Sharon Worcester

ATLANTA – Renal dysfunction is independently associated with incident cardiovascular disease in patients with rheumatoid arthritis, according to findings from a prospective Dutch cohort study.

Of 353 RA patients who were part of the Cardiovascular Research and Rheumatoid Arthritis (CARRE) study and who were followed for at least 3 years, 23 developed a cardiovascular event. Serum creatinine levels and glomerular filtration rate (GFR) findings were unfavorable in the patients who had a cardiovascular event, compared with those who did not, Dr. Alper M. van Sijl reported at the annual meeting of the American College of Rheumatology.

Patients with a cardiovascular event had a mean serum creatinine level of 101, compared with 88 micromol/L in the unaffected group; GFR as measured using the Cockcroft-Gault (CG) formula was 63 vs. 80 mL/min, and GFR as measured using the Modification of Diet in Renal Disease (MDRD) formula was 59 vs. 78 mL/min, in the groups, respectively, said Dr. van Sijl of the Jan van Breemen Institute and VU Medical Center, Amsterdam.

Dr. van Sijl and his colleagues used logistic regression analysis to calculate whether incremental increases of 5 micromol/L in serum creatinine level, and incremental decreases of 5 mL/min in glomerular filtration rate as measured using both the CG and MDRD formulas were associated with incident cardiovascular disease. Indeed, all were significantly positively associated with incident cardiovascular disease (odds ratios of 1.13, 1.12, and 1.21, respectively).

"When adjusted for age, gender, body mass index, and prior cardiovascular disease, the association remains. And when adjusted additionally for traditional cardiovascular risk factors, the association becomes even stronger," he said, explaining that a decrease in GFR of 5 mL/min was associated with a 30%-35% increased risk of cardiovascular disease, independent of traditional cardiovascular risk factors.

By comparison, a prior cohort study showed that diabetes patients have about a 20% cardiovascular disease risk increase for every 5-mL/min decrease in GFR, he noted.

The findings of the current study suggest that renal dysfunction might be a "missing link" in the established, but only partially defined, connection between RA and cardiovascular disease, he said.

RA patients are known to have an increased risk of mortality, compared with the general population, and much of that risk has been shown to be attributable to cardiovascular disease. However, standard cardiovascular risk factors – particularly hypercholesterolemia, hypertension, and insulin resistance – explain only part of this association.

Furthermore, renal dysfunction has been shown to be associated with cardiovascular disease in the general population, although findings from landmark studies have shown that risk depends on coexisting hypertension, prior cardiovascular disease, and diabetes, Dr. van Sijl said.

Study findings have shown an association between renal dysfunction and RA. Renal dysfunction in the RA population has been attributed to extra-articular manifestations, NSAID use, and chronic inflammation. At least one study showed an association between renal function and prevalent cardiovascular disease in RA, he said.

Although the current findings do support the idea that decreased renal function can help identify RA patients at increased risk for future cardiovascular disease, further study is needed to determine whether chronic inflammation causes the decreases in GFR, and whether GFR can accurately predict cardiovascular disease occurrence in RA, he said.

"Also still unknown to us is whether possible residual confounding is still present in the form of newly discovered markers of both renal dysfunction and cardiovascular disease such as uric acid, endothelial dysfunction, and cumulative inflammatory burden," he said.

Dr. van Sijl said he had no disclosures to report.

ATLANTA – Renal dysfunction is independently associated with incident cardiovascular disease in patients with rheumatoid arthritis, according to findings from a prospective Dutch cohort study.

Of 353 RA patients who were part of the Cardiovascular Research and Rheumatoid Arthritis (CARRE) study and who were followed for at least 3 years, 23 developed a cardiovascular event. Serum creatinine levels and glomerular filtration rate (GFR) findings were unfavorable in the patients who had a cardiovascular event, compared with those who did not, Dr. Alper M. van Sijl reported at the annual meeting of the American College of Rheumatology.

Patients with a cardiovascular event had a mean serum creatinine level of 101, compared with 88 micromol/L in the unaffected group; GFR as measured using the Cockcroft-Gault (CG) formula was 63 vs. 80 mL/min, and GFR as measured using the Modification of Diet in Renal Disease (MDRD) formula was 59 vs. 78 mL/min, in the groups, respectively, said Dr. van Sijl of the Jan van Breemen Institute and VU Medical Center, Amsterdam.

Dr. van Sijl and his colleagues used logistic regression analysis to calculate whether incremental increases of 5 micromol/L in serum creatinine level, and incremental decreases of 5 mL/min in glomerular filtration rate as measured using both the CG and MDRD formulas were associated with incident cardiovascular disease. Indeed, all were significantly positively associated with incident cardiovascular disease (odds ratios of 1.13, 1.12, and 1.21, respectively).

"When adjusted for age, gender, body mass index, and prior cardiovascular disease, the association remains. And when adjusted additionally for traditional cardiovascular risk factors, the association becomes even stronger," he said, explaining that a decrease in GFR of 5 mL/min was associated with a 30%-35% increased risk of cardiovascular disease, independent of traditional cardiovascular risk factors.

By comparison, a prior cohort study showed that diabetes patients have about a 20% cardiovascular disease risk increase for every 5-mL/min decrease in GFR, he noted.

The findings of the current study suggest that renal dysfunction might be a "missing link" in the established, but only partially defined, connection between RA and cardiovascular disease, he said.

RA patients are known to have an increased risk of mortality, compared with the general population, and much of that risk has been shown to be attributable to cardiovascular disease. However, standard cardiovascular risk factors – particularly hypercholesterolemia, hypertension, and insulin resistance – explain only part of this association.

Furthermore, renal dysfunction has been shown to be associated with cardiovascular disease in the general population, although findings from landmark studies have shown that risk depends on coexisting hypertension, prior cardiovascular disease, and diabetes, Dr. van Sijl said.

Study findings have shown an association between renal dysfunction and RA. Renal dysfunction in the RA population has been attributed to extra-articular manifestations, NSAID use, and chronic inflammation. At least one study showed an association between renal function and prevalent cardiovascular disease in RA, he said.

Although the current findings do support the idea that decreased renal function can help identify RA patients at increased risk for future cardiovascular disease, further study is needed to determine whether chronic inflammation causes the decreases in GFR, and whether GFR can accurately predict cardiovascular disease occurrence in RA, he said.

"Also still unknown to us is whether possible residual confounding is still present in the form of newly discovered markers of both renal dysfunction and cardiovascular disease such as uric acid, endothelial dysfunction, and cumulative inflammatory burden," he said.

Dr. van Sijl said he had no disclosures to report.

ATLANTA – Renal dysfunction is independently associated with incident cardiovascular disease in patients with rheumatoid arthritis, according to findings from a prospective Dutch cohort study.

Of 353 RA patients who were part of the Cardiovascular Research and Rheumatoid Arthritis (CARRE) study and who were followed for at least 3 years, 23 developed a cardiovascular event. Serum creatinine levels and glomerular filtration rate (GFR) findings were unfavorable in the patients who had a cardiovascular event, compared with those who did not, Dr. Alper M. van Sijl reported at the annual meeting of the American College of Rheumatology.

Patients with a cardiovascular event had a mean serum creatinine level of 101, compared with 88 micromol/L in the unaffected group; GFR as measured using the Cockcroft-Gault (CG) formula was 63 vs. 80 mL/min, and GFR as measured using the Modification of Diet in Renal Disease (MDRD) formula was 59 vs. 78 mL/min, in the groups, respectively, said Dr. van Sijl of the Jan van Breemen Institute and VU Medical Center, Amsterdam.

Dr. van Sijl and his colleagues used logistic regression analysis to calculate whether incremental increases of 5 micromol/L in serum creatinine level, and incremental decreases of 5 mL/min in glomerular filtration rate as measured using both the CG and MDRD formulas were associated with incident cardiovascular disease. Indeed, all were significantly positively associated with incident cardiovascular disease (odds ratios of 1.13, 1.12, and 1.21, respectively).

"When adjusted for age, gender, body mass index, and prior cardiovascular disease, the association remains. And when adjusted additionally for traditional cardiovascular risk factors, the association becomes even stronger," he said, explaining that a decrease in GFR of 5 mL/min was associated with a 30%-35% increased risk of cardiovascular disease, independent of traditional cardiovascular risk factors.

By comparison, a prior cohort study showed that diabetes patients have about a 20% cardiovascular disease risk increase for every 5-mL/min decrease in GFR, he noted.

The findings of the current study suggest that renal dysfunction might be a "missing link" in the established, but only partially defined, connection between RA and cardiovascular disease, he said.

RA patients are known to have an increased risk of mortality, compared with the general population, and much of that risk has been shown to be attributable to cardiovascular disease. However, standard cardiovascular risk factors – particularly hypercholesterolemia, hypertension, and insulin resistance – explain only part of this association.

Furthermore, renal dysfunction has been shown to be associated with cardiovascular disease in the general population, although findings from landmark studies have shown that risk depends on coexisting hypertension, prior cardiovascular disease, and diabetes, Dr. van Sijl said.

Study findings have shown an association between renal dysfunction and RA. Renal dysfunction in the RA population has been attributed to extra-articular manifestations, NSAID use, and chronic inflammation. At least one study showed an association between renal function and prevalent cardiovascular disease in RA, he said.

Although the current findings do support the idea that decreased renal function can help identify RA patients at increased risk for future cardiovascular disease, further study is needed to determine whether chronic inflammation causes the decreases in GFR, and whether GFR can accurately predict cardiovascular disease occurrence in RA, he said.

"Also still unknown to us is whether possible residual confounding is still present in the form of newly discovered markers of both renal dysfunction and cardiovascular disease such as uric acid, endothelial dysfunction, and cumulative inflammatory burden," he said.

Dr. van Sijl said he had no disclosures to report.

ATLANTA – Tocilizumab was highly effective for the treatment of systemic juvenile idiopathic arthritis, according to findings from the 12-week, double-blind, placebo-controlled portion of the phase III TENDER trial. The anti–interleukin-6 receptor antibody already is approved for use in the treatment of adults with rheumatoid arthritis.

Of 112 children with systemic JIA who are enrolled in the ongoing multinational trial, the 75 who were randomized to receive tocilizumab treatment were significantly more likely than the 37 who received placebo to experience JIA ACR 30 (defined as a 30% improvement in signs and symptoms of disease, according to criteria of the American College of Rheumatology) and to be free of fever at 12 weeks; 85% vs. 20% of patients in the treatment and placebo groups, respectively, achieved JIA ACR 30, according to Dr. Fabrizio De Benedetti said at the annual scientific meeting of the American College of Rheumatology.

Additionally, significantly more of the treatment group patients, compared with controls, achieved JIA ACR 50, ACR 70, and ACR 90 responses (85% vs. 11%, 71% vs. 8%, and 37% vs. 5%, respectively), said Dr. De Benedetti, who is director of the division of rheumatology at Ospedale Pediatrico Bambino Gesù in Rome.

In separate analyses, patients in the active-treatment group who had fever, anemia, or thrombocytosis at baseline were significantly more likely than controls with those conditions at baseline to have normal temperature, normal hemoglobin levels, and normal platelet counts at 12 weeks, he noted.

A post hoc analysis demonstrated that the findings of significant improvement with treatment vs. placebo persisted irrespective of baseline characteristics including active joint count and prior biologic-treatment use. For example, ACR 30 plus absence of fever was achieved by 90% of treated patients with 0-9 active joints, 82% of those with 10-29 active joints, and 80% of those with 30-71 active joints, Dr. De Benedetti said.

Study participants are children aged 2-17 years with active systemic JIA of at least 6 months’ duration and with inadequate response to previous NSAIDS and corticosteroids. They were randomly assigned to receive placebo or tocilizumab infusion every 2 weeks. Those who weighed at least 30 kg received 8 mg/kg, and those who weighed less than 30 kg received 12 mg/kg; dosing was based on models developed from prior studies.

Treatment was generally safe; four serious adverse events occurred, including urticaria and angioedema in one patient, varicella in one patient, and bacterial arthritis in one patient. All resolved without sequelae, he said.

The findings of this portion of the TENDER trial confirm those from two smaller trials of tocilizumab in children, including a Japanese phase III, placebo-controlled trial, he noted.

“Tocilizumab appears to be highly effective in the short-term treatment of systemic JIA; it improves systemic and laboratory features of the disease, and there were no differences based on baseline disease characteristics or by prior use of biologic treatment,” Dr. De Benedetti said, adding that no new tocilizumab safety signals, compared with what is known in adults, emerged in this study.

“Obviously, we are waiting for the long-term analysis from the long-term extension part of the study,” he said.

A 5-year open-label extension phase is currently underway.

The TENDER trial is sponsored by Roche, the maker of tocilizumab (Actemra). Dr. De Benedetti disclosed that he has received consulting fees or other payment from Bristol-Myers Squibb Co., Hoffmann-La Roche, and Pfizer Inc. He also has received research grants from Hoffmann-La Roche.

ATLANTA – Tocilizumab was highly effective for the treatment of systemic juvenile idiopathic arthritis, according to findings from the 12-week, double-blind, placebo-controlled portion of the phase III TENDER trial. The anti–interleukin-6 receptor antibody already is approved for use in the treatment of adults with rheumatoid arthritis.

Of 112 children with systemic JIA who are enrolled in the ongoing multinational trial, the 75 who were randomized to receive tocilizumab treatment were significantly more likely than the 37 who received placebo to experience JIA ACR 30 (defined as a 30% improvement in signs and symptoms of disease, according to criteria of the American College of Rheumatology) and to be free of fever at 12 weeks; 85% vs. 20% of patients in the treatment and placebo groups, respectively, achieved JIA ACR 30, according to Dr. Fabrizio De Benedetti said at the annual scientific meeting of the American College of Rheumatology.

Additionally, significantly more of the treatment group patients, compared with controls, achieved JIA ACR 50, ACR 70, and ACR 90 responses (85% vs. 11%, 71% vs. 8%, and 37% vs. 5%, respectively), said Dr. De Benedetti, who is director of the division of rheumatology at Ospedale Pediatrico Bambino Gesù in Rome.

In separate analyses, patients in the active-treatment group who had fever, anemia, or thrombocytosis at baseline were significantly more likely than controls with those conditions at baseline to have normal temperature, normal hemoglobin levels, and normal platelet counts at 12 weeks, he noted.

A post hoc analysis demonstrated that the findings of significant improvement with treatment vs. placebo persisted irrespective of baseline characteristics including active joint count and prior biologic-treatment use. For example, ACR 30 plus absence of fever was achieved by 90% of treated patients with 0-9 active joints, 82% of those with 10-29 active joints, and 80% of those with 30-71 active joints, Dr. De Benedetti said.

Study participants are children aged 2-17 years with active systemic JIA of at least 6 months’ duration and with inadequate response to previous NSAIDS and corticosteroids. They were randomly assigned to receive placebo or tocilizumab infusion every 2 weeks. Those who weighed at least 30 kg received 8 mg/kg, and those who weighed less than 30 kg received 12 mg/kg; dosing was based on models developed from prior studies.

Treatment was generally safe; four serious adverse events occurred, including urticaria and angioedema in one patient, varicella in one patient, and bacterial arthritis in one patient. All resolved without sequelae, he said.

