetics of the drug, you have more JAK inhibition holiday with once-a-day dosing," Dr. Zeiher explained. The notion that a daily JAK inhibition holiday provides added therapeutic benefit is both interesting and readily testable. A planned phase IIb study will evaluate once-daily oral dosing of ASP015K at a range of doses, with 150 mg as the maximum.

The JAK 1/3 inhibitor was well tolerated overall. Three subjects dropped out of the study because of drug-related side effects: two with decreased neutrophil counts but not frank neutropenia on doses of 60 and 100 mg b.i.d., and one as a result of GI upset while on 100 mg b.i.d.

b.jancin@elsevier.com

PRAGUE – The major role that the Janus kinases play in the pathogenesis of psoriasis is confirmed, based on the results of a phase II study of the investigational oral agent ASP015K, according to Dr. Bernhardt Zeiher.

ASP015K inhibits Janus kinase (JAK) 1 and 3, with relative sparing of JAK 2. In a 6-week dose-ranging study of 124 patients with moderate to severe psoriasis, all tested doses – 10, 25, 60, and 100 mg twice daily as well as 50 mg once daily – significantly outperformed placebo in terms of improvement in Psoriasis Area and Severity Index (PASI) scores.

Moreover, immunohistochemistry of skin biopsies gathered at baseline and at days 14 and 42 after initiation of ASP015K showed the drug reduced epidermal thickness, epidermal proliferation as measured by Ki67, and infiltration of CD3 T cells and CD11c dendritic cells. The greatest changes at the cellular level were seen at the highest dose, 100 mg twice daily.

"Although treatment was only for 6 weeks, the defining pathology of psoriasis was reversed in 62% of patients in the 100-mg b.i.d. cohort. In these patients, epidermal thickness was normalized and was comparable with nonlesional skin after treatment, parakeratosis was eliminated, and a granular layer was restored. Keratinocyte proliferation, judged by Ki67 staining, was reversed to levels of nonlesional skin. Major reductions in the number of T cells and inflammatory CD11c-positive dendritic cells were also measured in day 42 biopsies, along with elimination of organized lymphoid structures," according to Dr. Zeiher of Astellas Pharma, Deerfield, Ill., which is developing the JAK 1/3 inhibitor.

Improvements in cellular findings and PASI scores were largely dose-dependent.

Mean PASI scores fell by 12 points over a 6-week period in patients assigned to ASP015K at 100 mg b.i.d.; a 4-point drop in mean PASI scores was seen in placebo-treated controls.

Yet histologic improvements associated with the 50-mg once-daily dose were second in magnitude only to those seen with the 100-mg b.i.d. dose.

"When you look at the kinetics of the drug, you have more JAK inhibition holiday with once-a-day dosing," Dr. Zeiher explained. The notion that a daily JAK inhibition holiday provides added therapeutic benefit is both interesting and readily testable. A planned phase IIb study will evaluate once-daily oral dosing of ASP015K at a range of doses, with 150 mg as the maximum.

The JAK 1/3 inhibitor was well tolerated overall. Three subjects dropped out of the study because of drug-related side effects: two with decreased neutrophil counts but not frank neutropenia on doses of 60 and 100 mg b.i.d., and one as a result of GI upset while on 100 mg b.i.d.

b.jancin@elsevier.com

PRAGUE – The major role that the Janus kinases play in the pathogenesis of psoriasis is confirmed, based on the results of a phase II study of the investigational oral agent ASP015K, according to Dr. Bernhardt Zeiher.

ASP015K inhibits Janus kinase (JAK) 1 and 3, with relative sparing of JAK 2. In a 6-week dose-ranging study of 124 patients with moderate to severe psoriasis, all tested doses – 10, 25, 60, and 100 mg twice daily as well as 50 mg once daily – significantly outperformed placebo in terms of improvement in Psoriasis Area and Severity Index (PASI) scores.

Moreover, immunohistochemistry of skin biopsies gathered at baseline and at days 14 and 42 after initiation of ASP015K showed the drug reduced epidermal thickness, epidermal proliferation as measured by Ki67, and infiltration of CD3 T cells and CD11c dendritic cells. The greatest changes at the cellular level were seen at the highest dose, 100 mg twice daily.