The findings of this portion of the TENDER trial confirm those from two smaller trials of tocilizumab in children, including a Japanese phase III, placebo-controlled trial, he noted.

“Tocilizumab appears to be highly effective in the short-term treatment of systemic JIA; it improves systemic and laboratory features of the disease, and there were no differences based on baseline disease characteristics or by prior use of biologic treatment,” Dr. De Benedetti said, adding that no new tocilizumab safety signals, compared with what is known in adults, emerged in this study.

“Obviously, we are waiting for the long-term analysis from the long-term extension part of the study,” he said.

A 5-year open-label extension phase is currently underway.

The TENDER trial is sponsored by Roche, the maker of tocilizumab (Actemra). Dr. De Benedetti disclosed that he has received consulting fees or other payment from Bristol-Myers Squibb Co., Hoffmann-La Roche, and Pfizer Inc. He also has received research grants from Hoffmann-La Roche.

ATLANTA – Tocilizumab was highly effective for the treatment of systemic juvenile idiopathic arthritis, according to findings from the 12-week, double-blind, placebo-controlled portion of the phase III TENDER trial. The anti–interleukin-6 receptor antibody already is approved for use in the treatment of adults with rheumatoid arthritis.

Of 112 children with systemic JIA who are enrolled in the ongoing multinational trial, the 75 who were randomized to receive tocilizumab treatment were significantly more likely than the 37 who received placebo to experience JIA ACR 30 (defined as a 30% improvement in signs and symptoms of disease, according to criteria of the American College of Rheumatology) and to be free of fever at 12 weeks; 85% vs. 20% of patients in the treatment and placebo groups, respectively, achieved JIA ACR 30, according to Dr. Fabrizio De Benedetti said at the annual scientific meeting of the American College of Rheumatology.

Additionally, significantly more of the treatment group patients, compared with controls, achieved JIA ACR 50, ACR 70, and ACR 90 responses (85% vs. 11%, 71% vs. 8%, and 37% vs. 5%, respectively), said Dr. De Benedetti, who is director of the division of rheumatology at Ospedale Pediatrico Bambino Gesù in Rome.

In separate analyses, patients in the active-treatment group who had fever, anemia, or thrombocytosis at baseline were significantly more likely than controls with those conditions at baseline to have normal temperature, normal hemoglobin levels, and normal platelet counts at 12 weeks, he noted.

A post hoc analysis demonstrated that the findings of significant improvement with treatment vs. placebo persisted irrespective of baseline characteristics including active joint count and prior biologic-treatment use. For example, ACR 30 plus absence of fever was achieved by 90% of treated patients with 0-9 active joints, 82% of those with 10-29 active joints, and 80% of those with 30-71 active joints, Dr. De Benedetti said.

Study participants are children aged 2-17 years with active systemic JIA of at least 6 months’ duration and with inadequate response to previous NSAIDS and corticosteroids. They were randomly assigned to receive placebo or tocilizumab infusion every 2 weeks. Those who weighed at least 30 kg received 8 mg/kg, and those who weighed less than 30 kg received 12 mg/kg; dosing was based on models developed from prior studies.

Treatment was generally safe; four serious adverse events occurred, including urticaria and angioedema in one patient, varicella in one patient, and bacterial arthritis in one patient. All resolved without sequelae, he said.

The findings of this portion of the TENDER trial confirm those from two smaller trials of tocilizumab in children, including a Japanese phase III, placebo-controlled trial, he noted.

“Tocilizumab appears to be highly effective in the short-term treatment of systemic JIA; it improves systemic and laboratory features of the disease, and there were no differences based on baseline disease characteristics or by prior use of biologic treatment,” Dr. De Benedetti said, adding that no new tocilizumab safety signals, compared with what is known in adults, emerged in this study.

“Obviously, we are waiting for the long-term analysis from the long-term extension part of the study,” he said.

A 5-year open-label extension phase is currently underway.

The TENDER trial is sponsored by Roche, the maker of tocilizumab (Actemra). Dr. De Benedetti disclosed that he has received consulting fees or other payment from Bristol-Myers Squibb Co., Hoffmann-La Roche, and Pfizer Inc. He also has received research grants from Hoffmann-La Roche.

Major Finding: After 6 months of treatment, the mean reduction in disease activity score using 28 joint counts (DAS28) was lower in 23 of 187 RA patients who were treated with both statins and rituximab (RTX) than in 164 patients treated with RTX alone (mean reduction of 0.5 vs. 1.0 point).

Data Source: A prospective cohort study involving 187 patients from the DREAM registry.

Disclosures: The DREAM registry is funded by the Dutch affiliations of Wyeth Pharmaceuticals, Abbott Laboratories, Schering-Plough, Roche Pharmaceuticals, UCB Pharma, and Bristol-Myers Squibb.

Statins can inhibit the beneficial effects of rituximab on disease activity in rheumatoid arthritis patients, according to the findings of a study of 187 patients from the Dutch Rheumatoid Arthritis Monitoring registry.

After 6 months of treatment, the mean reduction in disease activity score using 28 joint counts (DAS28) was lower in 23 of 187 RA patients who were treated with both statins and rituximab (RTX) than in 164 patients treated with RTX alone (mean reduction of 0.5 vs. 1.0 point). The difference was of borderline statistical significance after adjustment for age, sex, baseline DAS28 score, and rheumatoid factor positivity, Dr. E.E.A. Arts of Radboud University Nijmegen (the Netherlands) Medical Center and colleagues reported.

Compared with the RTX-only patients, those exposed to statins also had a shorter effective period following RTX treatment (median of 7 months vs. 9 months), and were more likely to experience a failure event (hazard ratio, 2.3), after adjustment for the same confounders, the investigators said (Ann. Rheum. Dis. 2010 Oct. 18 [doi:10.1136/ard.2010.136093]).

All patients in the DREAM registry were included in the prospective cohort study, and all received 50 mg of prednisone with the first RTX infusion. Patients in both the RTX plus statin and the RTX-only groups had similar DAS28 scores at baseline.

The statin group was older (mean age, 66 vs. 58 years) and included a greater proportion of men than the RTX-only group (48% vs. 20%), but the groups were otherwise similar.

Although the study had a small sample size, it was sufficiently powered and showed a clinically relevant difference in DAS28 score changes over the 6-month study period, the investigators noted, adding that lack of randomization was another limitation of little concern, because “confounding by indication is unlikely.”

More studies to replicate these findings and measure the magnitude of the effect are needed, they said.

“Significant interactions of statins with RTX in RA have not previously been shown. A critical review of common practice regarding concomitant use of statins in RTX-treated patients with RA is needed,” they concluded.

Major Finding: After 6 months of treatment, the mean reduction in disease activity score using 28 joint counts (DAS28) was lower in 23 of 187 RA patients who were treated with both statins and rituximab (RTX) than in 164 patients treated with RTX alone (mean reduction of 0.5 vs. 1.0 point).

Data Source: A prospective cohort study involving 187 patients from the DREAM registry.

Disclosures: The DREAM registry is funded by the Dutch affiliations of Wyeth Pharmaceuticals, Abbott Laboratories, Schering-Plough, Roche Pharmaceuticals, UCB Pharma, and Bristol-Myers Squibb.

Statins can inhibit the beneficial effects of rituximab on disease activity in rheumatoid arthritis patients, according to the findings of a study of 187 patients from the Dutch Rheumatoid Arthritis Monitoring registry.

After 6 months of treatment, the mean reduction in disease activity score using 28 joint counts (DAS28) was lower in 23 of 187 RA patients who were treated with both statins and rituximab (RTX) than in 164 patients treated with RTX alone (mean reduction of 0.5 vs. 1.0 point). The difference was of borderline statistical significance after adjustment for age, sex, baseline DAS28 score, and rheumatoid factor positivity, Dr. E.E.A. Arts of Radboud University Nijmegen (the Netherlands) Medical Center and colleagues reported.

Compared with the RTX-only patients, those exposed to statins also had a shorter effective period following RTX treatment (median of 7 months vs. 9 months), and were more likely to experience a failure event (hazard ratio, 2.3), after adjustment for the same confounders, the investigators said (Ann. Rheum. Dis. 2010 Oct. 18 [doi:10.1136/ard.2010.136093]).

All patients in the DREAM registry were included in the prospective cohort study, and all received 50 mg of prednisone with the first RTX infusion. Patients in both the RTX plus statin and the RTX-only groups had similar DAS28 scores at baseline.

The statin group was older (mean age, 66 vs. 58 years) and included a greater proportion of men than the RTX-only group (48% vs. 20%), but the groups were otherwise similar.

Although the study had a small sample size, it was sufficiently powered and showed a clinically relevant difference in DAS28 score changes over the 6-month study period, the investigators noted, adding that lack of randomization was another limitation of little concern, because “confounding by indication is unlikely.”

More studies to replicate these findings and measure the magnitude of the effect are needed, they said.

“Significant interactions of statins with RTX in RA have not previously been shown. A critical review of common practice regarding concomitant use of statins in RTX-treated patients with RA is needed,” they concluded.

Major Finding: After 6 months of treatment, the mean reduction in disease activity score using 28 joint counts (DAS28) was lower in 23 of 187 RA patients who were treated with both statins and rituximab (RTX) than in 164 patients treated with RTX alone (mean reduction of 0.5 vs. 1.0 point).

Data Source: A prospective cohort study involving 187 patients from the DREAM registry.

Disclosures: The DREAM registry is funded by the Dutch affiliations of Wyeth Pharmaceuticals, Abbott Laboratories, Schering-Plough, Roche Pharmaceuticals, UCB Pharma, and Bristol-Myers Squibb.

Statins can inhibit the beneficial effects of rituximab on disease activity in rheumatoid arthritis patients, according to the findings of a study of 187 patients from the Dutch Rheumatoid Arthritis Monitoring registry.

After 6 months of treatment, the mean reduction in disease activity score using 28 joint counts (DAS28) was lower in 23 of 187 RA patients who were treated with both statins and rituximab (RTX) than in 164 patients treated with RTX alone (mean reduction of 0.5 vs. 1.0 point). The difference was of borderline statistical significance after adjustment for age, sex, baseline DAS28 score, and rheumatoid factor positivity, Dr. E.E.A. Arts of Radboud University Nijmegen (the Netherlands) Medical Center and colleagues reported.

Compared with the RTX-only patients, those exposed to statins also had a shorter effective period following RTX treatment (median of 7 months vs. 9 months), and were more likely to experience a failure event (hazard ratio, 2.3), after adjustment for the same confounders, the investigators said (Ann. Rheum. Dis. 2010 Oct. 18 [doi:10.1136/ard.2010.136093]).

All patients in the DREAM registry were included in the prospective cohort study, and all received 50 mg of prednisone with the first RTX infusion. Patients in both the RTX plus statin and the RTX-only groups had similar DAS28 scores at baseline.

The statin group was older (mean age, 66 vs. 58 years) and included a greater proportion of men than the RTX-only group (48% vs. 20%), but the groups were otherwise similar.

Although the study had a small sample size, it was sufficiently powered and showed a clinically relevant difference in DAS28 score changes over the 6-month study period, the investigators noted, adding that lack of randomization was another limitation of little concern, because “confounding by indication is unlikely.”

More studies to replicate these findings and measure the magnitude of the effect are needed, they said.

“Significant interactions of statins with RTX in RA have not previously been shown. A critical review of common practice regarding concomitant use of statins in RTX-treated patients with RA is needed,” they concluded.

The recent headway of two treatments for addiction to heroin and other opiates represents a major advancement and has the potential to put opioid addiction therapy within the purview of primary care providers, according to several experts.

The approval in October of a new indication for an injectable, extended-release formulation of the opioid receptor antagonist naltrexone, marketed as Vivitrol (Alkermes Inc.), now allows for its use as a treatment for preventing relapses in people who have undergone opioid detoxification. Moreover, an implantable form of the opiate agonist buprenorphine, that delivers a continuous dose of medication for up to 6 months, showed promise in a recently published phase III study.

Both advances have the potential for broadening access to care and improving treatment compliance, according to Dr. Nora D. Volkow, a psychiatrist and the director of the National Institute on Drug Abuse (NIDA).

Ultimately, the treatment options could help improve outcomes for the more than 800,000 people in the United States who are believed to be addicted to heroin, and the 1.85 million who abuse or are dependent on opioid pain relievers, such as Oxycontin and Vicodin, Dr. Volkow said in an interview.

Dr. Volkow said that she envisions an expanded role not just for psychiatrists and addiction medicine specialists, who have traditionally managed opioid-dependent patients, but also for primary care doctors and infectious disease specialists who could provide integrated care for heroin-addicted HIV patients.

Physicians Can Improve Tx Access

Access to care for all people with opioid dependence would be improved if more physicians adopt these new treatment options. Compliance also would improve, largely because both treatments involve extended dosing, Dr. Volkow pointed out.

Older treatment options such as methadone and daily sublingual buprenorphine can be effective, particularly when combined with counseling. However, they require more frequent dosing, a daunting hurdle for patients whose ability to be compliant is easily derailed by the forces of craving and the risk of relapse.

Furthermore, diversion is an issue with sublingual buprenorphine. And many treatment centers reject the idea of using opiates, even synthetic ones, to treat opioid addiction.

Vivitrol, which was approved in 2006 for the treatment of alcohol dependence, is the first non-narcotic, nonaddictive extended-release medication approved to treat opioid dependence. In a 6-month study of 250 patients, monthly intramuscular injection with the drug proved significantly more effective than placebo for preventing relapses: 36% of treated patients, compared with 23% of those on placebo, used no opioids between the 5th week and the end of the study, according to a statement released by the Food and Drug Administration following its approval of this new indication.

Importantly, all patients in the trial were completing or had recently completed detoxification and were no longer physically dependent on opioids at baseline.

Despite concerns that patients would not return for repeat injections, Dr. Volkow said she was particularly encouraged to learn that patients did return routinely in the Russian studies on which the new Vivitrol approval was based. “Patients were very compliant, which was not necessarily predictable,” she said. “That made me very excited about this particular medication.”

NIDA is funding a study to replicate and expand upon the Russian studies, to verify that U.S. patients would respond similarly. Investigators also plan to compare outcomes associated with Vivitrol vs. buprenorphine, she said.

In a phase III, randomized controlled study of 108 opioid addicts, implantable buprenorphine was associated with a 6-month significant reduction in drug use among 40% of patients, compared with 20% of those taking placebo.

About 60% of the treated participants completed the study without experiencing withdrawal symptoms or cravings that compelled them to drop out. By comparison, studies of the daily sublingual dose of buprenorphine currently available for use showed a median adherence of only 40 days in clinical settings, and retention rates in 6-month clinical trials were only 35%-38% (JAMA 2010;14:1576-83).

Dr. Volkow said that she hopes implantable buprenorphine will soon become part of the arsenal of weapons against the crippling effects of opioid addiction.

But will more primary care physicians and other specialists start to provide addiction care?

“It's going to be very interesting to watch,” said Dr. Peter D. Friedmann, professor of medicine and community health at Brown University, Providence, R.I.

“Traditionally, primary care doctors have not been very proactive in taking on the care of these patients,” he said.

However, he suggested that opioid dependence could be the new depression. That is, until the advent of relatively safe and easy-to-use depression medications in the early 1980s, the care of depressed patients was not seen as the purview of primary care doctors, but now they are routinely treating depression in their practices.

Will Opioid Dependence Become The New Depression?

It remains unclear whether that will be the case now, however, given that Vivitrol has been available for years for the treatment of alcohol abuse and primary care doctors have not exactly “flocked to take that on,” he said.

These are complicated patients who at times are difficult to manage, and there is still a lot of stigma and unease among doctors about how to care for them, he explained.

“It's clearly a positive for the field. It's going to improve things, but is it going to be a panacea? I doubt it,” he said, adding: “I'm cautiously optimistic.”

Dr. Thomas Kosten, former director of the U.S. National Buprenorphine Implementation Program and currently a professor in the psychiatry and neuroscience departments at Baylor College of Medicine, Houston, also expressed cautious optimism about expanded access to care for opioid-dependent patients.

“I can't imagine psychiatrists performing the minor surgical procedure involved with buprenorphine implants, but it is certainly within the purview of many internists and general practitioners,” he said, noting that in many cases in primary care, the machinery is already set up for providing such office procedures, and – in the case of Vivitrol – for providing injections.

“In fact, they would be more comfortable and better equipped to do this,” said Dr. Kosten, who also is research director of the Veterans Health Administration's National Substance Use Disorders Quality Enhancement Research Initiative, based in Houston.

A challenge might be in ensuring that patients receive counseling as needed, but research is increasingly indicating that patients can do well on medications alone if they remain compliant, so concern may be moot, he added.

Another deterrent for many providers has been the requirement of government-sponsored training and oversight of physicians who wish to prescribe buprenorphine.

Dr. H. Berryman Edwards, a psychiatrist in private practice in Bellevue, Wash., and an outspoken critic of the U.S. Drug Enforcement Administration's “disruptive” approach to the oversight of physicians who do prescribe buprenorphine, agreed that psychiatrists aren't likely to use the implantable formulation.

But he acknowledged that for primary care doctors and others who embrace this new formulation, it eliminates many of the concerns about diversion and compliance that have deterred physicians from using the treatment in the past.

It will take a certain level of commitment from those who have a desire to use these treatments in the primary care office setting, said Dr. Andrew J. Saxon, a professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and one of the site investigators for the implantable buprenorphine study.

While most primary care doctors probably won't have an interest, those who are willing to learn the implantation procedure – which can be a bit time consuming – and who undergo the required training, will certainly be able to provide this treatment in the office setting.

In some cases, it may be that the implants are done elsewhere but patients are followed by their primary care physician, he said.

Vivitrol's Primary Care Promise

Vivitrol, on the other hand, could quite easily be provided in the primary care setting. He described Vivitrol as “a pharmacological treatment that is almost perfection,” largely because of the requirement that patients be off opioids before they can receive it.

Vivitrol is safe, he said, with one exception: Patients receiving it will have a decreased tolerance for opioids, and may be at an increased risk of overdose.

The overdose risk must be closely monitored, but overall, the treatment has the potential to be a tremendous advantage, Dr. Saxon said.

Dr. Volkow and Dr. Edwards reported having no conflicts of interest. Dr. Friedmann has studied Vivitrol and has received in-kind donations of the medication for his research. He is on the speakers bureau for Reckitt Benckiser Pharmaceuticals, the maker of the sublingual formulation of buprenorphine. Dr. Kosten has served as a consultant to Reckitt Benckiser and to Alkermes. He has served on the data safety monitoring board for Titan Pharmaceuticals, which makes the implantable buprenorphine. Dr. Saxon has served as a consultant to Reckitt Benckiser, and was a site investigator for the Titan-sponsored buprenorphine implant study.

Patients were “very compliant. … That made me very excited about this particular medication,” Dr. Nora D. Volkow said.

Source Courtesy National Institute on Drug Abuse (NIDA)

The recent headway of two treatments for addiction to heroin and other opiates represents a major advancement and has the potential to put opioid addiction therapy within the purview of primary care providers, according to several experts.

The approval in October of a new indication for an injectable, extended-release formulation of the opioid receptor antagonist naltrexone, marketed as Vivitrol (Alkermes Inc.), now allows for its use as a treatment for preventing relapses in people who have undergone opioid detoxification. Moreover, an implantable form of the opiate agonist buprenorphine, that delivers a continuous dose of medication for up to 6 months, showed promise in a recently published phase III study.

Both advances have the potential for broadening access to care and improving treatment compliance, according to Dr. Nora D. Volkow, a psychiatrist and the director of the National Institute on Drug Abuse (NIDA).

Ultimately, the treatment options could help improve outcomes for the more than 800,000 people in the United States who are believed to be addicted to heroin, and the 1.85 million who abuse or are dependent on opioid pain relievers, such as Oxycontin and Vicodin, Dr. Volkow said in an interview.

Dr. Volkow said that she envisions an expanded role not just for psychiatrists and addiction medicine specialists, who have traditionally managed opioid-dependent patients, but also for primary care doctors and infectious disease specialists who could provide integrated care for heroin-addicted HIV patients.

Physicians Can Improve Tx Access

Access to care for all people with opioid dependence would be improved if more physicians adopt these new treatment options. Compliance also would improve, largely because both treatments involve extended dosing, Dr. Volkow pointed out.

Older treatment options such as methadone and daily sublingual buprenorphine can be effective, particularly when combined with counseling. However, they require more frequent dosing, a daunting hurdle for patients whose ability to be compliant is easily derailed by the forces of craving and the risk of relapse.

Furthermore, diversion is an issue with sublingual buprenorphine. And many treatment centers reject the idea of using opiates, even synthetic ones, to treat opioid addiction.

Vivitrol, which was approved in 2006 for the treatment of alcohol dependence, is the first non-narcotic, nonaddictive extended-release medication approved to treat opioid dependence. In a 6-month study of 250 patients, monthly intramuscular injection with the drug proved significantly more effective than placebo for preventing relapses: 36% of treated patients, compared with 23% of those on placebo, used no opioids between the 5th week and the end of the study, according to a statement released by the Food and Drug Administration following its approval of this new indication.

Importantly, all patients in the trial were completing or had recently completed detoxification and were no longer physically dependent on opioids at baseline.

Despite concerns that patients would not return for repeat injections, Dr. Volkow said she was particularly encouraged to learn that patients did return routinely in the Russian studies on which the new Vivitrol approval was based. “Patients were very compliant, which was not necessarily predictable,” she said. “That made me very excited about this particular medication.”

NIDA is funding a study to replicate and expand upon the Russian studies, to verify that U.S. patients would respond similarly. Investigators also plan to compare outcomes associated with Vivitrol vs. buprenorphine, she said.

In a phase III, randomized controlled study of 108 opioid addicts, implantable buprenorphine was associated with a 6-month significant reduction in drug use among 40% of patients, compared with 20% of those taking placebo.

About 60% of the treated participants completed the study without experiencing withdrawal symptoms or cravings that compelled them to drop out. By comparison, studies of the daily sublingual dose of buprenorphine currently available for use showed a median adherence of only 40 days in clinical settings, and retention rates in 6-month clinical trials were only 35%-38% (JAMA 2010;14:1576-83).

Dr. Volkow said that she hopes implantable buprenorphine will soon become part of the arsenal of weapons against the crippling effects of opioid addiction.

But will more primary care physicians and other specialists start to provide addiction care?

“It's going to be very interesting to watch,” said Dr. Peter D. Friedmann, professor of medicine and community health at Brown University, Providence, R.I.

“Traditionally, primary care doctors have not been very proactive in taking on the care of these patients,” he said.

However, he suggested that opioid dependence could be the new depression. That is, until the advent of relatively safe and easy-to-use depression medications in the early 1980s, the care of depressed patients was not seen as the purview of primary care doctors, but now they are routinely treating depression in their practices.

Will Opioid Dependence Become The New Depression?

It remains unclear whether that will be the case now, however, given that Vivitrol has been available for years for the treatment of alcohol abuse and primary care doctors have not exactly “flocked to take that on,” he said.

These are complicated patients who at times are difficult to manage, and there is still a lot of stigma and unease among doctors about how to care for them, he explained.

“It's clearly a positive for the field. It's going to improve things, but is it going to be a panacea? I doubt it,” he said, adding: “I'm cautiously optimistic.”

Dr. Thomas Kosten, former director of the U.S. National Buprenorphine Implementation Program and currently a professor in the psychiatry and neuroscience departments at Baylor College of Medicine, Houston, also expressed cautious optimism about expanded access to care for opioid-dependent patients.

“I can't imagine psychiatrists performing the minor surgical procedure involved with buprenorphine implants, but it is certainly within the purview of many internists and general practitioners,” he said, noting that in many cases in primary care, the machinery is already set up for providing such office procedures, and – in the case of Vivitrol – for providing injections.

“In fact, they would be more comfortable and better equipped to do this,” said Dr. Kosten, who also is research director of the Veterans Health Administration's National Substance Use Disorders Quality Enhancement Research Initiative, based in Houston.

A challenge might be in ensuring that patients receive counseling as needed, but research is increasingly indicating that patients can do well on medications alone if they remain compliant, so concern may be moot, he added.

Another deterrent for many providers has been the requirement of government-sponsored training and oversight of physicians who wish to prescribe buprenorphine.

Dr. H. Berryman Edwards, a psychiatrist in private practice in Bellevue, Wash., and an outspoken critic of the U.S. Drug Enforcement Administration's “disruptive” approach to the oversight of physicians who do prescribe buprenorphine, agreed that psychiatrists aren't likely to use the implantable formulation.

But he acknowledged that for primary care doctors and others who embrace this new formulation, it eliminates many of the concerns about diversion and compliance that have deterred physicians from using the treatment in the past.

It will take a certain level of commitment from those who have a desire to use these treatments in the primary care office setting, said Dr. Andrew J. Saxon, a professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and one of the site investigators for the implantable buprenorphine study.

While most primary care doctors probably won't have an interest, those who are willing to learn the implantation procedure – which can be a bit time consuming – and who undergo the required training, will certainly be able to provide this treatment in the office setting.

In some cases, it may be that the implants are done elsewhere but patients are followed by their primary care physician, he said.

Vivitrol's Primary Care Promise

Vivitrol, on the other hand, could quite easily be provided in the primary care setting. He described Vivitrol as “a pharmacological treatment that is almost perfection,” largely because of the requirement that patients be off opioids before they can receive it.

Vivitrol is safe, he said, with one exception: Patients receiving it will have a decreased tolerance for opioids, and may be at an increased risk of overdose.

The overdose risk must be closely monitored, but overall, the treatment has the potential to be a tremendous advantage, Dr. Saxon said.

Dr. Volkow and Dr. Edwards reported having no conflicts of interest. Dr. Friedmann has studied Vivitrol and has received in-kind donations of the medication for his research. He is on the speakers bureau for Reckitt Benckiser Pharmaceuticals, the maker of the sublingual formulation of buprenorphine. Dr. Kosten has served as a consultant to Reckitt Benckiser and to Alkermes. He has served on the data safety monitoring board for Titan Pharmaceuticals, which makes the implantable buprenorphine. Dr. Saxon has served as a consultant to Reckitt Benckiser, and was a site investigator for the Titan-sponsored buprenorphine implant study.

Patients were “very compliant. … That made me very excited about this particular medication,” Dr. Nora D. Volkow said.

Source Courtesy National Institute on Drug Abuse (NIDA)

The recent headway of two treatments for addiction to heroin and other opiates represents a major advancement and has the potential to put opioid addiction therapy within the purview of primary care providers, according to several experts.

The approval in October of a new indication for an injectable, extended-release formulation of the opioid receptor antagonist naltrexone, marketed as Vivitrol (Alkermes Inc.), now allows for its use as a treatment for preventing relapses in people who have undergone opioid detoxification. Moreover, an implantable form of the opiate agonist buprenorphine, that delivers a continuous dose of medication for up to 6 months, showed promise in a recently published phase III study.

Both advances have the potential for broadening access to care and improving treatment compliance, according to Dr. Nora D. Volkow, a psychiatrist and the director of the National Institute on Drug Abuse (NIDA).

Ultimately, the treatment options could help improve outcomes for the more than 800,000 people in the United States who are believed to be addicted to heroin, and the 1.85 million who abuse or are dependent on opioid pain relievers, such as Oxycontin and Vicodin, Dr. Volkow said in an interview.

Dr. Volkow said that she envisions an expanded role not just for psychiatrists and addiction medicine specialists, who have traditionally managed opioid-dependent patients, but also for primary care doctors and infectious disease specialists who could provide integrated care for heroin-addicted HIV patients.

Physicians Can Improve Tx Access

Access to care for all people with opioid dependence would be improved if more physicians adopt these new treatment options. Compliance also would improve, largely because both treatments involve extended dosing, Dr. Volkow pointed out.

Older treatment options such as methadone and daily sublingual buprenorphine can be effective, particularly when combined with counseling. However, they require more frequent dosing, a daunting hurdle for patients whose ability to be compliant is easily derailed by the forces of craving and the risk of relapse.

Furthermore, diversion is an issue with sublingual buprenorphine. And many treatment centers reject the idea of using opiates, even synthetic ones, to treat opioid addiction.

Vivitrol, which was approved in 2006 for the treatment of alcohol dependence, is the first non-narcotic, nonaddictive extended-release medication approved to treat opioid dependence. In a 6-month study of 250 patients, monthly intramuscular injection with the drug proved significantly more effective than placebo for preventing relapses: 36% of treated patients, compared with 23% of those on placebo, used no opioids between the 5th week and the end of the study, according to a statement released by the Food and Drug Administration following its approval of this new indication.

Importantly, all patients in the trial were completing or had recently completed detoxification and were no longer physically dependent on opioids at baseline.

Despite concerns that patients would not return for repeat injections, Dr. Volkow said she was particularly encouraged to learn that patients did return routinely in the Russian studies on which the new Vivitrol approval was based. “Patients were very compliant, which was not necessarily predictable,” she said. “That made me very excited about this particular medication.”

NIDA is funding a study to replicate and expand upon the Russian studies, to verify that U.S. patients would respond similarly. Investigators also plan to compare outcomes associated with Vivitrol vs. buprenorphine, she said.

In a phase III, randomized controlled study of 108 opioid addicts, implantable buprenorphine was associated with a 6-month significant reduction in drug use among 40% of patients, compared with 20% of those taking placebo.

About 60% of the treated participants completed the study without experiencing withdrawal symptoms or cravings that compelled them to drop out. By comparison, studies of the daily sublingual dose of buprenorphine currently available for use showed a median adherence of only 40 days in clinical settings, and retention rates in 6-month clinical trials were only 35%-38% (JAMA 2010;14:1576-83).

Dr. Volkow said that she hopes implantable buprenorphine will soon become part of the arsenal of weapons against the crippling effects of opioid addiction.

But will more primary care physicians and other specialists start to provide addiction care?

“It's going to be very interesting to watch,” said Dr. Peter D. Friedmann, professor of medicine and community health at Brown University, Providence, R.I.

“Traditionally, primary care doctors have not been very proactive in taking on the care of these patients,” he said.

However, he suggested that opioid dependence could be the new depression. That is, until the advent of relatively safe and easy-to-use depression medications in the early 1980s, the care of depressed patients was not seen as the purview of primary care doctors, but now they are routinely treating depression in their practices.