"Although treatment was only for 6 weeks, the defining pathology of psoriasis was reversed in 62% of patients in the 100-mg b.i.d. cohort. In these patients, epidermal thickness was normalized and was comparable with nonlesional skin after treatment, parakeratosis was eliminated, and a granular layer was restored. Keratinocyte proliferation, judged by Ki67 staining, was reversed to levels of nonlesional skin. Major reductions in the number of T cells and inflammatory CD11c-positive dendritic cells were also measured in day 42 biopsies, along with elimination of organized lymphoid structures," according to Dr. Zeiher of Astellas Pharma, Deerfield, Ill., which is developing the JAK 1/3 inhibitor.

Improvements in cellular findings and PASI scores were largely dose-dependent.

Mean PASI scores fell by 12 points over a 6-week period in patients assigned to ASP015K at 100 mg b.i.d.; a 4-point drop in mean PASI scores was seen in placebo-treated controls.

Yet histologic improvements associated with the 50-mg once-daily dose were second in magnitude only to those seen with the 100-mg b.i.d. dose.

"When you look at the kinetics of the drug, you have more JAK inhibition holiday with once-a-day dosing," Dr. Zeiher explained. The notion that a daily JAK inhibition holiday provides added therapeutic benefit is both interesting and readily testable. A planned phase IIb study will evaluate once-daily oral dosing of ASP015K at a range of doses, with 150 mg as the maximum.

The JAK 1/3 inhibitor was well tolerated overall. Three subjects dropped out of the study because of drug-related side effects: two with decreased neutrophil counts but not frank neutropenia on doses of 60 and 100 mg b.i.d., and one as a result of GI upset while on 100 mg b.i.d.

b.jancin@elsevier.com

As revenue sources for research dwindle, academic medical centers are under great stress today. There is a drop in patient care fees, Medicare and Medicaid reimbursement, money through philanthropy, state support, and grant support. At every center, institutional support for research is under pressure. And for those just starting their careers – particularly those with an interest in lupus research – these problems could not come at a worse time.

Lupus offers many challenges to researchers: It is hard to diagnose, it ravages different parts of the body, its symptoms come and go and often imitate other illnesses, and it manifests differently in each individual. Despite these challenges, we have come a long way, and the lupus community of clinician-scientists has worked persistently to unravel the mystery of lupus. In recent years, lupus research has produced important clues about the origin and effects of the disease. For instance, we know more than ever before about how the immune system malfunctions to cause lupus. We are beginning to recognize which individuals are at higher risk for life-threatening complications. We have learned which therapies used in other diseases are effective for treating symptoms of lupus.

But just as we reached this pivotal time, we were hit by a downturn in the economy. Funding for key research was harder to come by as the federal government, who along with the pharmaceutical industry represents the largest funders of research, was making cutbacks to all of its programs. For lupus alone, federal funding was reported to be $134 million in 2009 but dropped to just $105 million in 2012. Included in the cuts are programs supporting the growth and development of the scientific community.

As a result of the lack of funding, several promising young lupus investigators have decided not to pursue academic careers but have moved to private practice or industry. Even a number of senior lupus investigators have left academics primarily to enter the biopharmaceutical industry. Other investigators at academic institutions are focusing more on clinical trials rather than independent research.

Nonprofit organizations like the Lupus Foundation of America are making an effort to compensate for some of the loss in funding by creating comprehensive award programs of their own through private funding. Recently, the foundation announced a new Career Development Award that will offer professional development support to early-career clinician-scientists – a step meant to help stem the hemorrhage of young lupus researchers. The foundation already offers awards meant to support lupus researchers at all other stages in their career. Such support has been crucial in retaining some researchers in the field.

But without public funding, retaining scientists in the numbers that lupus really needs will remain close to impossible because the truth is that one cannot make an academic research career on foundation money alone, especially given the stress that academic centers are undergoing. Support from the National Institutes of Health and the Department of Defense, among other federal agencies that have supported lupus research, is key.