Will Opioid Dependence Become The New Depression?

It remains unclear whether that will be the case now, however, given that Vivitrol has been available for years for the treatment of alcohol abuse and primary care doctors have not exactly “flocked to take that on,” he said.

These are complicated patients who at times are difficult to manage, and there is still a lot of stigma and unease among doctors about how to care for them, he explained.

“It's clearly a positive for the field. It's going to improve things, but is it going to be a panacea? I doubt it,” he said, adding: “I'm cautiously optimistic.”

Dr. Thomas Kosten, former director of the U.S. National Buprenorphine Implementation Program and currently a professor in the psychiatry and neuroscience departments at Baylor College of Medicine, Houston, also expressed cautious optimism about expanded access to care for opioid-dependent patients.

“I can't imagine psychiatrists performing the minor surgical procedure involved with buprenorphine implants, but it is certainly within the purview of many internists and general practitioners,” he said, noting that in many cases in primary care, the machinery is already set up for providing such office procedures, and – in the case of Vivitrol – for providing injections.

“In fact, they would be more comfortable and better equipped to do this,” said Dr. Kosten, who also is research director of the Veterans Health Administration's National Substance Use Disorders Quality Enhancement Research Initiative, based in Houston.

A challenge might be in ensuring that patients receive counseling as needed, but research is increasingly indicating that patients can do well on medications alone if they remain compliant, so concern may be moot, he added.

Another deterrent for many providers has been the requirement of government-sponsored training and oversight of physicians who wish to prescribe buprenorphine.

Dr. H. Berryman Edwards, a psychiatrist in private practice in Bellevue, Wash., and an outspoken critic of the U.S. Drug Enforcement Administration's “disruptive” approach to the oversight of physicians who do prescribe buprenorphine, agreed that psychiatrists aren't likely to use the implantable formulation.

But he acknowledged that for primary care doctors and others who embrace this new formulation, it eliminates many of the concerns about diversion and compliance that have deterred physicians from using the treatment in the past.

It will take a certain level of commitment from those who have a desire to use these treatments in the primary care office setting, said Dr. Andrew J. Saxon, a professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and one of the site investigators for the implantable buprenorphine study.

While most primary care doctors probably won't have an interest, those who are willing to learn the implantation procedure – which can be a bit time consuming – and who undergo the required training, will certainly be able to provide this treatment in the office setting.

In some cases, it may be that the implants are done elsewhere but patients are followed by their primary care physician, he said.

Vivitrol's Primary Care Promise

Vivitrol, on the other hand, could quite easily be provided in the primary care setting. He described Vivitrol as “a pharmacological treatment that is almost perfection,” largely because of the requirement that patients be off opioids before they can receive it.

Vivitrol is safe, he said, with one exception: Patients receiving it will have a decreased tolerance for opioids, and may be at an increased risk of overdose.

The overdose risk must be closely monitored, but overall, the treatment has the potential to be a tremendous advantage, Dr. Saxon said.

Dr. Volkow and Dr. Edwards reported having no conflicts of interest. Dr. Friedmann has studied Vivitrol and has received in-kind donations of the medication for his research. He is on the speakers bureau for Reckitt Benckiser Pharmaceuticals, the maker of the sublingual formulation of buprenorphine. Dr. Kosten has served as a consultant to Reckitt Benckiser and to Alkermes. He has served on the data safety monitoring board for Titan Pharmaceuticals, which makes the implantable buprenorphine. Dr. Saxon has served as a consultant to Reckitt Benckiser, and was a site investigator for the Titan-sponsored buprenorphine implant study.

Patients were “very compliant. … That made me very excited about this particular medication,” Dr. Nora D. Volkow said.

Source Courtesy National Institute on Drug Abuse (NIDA)

Azelaic acid has been the focus of recent studies for treating rosacea – and the results have been encouraging, according to Dr. Julie C. Harper.

In a study published this year, 15% azelaic acid was shown to modulate the inflammatory response in normal human keratinocytes through peroxisome proliferator–activated receptor (PPAR)–gamma activation (Exp. Dermatol. 2010;19:813-20), said Dr. Harper of the department of dermatology at the University of Alabama at Birmingham.

"Azelaic acid was shown to suppress UVB light–induced interleukin-1 beta, IL-6, and [tumor necrosis factor]–alpha mRNA expression and protein secretion, and it induces PPAR-gamma in RNA; PPAR-gamma suppresses inflammation," she explained, adding that the study suggested this might be a pathway in which azelaic acid exerts its anti-inflammatory effects.

Azelaic acid has also been the focus of several clinical studies, she reported at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In a 12-week, double-blind parallel group study of 72 patients, a 15% gel formulation used once daily was shown to be as effective as the same formulation used twice daily. No significant difference was found between the once- and twice-daily groups in regard to mean investigator global assessment scores, treatment success, treatment response, mean number of inflammatory lesions, or erythema intensity (J. Drugs Dermatol. 2008;7:541-6).

In a randomized, phase IV parallel group study of 207 patients with mild to moderate rosacea, topical azelaic acid 15% gel plus 40 mg oral doxycycline was shown at treatment week 6 to be associated with significantly greater improvement in mean inflammatory lesion count, compared with metronidazole 1% gel plus oral doxycycline (J. Drugs Dermatol. 2010;9:607-13). A greater proportion of patients in the azelaic acid group achieved 25%, 50%, and 75% improvement in mean inflammatory lesion count. However, differences between the groups were not significant at other time points, Dr. Harper noted.

Finally, azelaic acid 15% gel plus oral doxycycline, and azelaic acid maintenance monotherapy, were shown in a two-phase study to provide rapid initial improvement in moderate to severe rosacea, and to maintain remission in 75% of patients, respectively. The first phase was an open-label, multicenter study of topical azelaic acid 15% gel plus oral doxycycline as initial therapy given for up to 12 weeks; the second phase was a multicenter, double-blind, randomized vehicle-controlled phase comparing maintenance azelaic acid gel twice a day versus a vehicle gel for 24 weeks in those who achieved at least a 75% reduction in inflammatory lesions in the first phase (J. Drugs Dermatol. 2009;8:639-48).

"Azelaic acid is a commonly prescribed topical medication for the treatment of rosacea. These new developments give us insight into why this product works so well," Dr. Harper noted. "We are also learning a great deal about the pathogenesis of rosacea and other skin diseases. The more we learn, the more efficiently and effectively we can treat these diseases."

Dr. Harper disclosed that she is a speaker and consultant for Allergan, and a speaker for Coria, Galderma, Intendis, and Stiefel/GlaxoSmithKline. She serves on advisory boards for Coria, Intendis, and Ranbaxy, and is a researcher for Intendis and Medicis. She has also received an honorarium from Ranbaxy.

SDEF and this new organization are owned by Elsevier.

Azelaic acid has been the focus of recent studies for treating rosacea – and the results have been encouraging, according to Dr. Julie C. Harper.

In a study published this year, 15% azelaic acid was shown to modulate the inflammatory response in normal human keratinocytes through peroxisome proliferator–activated receptor (PPAR)–gamma activation (Exp. Dermatol. 2010;19:813-20), said Dr. Harper of the department of dermatology at the University of Alabama at Birmingham.

"Azelaic acid was shown to suppress UVB light–induced interleukin-1 beta, IL-6, and [tumor necrosis factor]–alpha mRNA expression and protein secretion, and it induces PPAR-gamma in RNA; PPAR-gamma suppresses inflammation," she explained, adding that the study suggested this might be a pathway in which azelaic acid exerts its anti-inflammatory effects.

Azelaic acid has also been the focus of several clinical studies, she reported at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In a 12-week, double-blind parallel group study of 72 patients, a 15% gel formulation used once daily was shown to be as effective as the same formulation used twice daily. No significant difference was found between the once- and twice-daily groups in regard to mean investigator global assessment scores, treatment success, treatment response, mean number of inflammatory lesions, or erythema intensity (J. Drugs Dermatol. 2008;7:541-6).

In a randomized, phase IV parallel group study of 207 patients with mild to moderate rosacea, topical azelaic acid 15% gel plus 40 mg oral doxycycline was shown at treatment week 6 to be associated with significantly greater improvement in mean inflammatory lesion count, compared with metronidazole 1% gel plus oral doxycycline (J. Drugs Dermatol. 2010;9:607-13). A greater proportion of patients in the azelaic acid group achieved 25%, 50%, and 75% improvement in mean inflammatory lesion count. However, differences between the groups were not significant at other time points, Dr. Harper noted.

Finally, azelaic acid 15% gel plus oral doxycycline, and azelaic acid maintenance monotherapy, were shown in a two-phase study to provide rapid initial improvement in moderate to severe rosacea, and to maintain remission in 75% of patients, respectively. The first phase was an open-label, multicenter study of topical azelaic acid 15% gel plus oral doxycycline as initial therapy given for up to 12 weeks; the second phase was a multicenter, double-blind, randomized vehicle-controlled phase comparing maintenance azelaic acid gel twice a day versus a vehicle gel for 24 weeks in those who achieved at least a 75% reduction in inflammatory lesions in the first phase (J. Drugs Dermatol. 2009;8:639-48).

"Azelaic acid is a commonly prescribed topical medication for the treatment of rosacea. These new developments give us insight into why this product works so well," Dr. Harper noted. "We are also learning a great deal about the pathogenesis of rosacea and other skin diseases. The more we learn, the more efficiently and effectively we can treat these diseases."

Dr. Harper disclosed that she is a speaker and consultant for Allergan, and a speaker for Coria, Galderma, Intendis, and Stiefel/GlaxoSmithKline. She serves on advisory boards for Coria, Intendis, and Ranbaxy, and is a researcher for Intendis and Medicis. She has also received an honorarium from Ranbaxy.

SDEF and this new organization are owned by Elsevier.

Azelaic acid has been the focus of recent studies for treating rosacea – and the results have been encouraging, according to Dr. Julie C. Harper.

In a study published this year, 15% azelaic acid was shown to modulate the inflammatory response in normal human keratinocytes through peroxisome proliferator–activated receptor (PPAR)–gamma activation (Exp. Dermatol. 2010;19:813-20), said Dr. Harper of the department of dermatology at the University of Alabama at Birmingham.

"Azelaic acid was shown to suppress UVB light–induced interleukin-1 beta, IL-6, and [tumor necrosis factor]–alpha mRNA expression and protein secretion, and it induces PPAR-gamma in RNA; PPAR-gamma suppresses inflammation," she explained, adding that the study suggested this might be a pathway in which azelaic acid exerts its anti-inflammatory effects.

Azelaic acid has also been the focus of several clinical studies, she reported at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In a 12-week, double-blind parallel group study of 72 patients, a 15% gel formulation used once daily was shown to be as effective as the same formulation used twice daily. No significant difference was found between the once- and twice-daily groups in regard to mean investigator global assessment scores, treatment success, treatment response, mean number of inflammatory lesions, or erythema intensity (J. Drugs Dermatol. 2008;7:541-6).

In a randomized, phase IV parallel group study of 207 patients with mild to moderate rosacea, topical azelaic acid 15% gel plus 40 mg oral doxycycline was shown at treatment week 6 to be associated with significantly greater improvement in mean inflammatory lesion count, compared with metronidazole 1% gel plus oral doxycycline (J. Drugs Dermatol. 2010;9:607-13). A greater proportion of patients in the azelaic acid group achieved 25%, 50%, and 75% improvement in mean inflammatory lesion count. However, differences between the groups were not significant at other time points, Dr. Harper noted.

Finally, azelaic acid 15% gel plus oral doxycycline, and azelaic acid maintenance monotherapy, were shown in a two-phase study to provide rapid initial improvement in moderate to severe rosacea, and to maintain remission in 75% of patients, respectively. The first phase was an open-label, multicenter study of topical azelaic acid 15% gel plus oral doxycycline as initial therapy given for up to 12 weeks; the second phase was a multicenter, double-blind, randomized vehicle-controlled phase comparing maintenance azelaic acid gel twice a day versus a vehicle gel for 24 weeks in those who achieved at least a 75% reduction in inflammatory lesions in the first phase (J. Drugs Dermatol. 2009;8:639-48).

"Azelaic acid is a commonly prescribed topical medication for the treatment of rosacea. These new developments give us insight into why this product works so well," Dr. Harper noted. "We are also learning a great deal about the pathogenesis of rosacea and other skin diseases. The more we learn, the more efficiently and effectively we can treat these diseases."

Dr. Harper disclosed that she is a speaker and consultant for Allergan, and a speaker for Coria, Galderma, Intendis, and Stiefel/GlaxoSmithKline. She serves on advisory boards for Coria, Intendis, and Ranbaxy, and is a researcher for Intendis and Medicis. She has also received an honorarium from Ranbaxy.

SDEF and this new organization are owned by Elsevier.

Pigmentary disorders are more than just a cosmetic concern, according to Dr. Susan C. Taylor.

Studies show that disorders such as melasma and post-inflammatory hyperpigmentation (PIH) are particularly common in women with darker skin, and the conditions can have a profound effect on quality of life, Dr. Taylor said at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In one prospective cohort study, 47% of patients with pigmentation disorders said they felt self-conscious about their skin, 33% reported feeling unattractive, and 33% reported putting effort into hiding pigment changes. Nearly 24% said they thought their skin condition affected their activities, and 22% believed others focused on their skin (J. Cosmet. Dermatol. 2008;7:164-8).

"These conditions should be treated aggressively," said Dr. Taylor, founding director of the Skin of Color Center at St. Luke's–Roosevelt Hospital Center in New York. For both melasma and PIH, that means using treatments that decrease melanin formation, block the transfer of melanosomes, minimize inflammation, and nonselectively suppress melanogenesis, or increase melanin removal through desquamation, she said.

Photo credit: @2007 Elsevier Inc.

Dr. Taylor, who also is an assistant clinical professor of dermatology at Columbia University, New York, said topical therapies are not curative, but they can be effective.

For melasma, triple combination therapy with a cream containing hydroquinone (4%), retinoic acid (0.05%), and fluocinolone acetonide (0.01%) has been shown to be quite effective in multiple studies, and is Dr. Taylor’s preferred treatment.

Data from two 8-week randomized trials showed that significantly more patients treated with the triple combination cream experienced complete clearing, compared with patients treated with dyad creams (26% vs. 5%). An extension study showed that 80% of patients treated with, or switched to the triple-combination cream, were completely cleared or nearly cleared at 12 months. Only 2.5% of patients discontinued the study because of treatment-related adverse events (J. Drugs. Dermatol. 2005;4:592-7).

Other options shown to be of benefit for the topical treatment of melasma include 0.1% tretinoin cream or 20% azelaic acid cream, Dr. Taylor said.

Oral therapy with procyanidin plus vitamins A, C, and E also shows promise. In an 8-week randomized, double-blind, placebo-controlled trial in 60 Filipino women, treatment was associated with significant improvements in the left and right malar regions, and was safe and well tolerated (Int. J. Dermatol. 2009;48:896-901). However, additional studies are needed to confirm these results, she noted.

Chemical peeling agents can serve as good adjuncts to other therapies for melasma, particularly in recalcitrant cases. In one study, Dr. Taylor said, the addition of eight glycolic acid peels to topical therapy with azelaic acid and adapalene gel improved outcomes vs. the topical treatments alone. Priming agents such as 2% hydroquinone and 0.025% retinoic acid can boost the effects of such peels (J. Dermatol. 2007;34:25-30).

Finally, an emerging treatment option for melasma appears to be fractional photothermolysis.

In a pilot study, 10 female melasma patients who failed prior treatments received four to six fractional laser treatments at 1-2 week intervals using 1,535 nm and 1,550 nm wavelengths and 6-12 mJ/microthermal zone. Most patients (60%) had 75%-100% clearing, and 30% had less than 25% improvement, Dr. Taylor said (Dermatol. Surg. 2005;31:1645-50).

The investigators used microdermabrasion to improve penetration to the target site, followed by an effective tyrosinase inhibitor to suppress melanocytes and remove melanin from the stratum corneum, she explained, adding that sunscreens and topical vitamin C were also used.

"Fractional resurfacing may hold the key to treatment of dermal melasma," she said. It also appears to be useful in PIH.

A case report of its use in a patient with PIH on the neck that had failed to respond to topical therapies for 2 years showed that after 3 treatments, the patient had near-complete clearing with no post-procedural complications or recurrence at 7-month follow-up. Treatment was with a 1,550 nm wavelength erbium-doped Fraxel SR1500 laser at a fluence of 15 mJ, level of 6, with 8-10 passes (Dermatol. Surg. 2009;35:1844-8), Dr. Taylor said.

She cautioned, however, that using lasers in patients with skin of color can potentially cause PIH.

Other treatment options for PIH include hydroquinones, which remain the gold standard, and retinoids, mequinol, and azelaic acid, she said, noting that all patients with melasma and PIH should be advised to use sunblock, protective clothing, and sunglasses and to avoid ultraviolet exposure when possible.

Dr. Taylor serves on advisory boards for Beiersdorf, Johnson & Johnson, Medicis, and GlaxoSmithKline. She has been an investigator for Johnson & Johnson, Medicis, Merz, and Palomar, and is on the speakers bureau of Medicis and Stiefel. She owns stock in T2 Skincare.

SDEF and this news organization are owned by Elsevier.

Pigmentary disorders are more than just a cosmetic concern, according to Dr. Susan C. Taylor.

Studies show that disorders such as melasma and post-inflammatory hyperpigmentation (PIH) are particularly common in women with darker skin, and the conditions can have a profound effect on quality of life, Dr. Taylor said at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In one prospective cohort study, 47% of patients with pigmentation disorders said they felt self-conscious about their skin, 33% reported feeling unattractive, and 33% reported putting effort into hiding pigment changes. Nearly 24% said they thought their skin condition affected their activities, and 22% believed others focused on their skin (J. Cosmet. Dermatol. 2008;7:164-8).

"These conditions should be treated aggressively," said Dr. Taylor, founding director of the Skin of Color Center at St. Luke's–Roosevelt Hospital Center in New York. For both melasma and PIH, that means using treatments that decrease melanin formation, block the transfer of melanosomes, minimize inflammation, and nonselectively suppress melanogenesis, or increase melanin removal through desquamation, she said.

Photo credit: @2007 Elsevier Inc.

Dr. Taylor, who also is an assistant clinical professor of dermatology at Columbia University, New York, said topical therapies are not curative, but they can be effective.

For melasma, triple combination therapy with a cream containing hydroquinone (4%), retinoic acid (0.05%), and fluocinolone acetonide (0.01%) has been shown to be quite effective in multiple studies, and is Dr. Taylor’s preferred treatment.

Data from two 8-week randomized trials showed that significantly more patients treated with the triple combination cream experienced complete clearing, compared with patients treated with dyad creams (26% vs. 5%). An extension study showed that 80% of patients treated with, or switched to the triple-combination cream, were completely cleared or nearly cleared at 12 months. Only 2.5% of patients discontinued the study because of treatment-related adverse events (J. Drugs. Dermatol. 2005;4:592-7).

Other options shown to be of benefit for the topical treatment of melasma include 0.1% tretinoin cream or 20% azelaic acid cream, Dr. Taylor said.

Oral therapy with procyanidin plus vitamins A, C, and E also shows promise. In an 8-week randomized, double-blind, placebo-controlled trial in 60 Filipino women, treatment was associated with significant improvements in the left and right malar regions, and was safe and well tolerated (Int. J. Dermatol. 2009;48:896-901). However, additional studies are needed to confirm these results, she noted.

Chemical peeling agents can serve as good adjuncts to other therapies for melasma, particularly in recalcitrant cases. In one study, Dr. Taylor said, the addition of eight glycolic acid peels to topical therapy with azelaic acid and adapalene gel improved outcomes vs. the topical treatments alone. Priming agents such as 2% hydroquinone and 0.025% retinoic acid can boost the effects of such peels (J. Dermatol. 2007;34:25-30).

Finally, an emerging treatment option for melasma appears to be fractional photothermolysis.

In a pilot study, 10 female melasma patients who failed prior treatments received four to six fractional laser treatments at 1-2 week intervals using 1,535 nm and 1,550 nm wavelengths and 6-12 mJ/microthermal zone. Most patients (60%) had 75%-100% clearing, and 30% had less than 25% improvement, Dr. Taylor said (Dermatol. Surg. 2005;31:1645-50).

The investigators used microdermabrasion to improve penetration to the target site, followed by an effective tyrosinase inhibitor to suppress melanocytes and remove melanin from the stratum corneum, she explained, adding that sunscreens and topical vitamin C were also used.

"Fractional resurfacing may hold the key to treatment of dermal melasma," she said. It also appears to be useful in PIH.

A case report of its use in a patient with PIH on the neck that had failed to respond to topical therapies for 2 years showed that after 3 treatments, the patient had near-complete clearing with no post-procedural complications or recurrence at 7-month follow-up. Treatment was with a 1,550 nm wavelength erbium-doped Fraxel SR1500 laser at a fluence of 15 mJ, level of 6, with 8-10 passes (Dermatol. Surg. 2009;35:1844-8), Dr. Taylor said.

She cautioned, however, that using lasers in patients with skin of color can potentially cause PIH.

Other treatment options for PIH include hydroquinones, which remain the gold standard, and retinoids, mequinol, and azelaic acid, she said, noting that all patients with melasma and PIH should be advised to use sunblock, protective clothing, and sunglasses and to avoid ultraviolet exposure when possible.

Dr. Taylor serves on advisory boards for Beiersdorf, Johnson & Johnson, Medicis, and GlaxoSmithKline. She has been an investigator for Johnson & Johnson, Medicis, Merz, and Palomar, and is on the speakers bureau of Medicis and Stiefel. She owns stock in T2 Skincare.

SDEF and this news organization are owned by Elsevier.

Pigmentary disorders are more than just a cosmetic concern, according to Dr. Susan C. Taylor.

Studies show that disorders such as melasma and post-inflammatory hyperpigmentation (PIH) are particularly common in women with darker skin, and the conditions can have a profound effect on quality of life, Dr. Taylor said at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In one prospective cohort study, 47% of patients with pigmentation disorders said they felt self-conscious about their skin, 33% reported feeling unattractive, and 33% reported putting effort into hiding pigment changes. Nearly 24% said they thought their skin condition affected their activities, and 22% believed others focused on their skin (J. Cosmet. Dermatol. 2008;7:164-8).

"These conditions should be treated aggressively," said Dr. Taylor, founding director of the Skin of Color Center at St. Luke's–Roosevelt Hospital Center in New York. For both melasma and PIH, that means using treatments that decrease melanin formation, block the transfer of melanosomes, minimize inflammation, and nonselectively suppress melanogenesis, or increase melanin removal through desquamation, she said.

Photo credit: @2007 Elsevier Inc.

Dr. Taylor, who also is an assistant clinical professor of dermatology at Columbia University, New York, said topical therapies are not curative, but they can be effective.

For melasma, triple combination therapy with a cream containing hydroquinone (4%), retinoic acid (0.05%), and fluocinolone acetonide (0.01%) has been shown to be quite effective in multiple studies, and is Dr. Taylor’s preferred treatment.

Data from two 8-week randomized trials showed that significantly more patients treated with the triple combination cream experienced complete clearing, compared with patients treated with dyad creams (26% vs. 5%). An extension study showed that 80% of patients treated with, or switched to the triple-combination cream, were completely cleared or nearly cleared at 12 months. Only 2.5% of patients discontinued the study because of treatment-related adverse events (J. Drugs. Dermatol. 2005;4:592-7).

Other options shown to be of benefit for the topical treatment of melasma include 0.1% tretinoin cream or 20% azelaic acid cream, Dr. Taylor said.

Oral therapy with procyanidin plus vitamins A, C, and E also shows promise. In an 8-week randomized, double-blind, placebo-controlled trial in 60 Filipino women, treatment was associated with significant improvements in the left and right malar regions, and was safe and well tolerated (Int. J. Dermatol. 2009;48:896-901). However, additional studies are needed to confirm these results, she noted.

Chemical peeling agents can serve as good adjuncts to other therapies for melasma, particularly in recalcitrant cases. In one study, Dr. Taylor said, the addition of eight glycolic acid peels to topical therapy with azelaic acid and adapalene gel improved outcomes vs. the topical treatments alone. Priming agents such as 2% hydroquinone and 0.025% retinoic acid can boost the effects of such peels (J. Dermatol. 2007;34:25-30).

Finally, an emerging treatment option for melasma appears to be fractional photothermolysis.

In a pilot study, 10 female melasma patients who failed prior treatments received four to six fractional laser treatments at 1-2 week intervals using 1,535 nm and 1,550 nm wavelengths and 6-12 mJ/microthermal zone. Most patients (60%) had 75%-100% clearing, and 30% had less than 25% improvement, Dr. Taylor said (Dermatol. Surg. 2005;31:1645-50).

The investigators used microdermabrasion to improve penetration to the target site, followed by an effective tyrosinase inhibitor to suppress melanocytes and remove melanin from the stratum corneum, she explained, adding that sunscreens and topical vitamin C were also used.

"Fractional resurfacing may hold the key to treatment of dermal melasma," she said. It also appears to be useful in PIH.

A case report of its use in a patient with PIH on the neck that had failed to respond to topical therapies for 2 years showed that after 3 treatments, the patient had near-complete clearing with no post-procedural complications or recurrence at 7-month follow-up. Treatment was with a 1,550 nm wavelength erbium-doped Fraxel SR1500 laser at a fluence of 15 mJ, level of 6, with 8-10 passes (Dermatol. Surg. 2009;35:1844-8), Dr. Taylor said.

She cautioned, however, that using lasers in patients with skin of color can potentially cause PIH.

Other treatment options for PIH include hydroquinones, which remain the gold standard, and retinoids, mequinol, and azelaic acid, she said, noting that all patients with melasma and PIH should be advised to use sunblock, protective clothing, and sunglasses and to avoid ultraviolet exposure when possible.

Dr. Taylor serves on advisory boards for Beiersdorf, Johnson & Johnson, Medicis, and GlaxoSmithKline. She has been an investigator for Johnson & Johnson, Medicis, Merz, and Palomar, and is on the speakers bureau of Medicis and Stiefel. She owns stock in T2 Skincare.

SDEF and this news organization are owned by Elsevier.

Pigmentary disorders are more than just a cosmetic concern, according to Dr. Susan C. Taylor.

Studies show that disorders such as melasma and post-inflammatory hyperpigmentation (PIH) are particularly common in women with darker skin, and the conditions can have a profound effect on quality of life, Dr. Taylor said at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In one prospective cohort study, 47% of patients with pigmentation disorders said they felt self-conscious about their skin, 33% reported feeling unattractive, and 33% reported putting effort into hiding pigment changes. Nearly 24% said they thought their skin condition affected their activities, and 22% believed others focused on their skin (J. Cosmet. Dermatol. 2008;7:164-8).

"These conditions should be treated aggressively," said Dr. Taylor, founding director of the Skin of Color Center at St. Luke's–Roosevelt Hospital Center in New York. For both melasma and PIH, that means using treatments that decrease melanin formation, block the transfer of melanosomes, minimize inflammation, and nonselectively suppress melanogenesis, or increase melanin removal through desquamation, she said.

Photo credit: @2007 Elsevier Inc.

Dr. Taylor, who also is an assistant clinical professor of dermatology at Columbia University, New York, said topical therapies are not curative, but they can be effective.

For melasma, triple combination therapy with a cream containing hydroquinone (4%), retinoic acid (0.05%), and fluocinolone acetonide (0.01%) has been shown to be quite effective in multiple studies, and is Dr. Taylor’s preferred treatment.

Data from two 8-week randomized trials showed that significantly more patients treated with the triple combination cream experienced complete clearing, compared with patients treated with dyad creams (26% vs. 5%). An extension study showed that 80% of patients treated with, or switched to the triple-combination cream, were completely cleared or nearly cleared at 12 months. Only 2.5% of patients discontinued the study because of treatment-related adverse events (J. Drugs. Dermatol. 2005;4:592-7).

Other options shown to be of benefit for the topical treatment of melasma include 0.1% tretinoin cream or 20% azelaic acid cream, Dr. Taylor said.

Oral therapy with procyanidin plus vitamins A, C, and E also shows promise. In an 8-week randomized, double-blind, placebo-controlled trial in 60 Filipino women, treatment was associated with significant improvements in the left and right malar regions, and was safe and well tolerated (Int. J. Dermatol. 2009;48:896-901). However, additional studies are needed to confirm these results, she noted.

Chemical peeling agents can serve as good adjuncts to other therapies for melasma, particularly in recalcitrant cases. In one study, Dr. Taylor said, the addition of eight glycolic acid peels to topical therapy with azelaic acid and adapalene gel improved outcomes vs. the topical treatments alone. Priming agents such as 2% hydroquinone and 0.025% retinoic acid can boost the effects of such peels (J. Dermatol. 2007;34:25-30).

Finally, an emerging treatment option for melasma appears to be fractional photothermolysis.

In a pilot study, 10 female melasma patients who failed prior treatments received four to six fractional laser treatments at 1-2 week intervals using 1,535 nm and 1,550 nm wavelengths and 6-12 mJ/microthermal zone. Most patients (60%) had 75%-100% clearing, and 30% had less than 25% improvement, Dr. Taylor said (Dermatol. Surg. 2005;31:1645-50).

The investigators used microdermabrasion to improve penetration to the target site, followed by an effective tyrosinase inhibitor to suppress melanocytes and remove melanin from the stratum corneum, she explained, adding that sunscreens and topical vitamin C were also used.

"Fractional resurfacing may hold the key to treatment of dermal melasma," she said. It also appears to be useful in PIH.

A case report of its use in a patient with PIH on the neck that had failed to respond to topical therapies for 2 years showed that after 3 treatments, the patient had near-complete clearing with no post-procedural complications or recurrence at 7-month follow-up. Treatment was with a 1,550 nm wavelength erbium-doped Fraxel SR1500 laser at a fluence of 15 mJ, level of 6, with 8-10 passes (Dermatol. Surg. 2009;35:1844-8), Dr. Taylor said.

She cautioned, however, that using lasers in patients with skin of color can potentially cause PIH.

Other treatment options for PIH include hydroquinones, which remain the gold standard, and retinoids, mequinol, and azelaic acid, she said, noting that all patients with melasma and PIH should be advised to use sunblock, protective clothing, and sunglasses and to avoid ultraviolet exposure when possible.