The most disturbing impact of failing to keep up the momentum of lupus research could be on treatment development and patient care for the estimated 1.5 million Americans with the disease. While there has not been a significant impact on those so far, it is easy to see the problems we may face down the road. Research and discovery conducted at the academic level is vital to target development. If there are no academics to develop ideas, there will be no new lupus drugs in the pipeline.

Another way that the drop in lupus researchers could impact patients is that most academic centers now have lupologists, individuals who specialize in lupus. The number of lupologists continues to dwindle because of financial stress on academic centers, and not as many new lupologists are entering the field. This makes the Lupus Foundation of America’s Career Development Award important because it offers a start to retaining early-career lupus specialists.

Studies indicate that patients do better when they are cared for by lupologists, who see a large number of lupus patients, compared with rheumatologists who see a more limited number. That’s because as with anything else, you get better at doing something you do all the time. If you see a lot of people with lupus, you get better at treating it. With the loss of lupologists at academic research centers, this specialized expertise will no longer be available and patient care could suffer.

Dr. Gilkeson is chair of the Lupus Foundation of America’s Medical-Scientific Advisory Council and professor of medicine and associate dean of faculty affairs and faculty development at the Medical University of South Carolina, Charleston. He reported having no relevant financial disclosures.

As revenue sources for research dwindle, academic medical centers are under great stress today. There is a drop in patient care fees, Medicare and Medicaid reimbursement, money through philanthropy, state support, and grant support. At every center, institutional support for research is under pressure. And for those just starting their careers – particularly those with an interest in lupus research – these problems could not come at a worse time.

Lupus offers many challenges to researchers: It is hard to diagnose, it ravages different parts of the body, its symptoms come and go and often imitate other illnesses, and it manifests differently in each individual. Despite these challenges, we have come a long way, and the lupus community of clinician-scientists has worked persistently to unravel the mystery of lupus. In recent years, lupus research has produced important clues about the origin and effects of the disease. For instance, we know more than ever before about how the immune system malfunctions to cause lupus. We are beginning to recognize which individuals are at higher risk for life-threatening complications. We have learned which therapies used in other diseases are effective for treating symptoms of lupus.

But just as we reached this pivotal time, we were hit by a downturn in the economy. Funding for key research was harder to come by as the federal government, who along with the pharmaceutical industry represents the largest funders of research, was making cutbacks to all of its programs. For lupus alone, federal funding was reported to be $134 million in 2009 but dropped to just $105 million in 2012. Included in the cuts are programs supporting the growth and development of the scientific community.

As a result of the lack of funding, several promising young lupus investigators have decided not to pursue academic careers but have moved to private practice or industry. Even a number of senior lupus investigators have left academics primarily to enter the biopharmaceutical industry. Other investigators at academic institutions are focusing more on clinical trials rather than independent research.

Nonprofit organizations like the Lupus Foundation of America are making an effort to compensate for some of the loss in funding by creating comprehensive award programs of their own through private funding. Recently, the foundation announced a new Career Development Award that will offer professional development support to early-career clinician-scientists – a step meant to help stem the hemorrhage of young lupus researchers. The foundation already offers awards meant to support lupus researchers at all other stages in their career. Such support has been crucial in retaining some researchers in the field.

But without public funding, retaining scientists in the numbers that lupus really needs will remain close to impossible because the truth is that one cannot make an academic research career on foundation money alone, especially given the stress that academic centers are undergoing. Support from the National Institutes of Health and the Department of Defense, among other federal agencies that have supported lupus research, is key.

The most disturbing impact of failing to keep up the momentum of lupus research could be on treatment development and patient care for the estimated 1.5 million Americans with the disease. While there has not been a significant impact on those so far, it is easy to see the problems we may face down the road. Research and discovery conducted at the academic level is vital to target development. If there are no academics to develop ideas, there will be no new lupus drugs in the pipeline.

Another way that the drop in lupus researchers could impact patients is that most academic centers now have lupologists, individuals who specialize in lupus. The number of lupologists continues to dwindle because of financial stress on academic centers, and not as many new lupologists are entering the field. This makes the Lupus Foundation of America’s Career Development Award important because it offers a start to retaining early-career lupus specialists.