Dr. Taylor serves on advisory boards for Beiersdorf, Johnson & Johnson, Medicis, and GlaxoSmithKline. She has been an investigator for Johnson & Johnson, Medicis, Merz, and Palomar, and is on the speakers bureau of Medicis and Stiefel. She owns stock in T2 Skincare.

SDEF and this news organization are owned by Elsevier.

Pigmentary disorders are more than just a cosmetic concern, according to Dr. Susan C. Taylor.

Studies show that disorders such as melasma and post-inflammatory hyperpigmentation (PIH) are particularly common in women with darker skin, and the conditions can have a profound effect on quality of life, Dr. Taylor said at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In one prospective cohort study, 47% of patients with pigmentation disorders said they felt self-conscious about their skin, 33% reported feeling unattractive, and 33% reported putting effort into hiding pigment changes. Nearly 24% said they thought their skin condition affected their activities, and 22% believed others focused on their skin (J. Cosmet. Dermatol. 2008;7:164-8).

"These conditions should be treated aggressively," said Dr. Taylor, founding director of the Skin of Color Center at St. Luke's–Roosevelt Hospital Center in New York. For both melasma and PIH, that means using treatments that decrease melanin formation, block the transfer of melanosomes, minimize inflammation, and nonselectively suppress melanogenesis, or increase melanin removal through desquamation, she said.

Photo credit: @2007 Elsevier Inc.

Dr. Taylor, who also is an assistant clinical professor of dermatology at Columbia University, New York, said topical therapies are not curative, but they can be effective.

For melasma, triple combination therapy with a cream containing hydroquinone (4%), retinoic acid (0.05%), and fluocinolone acetonide (0.01%) has been shown to be quite effective in multiple studies, and is Dr. Taylor’s preferred treatment.

Data from two 8-week randomized trials showed that significantly more patients treated with the triple combination cream experienced complete clearing, compared with patients treated with dyad creams (26% vs. 5%). An extension study showed that 80% of patients treated with, or switched to the triple-combination cream, were completely cleared or nearly cleared at 12 months. Only 2.5% of patients discontinued the study because of treatment-related adverse events (J. Drugs. Dermatol. 2005;4:592-7).

Other options shown to be of benefit for the topical treatment of melasma include 0.1% tretinoin cream or 20% azelaic acid cream, Dr. Taylor said.

Oral therapy with procyanidin plus vitamins A, C, and E also shows promise. In an 8-week randomized, double-blind, placebo-controlled trial in 60 Filipino women, treatment was associated with significant improvements in the left and right malar regions, and was safe and well tolerated (Int. J. Dermatol. 2009;48:896-901). However, additional studies are needed to confirm these results, she noted.

Chemical peeling agents can serve as good adjuncts to other therapies for melasma, particularly in recalcitrant cases. In one study, Dr. Taylor said, the addition of eight glycolic acid peels to topical therapy with azelaic acid and adapalene gel improved outcomes vs. the topical treatments alone. Priming agents such as 2% hydroquinone and 0.025% retinoic acid can boost the effects of such peels (J. Dermatol. 2007;34:25-30).

Finally, an emerging treatment option for melasma appears to be fractional photothermolysis.

In a pilot study, 10 female melasma patients who failed prior treatments received four to six fractional laser treatments at 1-2 week intervals using 1,535 nm and 1,550 nm wavelengths and 6-12 mJ/microthermal zone. Most patients (60%) had 75%-100% clearing, and 30% had less than 25% improvement, Dr. Taylor said (Dermatol. Surg. 2005;31:1645-50).

The investigators used microdermabrasion to improve penetration to the target site, followed by an effective tyrosinase inhibitor to suppress melanocytes and remove melanin from the stratum corneum, she explained, adding that sunscreens and topical vitamin C were also used.

"Fractional resurfacing may hold the key to treatment of dermal melasma," she said. It also appears to be useful in PIH.

A case report of its use in a patient with PIH on the neck that had failed to respond to topical therapies for 2 years showed that after 3 treatments, the patient had near-complete clearing with no post-procedural complications or recurrence at 7-month follow-up. Treatment was with a 1,550 nm wavelength erbium-doped Fraxel SR1500 laser at a fluence of 15 mJ, level of 6, with 8-10 passes (Dermatol. Surg. 2009;35:1844-8), Dr. Taylor said.

She cautioned, however, that using lasers in patients with skin of color can potentially cause PIH.

Other treatment options for PIH include hydroquinones, which remain the gold standard, and retinoids, mequinol, and azelaic acid, she said, noting that all patients with melasma and PIH should be advised to use sunblock, protective clothing, and sunglasses and to avoid ultraviolet exposure when possible.

Dr. Taylor serves on advisory boards for Beiersdorf, Johnson & Johnson, Medicis, and GlaxoSmithKline. She has been an investigator for Johnson & Johnson, Medicis, Merz, and Palomar, and is on the speakers bureau of Medicis and Stiefel. She owns stock in T2 Skincare.

SDEF and this news organization are owned by Elsevier.

Pigmentary disorders are more than just a cosmetic concern, according to Dr. Susan C. Taylor.

Studies show that disorders such as melasma and post-inflammatory hyperpigmentation (PIH) are particularly common in women with darker skin, and the conditions can have a profound effect on quality of life, Dr. Taylor said at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

In one prospective cohort study, 47% of patients with pigmentation disorders said they felt self-conscious about their skin, 33% reported feeling unattractive, and 33% reported putting effort into hiding pigment changes. Nearly 24% said they thought their skin condition affected their activities, and 22% believed others focused on their skin (J. Cosmet. Dermatol. 2008;7:164-8).

"These conditions should be treated aggressively," said Dr. Taylor, founding director of the Skin of Color Center at St. Luke's–Roosevelt Hospital Center in New York. For both melasma and PIH, that means using treatments that decrease melanin formation, block the transfer of melanosomes, minimize inflammation, and nonselectively suppress melanogenesis, or increase melanin removal through desquamation, she said.

Photo credit: @2007 Elsevier Inc.

Dr. Taylor, who also is an assistant clinical professor of dermatology at Columbia University, New York, said topical therapies are not curative, but they can be effective.

For melasma, triple combination therapy with a cream containing hydroquinone (4%), retinoic acid (0.05%), and fluocinolone acetonide (0.01%) has been shown to be quite effective in multiple studies, and is Dr. Taylor’s preferred treatment.

Data from two 8-week randomized trials showed that significantly more patients treated with the triple combination cream experienced complete clearing, compared with patients treated with dyad creams (26% vs. 5%). An extension study showed that 80% of patients treated with, or switched to the triple-combination cream, were completely cleared or nearly cleared at 12 months. Only 2.5% of patients discontinued the study because of treatment-related adverse events (J. Drugs. Dermatol. 2005;4:592-7).

Other options shown to be of benefit for the topical treatment of melasma include 0.1% tretinoin cream or 20% azelaic acid cream, Dr. Taylor said.

Oral therapy with procyanidin plus vitamins A, C, and E also shows promise. In an 8-week randomized, double-blind, placebo-controlled trial in 60 Filipino women, treatment was associated with significant improvements in the left and right malar regions, and was safe and well tolerated (Int. J. Dermatol. 2009;48:896-901). However, additional studies are needed to confirm these results, she noted.

Chemical peeling agents can serve as good adjuncts to other therapies for melasma, particularly in recalcitrant cases. In one study, Dr. Taylor said, the addition of eight glycolic acid peels to topical therapy with azelaic acid and adapalene gel improved outcomes vs. the topical treatments alone. Priming agents such as 2% hydroquinone and 0.025% retinoic acid can boost the effects of such peels (J. Dermatol. 2007;34:25-30).

Finally, an emerging treatment option for melasma appears to be fractional photothermolysis.

In a pilot study, 10 female melasma patients who failed prior treatments received four to six fractional laser treatments at 1-2 week intervals using 1,535 nm and 1,550 nm wavelengths and 6-12 mJ/microthermal zone. Most patients (60%) had 75%-100% clearing, and 30% had less than 25% improvement, Dr. Taylor said (Dermatol. Surg. 2005;31:1645-50).

The investigators used microdermabrasion to improve penetration to the target site, followed by an effective tyrosinase inhibitor to suppress melanocytes and remove melanin from the stratum corneum, she explained, adding that sunscreens and topical vitamin C were also used.

"Fractional resurfacing may hold the key to treatment of dermal melasma," she said. It also appears to be useful in PIH.

A case report of its use in a patient with PIH on the neck that had failed to respond to topical therapies for 2 years showed that after 3 treatments, the patient had near-complete clearing with no post-procedural complications or recurrence at 7-month follow-up. Treatment was with a 1,550 nm wavelength erbium-doped Fraxel SR1500 laser at a fluence of 15 mJ, level of 6, with 8-10 passes (Dermatol. Surg. 2009;35:1844-8), Dr. Taylor said.

She cautioned, however, that using lasers in patients with skin of color can potentially cause PIH.

Other treatment options for PIH include hydroquinones, which remain the gold standard, and retinoids, mequinol, and azelaic acid, she said, noting that all patients with melasma and PIH should be advised to use sunblock, protective clothing, and sunglasses and to avoid ultraviolet exposure when possible.

Dr. Taylor serves on advisory boards for Beiersdorf, Johnson & Johnson, Medicis, and GlaxoSmithKline. She has been an investigator for Johnson & Johnson, Medicis, Merz, and Palomar, and is on the speakers bureau of Medicis and Stiefel. She owns stock in T2 Skincare.

SDEF and this news organization are owned by Elsevier.

Selective vitamin D receptor activation with paricalcitol lowers residual albuminuria and could provide renal protection in patients with diabetic nephropathy when added to standard therapies, according the findings of the randomized, controlled VITAL study.

Patients with a high-sodium diet were among those who benefited from the combination of paricalcitol and renin-angiotensin-aldosterone system (RAAS) inhibition therapy, researchers reported online Nov. 4 in the Lancet.

Participants in the multinational, double-blind VITAL study were type 2 diabetes patients who had residual albuminuria – and who thus were at risk of progressive renal failure – despite receiving stable doses of ACE inhibitors or angiotensin receptor blockers (ARBs). They were enrolled between February 2008 and October 2008.

Of 281 patients enrolled in the study and randomized to receive either placebo, 1 mcg, or 2 mcg of paricalcitol for 24 weeks, along with their usual care for diabetes and cardiovascular protection, those in the 2-mcg group had the greatest – and the only statistically significant – percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) at final measurement during treatment, compared with the 1-mcg and placebo groups (–20%, compared with –16% and –3%, respectively). The between-group difference vs. placebo was –18% and –11% for the 2-mcg and 1-mcg groups, respectively, Dr. Dick de Zeeuw of the University of Groningen, the Netherlands, and his colleagues reported.

UACR was reduced significantly by treatment week 4 in the 2-mcg group, and the reduction was sustained during the entire treatment phase, peaking at –28% at week 12. The estimated glomerular filtration rate (eGFR) also decreased substantially by week 4 in the 2-mcg group vs. placebo and remained stable during treatment. An early reduction in systolic blood pressure fluctuated throughout treatment, the investigators found (Lancet 2010[doi:10.1016/S0140-6736(10)61032-X]).

In a post hoc analysis, it was shown that the greatest reduction in UACR was in 29 patients on 2 mcg paricalcitol who had urinary sodium excretion of more than 178 mmol in 24 h.

No serious adverse events deemed to be related to study drug occurred during the course of the study.

"We have shown that 24 weeks’ treatment with 2 mcg paricalcitol daily reduced residual albuminuria in patients with type 2 diabetic nephropathy who were on stable doses of ACE inhibitors or ARBs, particularly in those with high dietary sodium intake," the investigators wrote, adding that the effect on albuminuria, systolic blood pressure, and eGFR all occurred within 4 weeks, and that the reductions in UACR and eGFR were "fairly stable during the treatment phase."

These measurements returned toward baseline after drug withdrawal, indicating that the effects were real and reversible, they said.

The mechanisms of action for paricalcitol for lowering albuminuria appear to be multiple; activation of the vitamin D receptor, which is currently licensed for the prevention and treatment of secondary hyperparathyroidism, intervenes in pathways with well-known associations with renal and vascular progressive disease, they explained.

Additional study to assess the composite end point of doubling of serum creatinine, end stage renal disease, and death is needed for final verification of paricalcitol’s renoprotective effects," they added.

Despite some study limitations, including the use of albuminuria as a surrogate marker of renal disease progression, the lack of measurement of true GFR and ambulatory blood pressure in the study, and fairly small sample size, the findings suggest paricalcitol could be "an important adjunctive treatment providing optimum management to renal osteodystrophy with little hypercalcemia and lowering residual albuminuria.

"Additionally, findings of our study suggest that paricalcitol lowers albuminuria, even when dietary sodium intake is high, which is important because resistance to RAAS intervention occurs in people with high dietary sodium intake and adherence to low sodium diets is desirable but difficult, especially in those with diabetic nephropathy who already have restricted diets," they said.

In an accompanying editorial, Dr. Merlin C. Thomas and Dr. Mark E. Cooper wrote that the findings from the VITAL study add to existing data demonstrating the potential antiproteinuric actions of paricalcitol when added to standard therapies.

They also underscore the fact that patients with diabetes, and particularly those with chronic kidney disease, "in whom the urinary loss of protein-associated vitamin D magnifies reduced activation of vitamin D by the proximal tubule and reduced expression of the vitamin D receptor," have increased rates of vitamin D deficiency. For these patients it "seems rational to replace vitamin D," they wrote (Lancet 2010[doi:10.1016/S0140-6736(10)61301-3]).

Selective analogues that restore vitamin D receptor-signaling without risking hypercalcemia or hyperphosphatemia – as paricalcitol appears to do in the VITAL study – might be of particular benefit, they said, adding that trials in patients with diabetes "should now test whether such analogues can ultimately improve mortality and cardiovascular outcomes, as suggested in studied of patients with end-stage renal disease."

Dr. Thomas and Dr. Cooper are with the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Dr. Thomas is also with Monash University in Melbourne.

The VITAL study was sponsored by Abbott. Dr. de Zeeuw disclosed that he has been a consultant for, and his institution has received honoraria from, Abbott, Amgen, AztraZeneca, Bristol-Myers Squibb, Novartis, Noxxon, Johnson & Johnson, Hemcue, and Merck Sharp & Dohme. Other study authors and/or their institutions have served as board members, consultants, or received honoraria, research, or other funding from Abbott, Watson, Merck, Novartis, AstraZeneca, Amgen, Daiichi Sankyo, and Roche. Five of the authors on the study are employed by Abbott and own stock and have stock options in Abbott.

Dr. Thomas and Dr. Cooper reported having no disclosures.

Selective vitamin D receptor activation with paricalcitol lowers residual albuminuria and could provide renal protection in patients with diabetic nephropathy when added to standard therapies, according the findings of the randomized, controlled VITAL study.

Patients with a high-sodium diet were among those who benefited from the combination of paricalcitol and renin-angiotensin-aldosterone system (RAAS) inhibition therapy, researchers reported online Nov. 4 in the Lancet.

Participants in the multinational, double-blind VITAL study were type 2 diabetes patients who had residual albuminuria – and who thus were at risk of progressive renal failure – despite receiving stable doses of ACE inhibitors or angiotensin receptor blockers (ARBs). They were enrolled between February 2008 and October 2008.

Of 281 patients enrolled in the study and randomized to receive either placebo, 1 mcg, or 2 mcg of paricalcitol for 24 weeks, along with their usual care for diabetes and cardiovascular protection, those in the 2-mcg group had the greatest – and the only statistically significant – percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) at final measurement during treatment, compared with the 1-mcg and placebo groups (–20%, compared with –16% and –3%, respectively). The between-group difference vs. placebo was –18% and –11% for the 2-mcg and 1-mcg groups, respectively, Dr. Dick de Zeeuw of the University of Groningen, the Netherlands, and his colleagues reported.

UACR was reduced significantly by treatment week 4 in the 2-mcg group, and the reduction was sustained during the entire treatment phase, peaking at –28% at week 12. The estimated glomerular filtration rate (eGFR) also decreased substantially by week 4 in the 2-mcg group vs. placebo and remained stable during treatment. An early reduction in systolic blood pressure fluctuated throughout treatment, the investigators found (Lancet 2010[doi:10.1016/S0140-6736(10)61032-X]).

In a post hoc analysis, it was shown that the greatest reduction in UACR was in 29 patients on 2 mcg paricalcitol who had urinary sodium excretion of more than 178 mmol in 24 h.

No serious adverse events deemed to be related to study drug occurred during the course of the study.

"We have shown that 24 weeks’ treatment with 2 mcg paricalcitol daily reduced residual albuminuria in patients with type 2 diabetic nephropathy who were on stable doses of ACE inhibitors or ARBs, particularly in those with high dietary sodium intake," the investigators wrote, adding that the effect on albuminuria, systolic blood pressure, and eGFR all occurred within 4 weeks, and that the reductions in UACR and eGFR were "fairly stable during the treatment phase."

These measurements returned toward baseline after drug withdrawal, indicating that the effects were real and reversible, they said.

The mechanisms of action for paricalcitol for lowering albuminuria appear to be multiple; activation of the vitamin D receptor, which is currently licensed for the prevention and treatment of secondary hyperparathyroidism, intervenes in pathways with well-known associations with renal and vascular progressive disease, they explained.

Additional study to assess the composite end point of doubling of serum creatinine, end stage renal disease, and death is needed for final verification of paricalcitol’s renoprotective effects," they added.

Despite some study limitations, including the use of albuminuria as a surrogate marker of renal disease progression, the lack of measurement of true GFR and ambulatory blood pressure in the study, and fairly small sample size, the findings suggest paricalcitol could be "an important adjunctive treatment providing optimum management to renal osteodystrophy with little hypercalcemia and lowering residual albuminuria.

"Additionally, findings of our study suggest that paricalcitol lowers albuminuria, even when dietary sodium intake is high, which is important because resistance to RAAS intervention occurs in people with high dietary sodium intake and adherence to low sodium diets is desirable but difficult, especially in those with diabetic nephropathy who already have restricted diets," they said.

In an accompanying editorial, Dr. Merlin C. Thomas and Dr. Mark E. Cooper wrote that the findings from the VITAL study add to existing data demonstrating the potential antiproteinuric actions of paricalcitol when added to standard therapies.

They also underscore the fact that patients with diabetes, and particularly those with chronic kidney disease, "in whom the urinary loss of protein-associated vitamin D magnifies reduced activation of vitamin D by the proximal tubule and reduced expression of the vitamin D receptor," have increased rates of vitamin D deficiency. For these patients it "seems rational to replace vitamin D," they wrote (Lancet 2010[doi:10.1016/S0140-6736(10)61301-3]).

Selective analogues that restore vitamin D receptor-signaling without risking hypercalcemia or hyperphosphatemia – as paricalcitol appears to do in the VITAL study – might be of particular benefit, they said, adding that trials in patients with diabetes "should now test whether such analogues can ultimately improve mortality and cardiovascular outcomes, as suggested in studied of patients with end-stage renal disease."

Dr. Thomas and Dr. Cooper are with the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Dr. Thomas is also with Monash University in Melbourne.

The VITAL study was sponsored by Abbott. Dr. de Zeeuw disclosed that he has been a consultant for, and his institution has received honoraria from, Abbott, Amgen, AztraZeneca, Bristol-Myers Squibb, Novartis, Noxxon, Johnson & Johnson, Hemcue, and Merck Sharp & Dohme. Other study authors and/or their institutions have served as board members, consultants, or received honoraria, research, or other funding from Abbott, Watson, Merck, Novartis, AstraZeneca, Amgen, Daiichi Sankyo, and Roche. Five of the authors on the study are employed by Abbott and own stock and have stock options in Abbott.

Dr. Thomas and Dr. Cooper reported having no disclosures.

Selective vitamin D receptor activation with paricalcitol lowers residual albuminuria and could provide renal protection in patients with diabetic nephropathy when added to standard therapies, according the findings of the randomized, controlled VITAL study.

Patients with a high-sodium diet were among those who benefited from the combination of paricalcitol and renin-angiotensin-aldosterone system (RAAS) inhibition therapy, researchers reported online Nov. 4 in the Lancet.

Participants in the multinational, double-blind VITAL study were type 2 diabetes patients who had residual albuminuria – and who thus were at risk of progressive renal failure – despite receiving stable doses of ACE inhibitors or angiotensin receptor blockers (ARBs). They were enrolled between February 2008 and October 2008.

Of 281 patients enrolled in the study and randomized to receive either placebo, 1 mcg, or 2 mcg of paricalcitol for 24 weeks, along with their usual care for diabetes and cardiovascular protection, those in the 2-mcg group had the greatest – and the only statistically significant – percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) at final measurement during treatment, compared with the 1-mcg and placebo groups (–20%, compared with –16% and –3%, respectively). The between-group difference vs. placebo was –18% and –11% for the 2-mcg and 1-mcg groups, respectively, Dr. Dick de Zeeuw of the University of Groningen, the Netherlands, and his colleagues reported.

UACR was reduced significantly by treatment week 4 in the 2-mcg group, and the reduction was sustained during the entire treatment phase, peaking at –28% at week 12. The estimated glomerular filtration rate (eGFR) also decreased substantially by week 4 in the 2-mcg group vs. placebo and remained stable during treatment. An early reduction in systolic blood pressure fluctuated throughout treatment, the investigators found (Lancet 2010[doi:10.1016/S0140-6736(10)61032-X]).

In a post hoc analysis, it was shown that the greatest reduction in UACR was in 29 patients on 2 mcg paricalcitol who had urinary sodium excretion of more than 178 mmol in 24 h.

No serious adverse events deemed to be related to study drug occurred during the course of the study.

"We have shown that 24 weeks’ treatment with 2 mcg paricalcitol daily reduced residual albuminuria in patients with type 2 diabetic nephropathy who were on stable doses of ACE inhibitors or ARBs, particularly in those with high dietary sodium intake," the investigators wrote, adding that the effect on albuminuria, systolic blood pressure, and eGFR all occurred within 4 weeks, and that the reductions in UACR and eGFR were "fairly stable during the treatment phase."

These measurements returned toward baseline after drug withdrawal, indicating that the effects were real and reversible, they said.

The mechanisms of action for paricalcitol for lowering albuminuria appear to be multiple; activation of the vitamin D receptor, which is currently licensed for the prevention and treatment of secondary hyperparathyroidism, intervenes in pathways with well-known associations with renal and vascular progressive disease, they explained.

Additional study to assess the composite end point of doubling of serum creatinine, end stage renal disease, and death is needed for final verification of paricalcitol’s renoprotective effects," they added.

Despite some study limitations, including the use of albuminuria as a surrogate marker of renal disease progression, the lack of measurement of true GFR and ambulatory blood pressure in the study, and fairly small sample size, the findings suggest paricalcitol could be "an important adjunctive treatment providing optimum management to renal osteodystrophy with little hypercalcemia and lowering residual albuminuria.

"Additionally, findings of our study suggest that paricalcitol lowers albuminuria, even when dietary sodium intake is high, which is important because resistance to RAAS intervention occurs in people with high dietary sodium intake and adherence to low sodium diets is desirable but difficult, especially in those with diabetic nephropathy who already have restricted diets," they said.

In an accompanying editorial, Dr. Merlin C. Thomas and Dr. Mark E. Cooper wrote that the findings from the VITAL study add to existing data demonstrating the potential antiproteinuric actions of paricalcitol when added to standard therapies.

They also underscore the fact that patients with diabetes, and particularly those with chronic kidney disease, "in whom the urinary loss of protein-associated vitamin D magnifies reduced activation of vitamin D by the proximal tubule and reduced expression of the vitamin D receptor," have increased rates of vitamin D deficiency. For these patients it "seems rational to replace vitamin D," they wrote (Lancet 2010[doi:10.1016/S0140-6736(10)61301-3]).

Selective analogues that restore vitamin D receptor-signaling without risking hypercalcemia or hyperphosphatemia – as paricalcitol appears to do in the VITAL study – might be of particular benefit, they said, adding that trials in patients with diabetes "should now test whether such analogues can ultimately improve mortality and cardiovascular outcomes, as suggested in studied of patients with end-stage renal disease."

Dr. Thomas and Dr. Cooper are with the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Dr. Thomas is also with Monash University in Melbourne.

The VITAL study was sponsored by Abbott. Dr. de Zeeuw disclosed that he has been a consultant for, and his institution has received honoraria from, Abbott, Amgen, AztraZeneca, Bristol-Myers Squibb, Novartis, Noxxon, Johnson & Johnson, Hemcue, and Merck Sharp & Dohme. Other study authors and/or their institutions have served as board members, consultants, or received honoraria, research, or other funding from Abbott, Watson, Merck, Novartis, AstraZeneca, Amgen, Daiichi Sankyo, and Roche. Five of the authors on the study are employed by Abbott and own stock and have stock options in Abbott.

Dr. Thomas and Dr. Cooper reported having no disclosures.

Selective vitamin D receptor activation with paricalcitol lowers residual albuminuria and could provide renal protection in patients with diabetic nephropathy when added to standard therapies, according the findings of the randomized, controlled VITAL study.

Patients with a high-sodium diet were among those who benefited from the combination of paricalcitol and renin-angiotensin-aldosterone system (RAAS) inhibition therapy, researchers reported online Nov. 4 in the Lancet.

Participants in the multinational, double-blind VITAL study were type 2 diabetes patients who had residual albuminuria – and who thus were at risk of progressive renal failure – despite receiving stable doses of ACE inhibitors or angiotensin receptor blockers (ARBs). They were enrolled between February 2008 and October 2008.

Of 281 patients enrolled in the study and randomized to receive either placebo, 1 mcg, or 2 mcg of paricalcitol for 24 weeks, along with their usual care for diabetes and cardiovascular protection, those in the 2-mcg group had the greatest – and the only statistically significant – percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) at final measurement during treatment, compared with the 1-mcg and placebo groups (–20%, compared with –16% and –3%, respectively). The between-group difference vs. placebo was –18% and –11% for the 2-mcg and 1-mcg groups, respectively, Dr. Dick de Zeeuw of the University of Groningen, the Netherlands, and his colleagues reported.

UACR was reduced significantly by treatment week 4 in the 2-mcg group, and the reduction was sustained during the entire treatment phase, peaking at –28% at week 12. The estimated glomerular filtration rate (eGFR) also decreased substantially by week 4 in the 2-mcg group vs. placebo and remained stable during treatment. An early reduction in systolic blood pressure fluctuated throughout treatment, the investigators found (Lancet 2010[doi:10.1016/S0140-6736(10)61032-X]).

In a post hoc analysis, it was shown that the greatest reduction in UACR was in 29 patients on 2 mcg paricalcitol who had urinary sodium excretion of more than 178 mmol in 24 h.

No serious adverse events deemed to be related to study drug occurred during the course of the study.

"We have shown that 24 weeks’ treatment with 2 mcg paricalcitol daily reduced residual albuminuria in patients with type 2 diabetic nephropathy who were on stable doses of ACE inhibitors or ARBs, particularly in those with high dietary sodium intake," the investigators wrote, adding that the effect on albuminuria, systolic blood pressure, and eGFR all occurred within 4 weeks, and that the reductions in UACR and eGFR were "fairly stable during the treatment phase."

These measurements returned toward baseline after drug withdrawal, indicating that the effects were real and reversible, they said.

The mechanisms of action for paricalcitol for lowering albuminuria appear to be multiple; activation of the vitamin D receptor, which is currently licensed for the prevention and treatment of secondary hyperparathyroidism, intervenes in pathways with well-known associations with renal and vascular progressive disease, they explained.

Additional study to assess the composite end point of doubling of serum creatinine, end stage renal disease, and death is needed for final verification of paricalcitol’s renoprotective effects," they added.

Despite some study limitations, including the use of albuminuria as a surrogate marker of renal disease progression, the lack of measurement of true GFR and ambulatory blood pressure in the study, and fairly small sample size, the findings suggest paricalcitol could be "an important adjunctive treatment providing optimum management to renal osteodystrophy with little hypercalcemia and lowering residual albuminuria.

"Additionally, findings of our study suggest that paricalcitol lowers albuminuria, even when dietary sodium intake is high, which is important because resistance to RAAS intervention occurs in people with high dietary sodium intake and adherence to low sodium diets is desirable but difficult, especially in those with diabetic nephropathy who already have restricted diets," they said.

In an accompanying editorial, Dr. Merlin C. Thomas and Dr. Mark E. Cooper wrote that the findings from the VITAL study add to existing data demonstrating the potential antiproteinuric actions of paricalcitol when added to standard therapies.

They also underscore the fact that patients with diabetes, and particularly those with chronic kidney disease, "in whom the urinary loss of protein-associated vitamin D magnifies reduced activation of vitamin D by the proximal tubule and reduced expression of the vitamin D receptor," have increased rates of vitamin D deficiency. For these patients it "seems rational to replace vitamin D," they wrote (Lancet 2010[doi:10.1016/S0140-6736(10)61301-3]).

Selective analogues that restore vitamin D receptor-signaling without risking hypercalcemia or hyperphosphatemia – as paricalcitol appears to do in the VITAL study – might be of particular benefit, they said, adding that trials in patients with diabetes "should now test whether such analogues can ultimately improve mortality and cardiovascular outcomes, as suggested in studied of patients with end-stage renal disease."

Dr. Thomas and Dr. Cooper are with the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Dr. Thomas is also with Monash University in Melbourne.

The VITAL study was sponsored by Abbott. Dr. de Zeeuw disclosed that he has been a consultant for, and his institution has received honoraria from, Abbott, Amgen, AztraZeneca, Bristol-Myers Squibb, Novartis, Noxxon, Johnson & Johnson, Hemcue, and Merck Sharp & Dohme. Other study authors and/or their institutions have served as board members, consultants, or received honoraria, research, or other funding from Abbott, Watson, Merck, Novartis, AstraZeneca, Amgen, Daiichi Sankyo, and Roche. Five of the authors on the study are employed by Abbott and own stock and have stock options in Abbott.

Dr. Thomas and Dr. Cooper reported having no disclosures.

Selective vitamin D receptor activation with paricalcitol lowers residual albuminuria and could provide renal protection in patients with diabetic nephropathy when added to standard therapies, according the findings of the randomized, controlled VITAL study.