Studies indicate that patients do better when they are cared for by lupologists, who see a large number of lupus patients, compared with rheumatologists who see a more limited number. That’s because as with anything else, you get better at doing something you do all the time. If you see a lot of people with lupus, you get better at treating it. With the loss of lupologists at academic research centers, this specialized expertise will no longer be available and patient care could suffer.

Dr. Gilkeson is chair of the Lupus Foundation of America’s Medical-Scientific Advisory Council and professor of medicine and associate dean of faculty affairs and faculty development at the Medical University of South Carolina, Charleston. He reported having no relevant financial disclosures.

As revenue sources for research dwindle, academic medical centers are under great stress today. There is a drop in patient care fees, Medicare and Medicaid reimbursement, money through philanthropy, state support, and grant support. At every center, institutional support for research is under pressure. And for those just starting their careers – particularly those with an interest in lupus research – these problems could not come at a worse time.

Lupus offers many challenges to researchers: It is hard to diagnose, it ravages different parts of the body, its symptoms come and go and often imitate other illnesses, and it manifests differently in each individual. Despite these challenges, we have come a long way, and the lupus community of clinician-scientists has worked persistently to unravel the mystery of lupus. In recent years, lupus research has produced important clues about the origin and effects of the disease. For instance, we know more than ever before about how the immune system malfunctions to cause lupus. We are beginning to recognize which individuals are at higher risk for life-threatening complications. We have learned which therapies used in other diseases are effective for treating symptoms of lupus.

But just as we reached this pivotal time, we were hit by a downturn in the economy. Funding for key research was harder to come by as the federal government, who along with the pharmaceutical industry represents the largest funders of research, was making cutbacks to all of its programs. For lupus alone, federal funding was reported to be $134 million in 2009 but dropped to just $105 million in 2012. Included in the cuts are programs supporting the growth and development of the scientific community.

As a result of the lack of funding, several promising young lupus investigators have decided not to pursue academic careers but have moved to private practice or industry. Even a number of senior lupus investigators have left academics primarily to enter the biopharmaceutical industry. Other investigators at academic institutions are focusing more on clinical trials rather than independent research.

Nonprofit organizations like the Lupus Foundation of America are making an effort to compensate for some of the loss in funding by creating comprehensive award programs of their own through private funding. Recently, the foundation announced a new Career Development Award that will offer professional development support to early-career clinician-scientists – a step meant to help stem the hemorrhage of young lupus researchers. The foundation already offers awards meant to support lupus researchers at all other stages in their career. Such support has been crucial in retaining some researchers in the field.

But without public funding, retaining scientists in the numbers that lupus really needs will remain close to impossible because the truth is that one cannot make an academic research career on foundation money alone, especially given the stress that academic centers are undergoing. Support from the National Institutes of Health and the Department of Defense, among other federal agencies that have supported lupus research, is key.

The most disturbing impact of failing to keep up the momentum of lupus research could be on treatment development and patient care for the estimated 1.5 million Americans with the disease. While there has not been a significant impact on those so far, it is easy to see the problems we may face down the road. Research and discovery conducted at the academic level is vital to target development. If there are no academics to develop ideas, there will be no new lupus drugs in the pipeline.

Another way that the drop in lupus researchers could impact patients is that most academic centers now have lupologists, individuals who specialize in lupus. The number of lupologists continues to dwindle because of financial stress on academic centers, and not as many new lupologists are entering the field. This makes the Lupus Foundation of America’s Career Development Award important because it offers a start to retaining early-career lupus specialists.

Studies indicate that patients do better when they are cared for by lupologists, who see a large number of lupus patients, compared with rheumatologists who see a more limited number. That’s because as with anything else, you get better at doing something you do all the time. If you see a lot of people with lupus, you get better at treating it. With the loss of lupologists at academic research centers, this specialized expertise will no longer be available and patient care could suffer.

Dr. Gilkeson is chair of the Lupus Foundation of America’s Medical-Scientific Advisory Council and professor of medicine and associate dean of faculty affairs and faculty development at the Medical University of South Carolina, Charleston. He reported having no relevant financial disclosures.