Patients with a high-sodium diet were among those who benefited from the combination of paricalcitol and renin-angiotensin-aldosterone system (RAAS) inhibition therapy, researchers reported online Nov. 4 in the Lancet.

Participants in the multinational, double-blind VITAL study were type 2 diabetes patients who had residual albuminuria – and who thus were at risk of progressive renal failure – despite receiving stable doses of ACE inhibitors or angiotensin receptor blockers (ARBs). They were enrolled between February 2008 and October 2008.

Of 281 patients enrolled in the study and randomized to receive either placebo, 1 mcg, or 2 mcg of paricalcitol for 24 weeks, along with their usual care for diabetes and cardiovascular protection, those in the 2-mcg group had the greatest – and the only statistically significant – percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) at final measurement during treatment, compared with the 1-mcg and placebo groups (–20%, compared with –16% and –3%, respectively). The between-group difference vs. placebo was –18% and –11% for the 2-mcg and 1-mcg groups, respectively, Dr. Dick de Zeeuw of the University of Groningen, the Netherlands, and his colleagues reported.

UACR was reduced significantly by treatment week 4 in the 2-mcg group, and the reduction was sustained during the entire treatment phase, peaking at –28% at week 12. The estimated glomerular filtration rate (eGFR) also decreased substantially by week 4 in the 2-mcg group vs. placebo and remained stable during treatment. An early reduction in systolic blood pressure fluctuated throughout treatment, the investigators found (Lancet 2010[doi:10.1016/S0140-6736(10)61032-X]).

In a post hoc analysis, it was shown that the greatest reduction in UACR was in 29 patients on 2 mcg paricalcitol who had urinary sodium excretion of more than 178 mmol in 24 h.

No serious adverse events deemed to be related to study drug occurred during the course of the study.

"We have shown that 24 weeks’ treatment with 2 mcg paricalcitol daily reduced residual albuminuria in patients with type 2 diabetic nephropathy who were on stable doses of ACE inhibitors or ARBs, particularly in those with high dietary sodium intake," the investigators wrote, adding that the effect on albuminuria, systolic blood pressure, and eGFR all occurred within 4 weeks, and that the reductions in UACR and eGFR were "fairly stable during the treatment phase."

These measurements returned toward baseline after drug withdrawal, indicating that the effects were real and reversible, they said.

The mechanisms of action for paricalcitol for lowering albuminuria appear to be multiple; activation of the vitamin D receptor, which is currently licensed for the prevention and treatment of secondary hyperparathyroidism, intervenes in pathways with well-known associations with renal and vascular progressive disease, they explained.

Additional study to assess the composite end point of doubling of serum creatinine, end stage renal disease, and death is needed for final verification of paricalcitol’s renoprotective effects," they added.

Despite some study limitations, including the use of albuminuria as a surrogate marker of renal disease progression, the lack of measurement of true GFR and ambulatory blood pressure in the study, and fairly small sample size, the findings suggest paricalcitol could be "an important adjunctive treatment providing optimum management to renal osteodystrophy with little hypercalcemia and lowering residual albuminuria.

"Additionally, findings of our study suggest that paricalcitol lowers albuminuria, even when dietary sodium intake is high, which is important because resistance to RAAS intervention occurs in people with high dietary sodium intake and adherence to low sodium diets is desirable but difficult, especially in those with diabetic nephropathy who already have restricted diets," they said.

In an accompanying editorial, Dr. Merlin C. Thomas and Dr. Mark E. Cooper wrote that the findings from the VITAL study add to existing data demonstrating the potential antiproteinuric actions of paricalcitol when added to standard therapies.

They also underscore the fact that patients with diabetes, and particularly those with chronic kidney disease, "in whom the urinary loss of protein-associated vitamin D magnifies reduced activation of vitamin D by the proximal tubule and reduced expression of the vitamin D receptor," have increased rates of vitamin D deficiency. For these patients it "seems rational to replace vitamin D," they wrote (Lancet 2010[doi:10.1016/S0140-6736(10)61301-3]).

Selective analogues that restore vitamin D receptor-signaling without risking hypercalcemia or hyperphosphatemia – as paricalcitol appears to do in the VITAL study – might be of particular benefit, they said, adding that trials in patients with diabetes "should now test whether such analogues can ultimately improve mortality and cardiovascular outcomes, as suggested in studied of patients with end-stage renal disease."

Dr. Thomas and Dr. Cooper are with the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Dr. Thomas is also with Monash University in Melbourne.

The VITAL study was sponsored by Abbott. Dr. de Zeeuw disclosed that he has been a consultant for, and his institution has received honoraria from, Abbott, Amgen, AztraZeneca, Bristol-Myers Squibb, Novartis, Noxxon, Johnson & Johnson, Hemcue, and Merck Sharp & Dohme. Other study authors and/or their institutions have served as board members, consultants, or received honoraria, research, or other funding from Abbott, Watson, Merck, Novartis, AstraZeneca, Amgen, Daiichi Sankyo, and Roche. Five of the authors on the study are employed by Abbott and own stock and have stock options in Abbott.

Dr. Thomas and Dr. Cooper reported having no disclosures.

Selective vitamin D receptor activation with paricalcitol lowers residual albuminuria and could provide renal protection in patients with diabetic nephropathy when added to standard therapies, according the findings of the randomized, controlled VITAL study.

Patients with a high-sodium diet were among those who benefited from the combination of paricalcitol and renin-angiotensin-aldosterone system (RAAS) inhibition therapy, researchers reported online Nov. 4 in the Lancet.

Participants in the multinational, double-blind VITAL study were type 2 diabetes patients who had residual albuminuria – and who thus were at risk of progressive renal failure – despite receiving stable doses of ACE inhibitors or angiotensin receptor blockers (ARBs). They were enrolled between February 2008 and October 2008.

Of 281 patients enrolled in the study and randomized to receive either placebo, 1 mcg, or 2 mcg of paricalcitol for 24 weeks, along with their usual care for diabetes and cardiovascular protection, those in the 2-mcg group had the greatest – and the only statistically significant – percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) at final measurement during treatment, compared with the 1-mcg and placebo groups (–20%, compared with –16% and –3%, respectively). The between-group difference vs. placebo was –18% and –11% for the 2-mcg and 1-mcg groups, respectively, Dr. Dick de Zeeuw of the University of Groningen, the Netherlands, and his colleagues reported.

UACR was reduced significantly by treatment week 4 in the 2-mcg group, and the reduction was sustained during the entire treatment phase, peaking at –28% at week 12. The estimated glomerular filtration rate (eGFR) also decreased substantially by week 4 in the 2-mcg group vs. placebo and remained stable during treatment. An early reduction in systolic blood pressure fluctuated throughout treatment, the investigators found (Lancet 2010[doi:10.1016/S0140-6736(10)61032-X]).

In a post hoc analysis, it was shown that the greatest reduction in UACR was in 29 patients on 2 mcg paricalcitol who had urinary sodium excretion of more than 178 mmol in 24 h.

No serious adverse events deemed to be related to study drug occurred during the course of the study.

"We have shown that 24 weeks’ treatment with 2 mcg paricalcitol daily reduced residual albuminuria in patients with type 2 diabetic nephropathy who were on stable doses of ACE inhibitors or ARBs, particularly in those with high dietary sodium intake," the investigators wrote, adding that the effect on albuminuria, systolic blood pressure, and eGFR all occurred within 4 weeks, and that the reductions in UACR and eGFR were "fairly stable during the treatment phase."

These measurements returned toward baseline after drug withdrawal, indicating that the effects were real and reversible, they said.

The mechanisms of action for paricalcitol for lowering albuminuria appear to be multiple; activation of the vitamin D receptor, which is currently licensed for the prevention and treatment of secondary hyperparathyroidism, intervenes in pathways with well-known associations with renal and vascular progressive disease, they explained.

Additional study to assess the composite end point of doubling of serum creatinine, end stage renal disease, and death is needed for final verification of paricalcitol’s renoprotective effects," they added.

Despite some study limitations, including the use of albuminuria as a surrogate marker of renal disease progression, the lack of measurement of true GFR and ambulatory blood pressure in the study, and fairly small sample size, the findings suggest paricalcitol could be "an important adjunctive treatment providing optimum management to renal osteodystrophy with little hypercalcemia and lowering residual albuminuria.

"Additionally, findings of our study suggest that paricalcitol lowers albuminuria, even when dietary sodium intake is high, which is important because resistance to RAAS intervention occurs in people with high dietary sodium intake and adherence to low sodium diets is desirable but difficult, especially in those with diabetic nephropathy who already have restricted diets," they said.

In an accompanying editorial, Dr. Merlin C. Thomas and Dr. Mark E. Cooper wrote that the findings from the VITAL study add to existing data demonstrating the potential antiproteinuric actions of paricalcitol when added to standard therapies.

They also underscore the fact that patients with diabetes, and particularly those with chronic kidney disease, "in whom the urinary loss of protein-associated vitamin D magnifies reduced activation of vitamin D by the proximal tubule and reduced expression of the vitamin D receptor," have increased rates of vitamin D deficiency. For these patients it "seems rational to replace vitamin D," they wrote (Lancet 2010[doi:10.1016/S0140-6736(10)61301-3]).

Selective analogues that restore vitamin D receptor-signaling without risking hypercalcemia or hyperphosphatemia – as paricalcitol appears to do in the VITAL study – might be of particular benefit, they said, adding that trials in patients with diabetes "should now test whether such analogues can ultimately improve mortality and cardiovascular outcomes, as suggested in studied of patients with end-stage renal disease."

Dr. Thomas and Dr. Cooper are with the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Dr. Thomas is also with Monash University in Melbourne.

The VITAL study was sponsored by Abbott. Dr. de Zeeuw disclosed that he has been a consultant for, and his institution has received honoraria from, Abbott, Amgen, AztraZeneca, Bristol-Myers Squibb, Novartis, Noxxon, Johnson & Johnson, Hemcue, and Merck Sharp & Dohme. Other study authors and/or their institutions have served as board members, consultants, or received honoraria, research, or other funding from Abbott, Watson, Merck, Novartis, AstraZeneca, Amgen, Daiichi Sankyo, and Roche. Five of the authors on the study are employed by Abbott and own stock and have stock options in Abbott.

Dr. Thomas and Dr. Cooper reported having no disclosures.

Half of the respondents in a recent survey of more than 43,000 public and private high school students said they had bullied someone in the last year, and 47% said they had been the victim of bullying.

Moreover, 33% of the students surveyed said that violence is a big problem at their school, and 24% said they don’t feel very safe at school, according to the Josephson Institute Center for Youth Ethics, a Los Angeles–based nonprofit, nonpartisan organization that has conducted biannual studies of the ethics of American youth since 1992, and which administers a national values-based program for students titled "CHARACTER COUNTS!"

The problem of bullying, which has garnered a great deal of media attention in the wake of a number of bullying-related incidents – perhaps most notably the suicide of 18-year-old Rutgers University freshman Tyler Clementi in September, after his roommate used a webcam to stream video over the Internet of him during a gay sexual encounter – is one that requires the attention of parents and educators. In fact, on the day the Josephson Institute survey results were released, the U.S. Department of Education issued guidance "to support educators in combating bullying in schools by clarifying when student bullying may violate federal education antidiscrimination laws," according to a press release from the department, and by explaining educators’ legal obligations in regard to protecting students from harassment.

But the problem is one that physicians who care for children also should be addressing routinely, according to Dr. Carl C. Bell, clinical professor of psychiatry and public health, and director of the Institute for Juvenile Research at the University of Illinois at Chicago.

The American Academy of Pediatrics has an anticipatory guidance regarding violence prevention, and this also should apply to bullying, which is a form of violence, Dr. Bell said.

"It should be part of the standard protocol in the office," he said.

The goal should be to ensure that the social fabric that youngsters need for healthy development is in place. "Make sure they are learning social and emotional skills – kids with good people skills can deal with a bully," he said, adding that "catastrophizing" bullying doesn’t fix anything.

Focusing on the effects of bullying can perpetuate the problem. But focusing on what it is that prevents children from being traumatized by it can make a difference, he explained.

The media tend to focus on the catastrophes – the teens who commit suicide. The reality is that suicide rates in teens are about 20 per 100,000, but the attempt rates are 5,000 per 100,000, he said.

"You would think maybe half would complete [suicide] later on, but they don’t," he said, adding that what is stopping them is the social fabric and support systems that are necessary for healthy development.

"Kids with good emotional affect regulation aren’t going to be tripped up, stressed out, or traumatized by a bully," he said.

Physicians can help by encouraging patients to voice their protective factors, he added.

"A lot of the problems we see in children could be curtailed by pediatricians making sure they are in good protective villages, that they have an adult monitoring their behavior, and that they have good skills such as affect regulation. I know pediatricians are not social workers, but ... they have a huge responsibility to try to make sure children are in safe environments, and – equally importantly – in supportive environments that foster emotional, social, mental, and spiritual growth."

That responsibility has particular importance in a society where bullying is no longer defined simply by playground taunts.

The Josephson Institute survey showed that in the prior year, 52% of students had hit a person out of anger, 10% had taken a weapon to school, and 16% admitted to having been under the influence of drugs or alcohol while at school.

The combination of bullying along with these factors significantly increases the likelihood of retaliatory violence, and it’s not only the prevalence of bullying behavior and victimization that’s troublesome, according to Michael Josephson, founder and president of the Institute.

"The Internet has intensified the injury," he said in a statement on the findings.

"What’s posted on the Internet is permanent, and it spreads like a virus – there is no refuge. The difference between the impact of bullying today versus 20 years ago is the difference between getting into a fist fight and using a gun," he said.

Dr. Bell reported having no disclosures other than having been bullied himself as a child. Michael Josephson is founder and president of the Josephson Institute of Ethics.

Half of the respondents in a recent survey of more than 43,000 public and private high school students said they had bullied someone in the last year, and 47% said they had been the victim of bullying.

Moreover, 33% of the students surveyed said that violence is a big problem at their school, and 24% said they don’t feel very safe at school, according to the Josephson Institute Center for Youth Ethics, a Los Angeles–based nonprofit, nonpartisan organization that has conducted biannual studies of the ethics of American youth since 1992, and which administers a national values-based program for students titled "CHARACTER COUNTS!"

The problem of bullying, which has garnered a great deal of media attention in the wake of a number of bullying-related incidents – perhaps most notably the suicide of 18-year-old Rutgers University freshman Tyler Clementi in September, after his roommate used a webcam to stream video over the Internet of him during a gay sexual encounter – is one that requires the attention of parents and educators. In fact, on the day the Josephson Institute survey results were released, the U.S. Department of Education issued guidance "to support educators in combating bullying in schools by clarifying when student bullying may violate federal education antidiscrimination laws," according to a press release from the department, and by explaining educators’ legal obligations in regard to protecting students from harassment.

But the problem is one that physicians who care for children also should be addressing routinely, according to Dr. Carl C. Bell, clinical professor of psychiatry and public health, and director of the Institute for Juvenile Research at the University of Illinois at Chicago.

The American Academy of Pediatrics has an anticipatory guidance regarding violence prevention, and this also should apply to bullying, which is a form of violence, Dr. Bell said.

"It should be part of the standard protocol in the office," he said.

The goal should be to ensure that the social fabric that youngsters need for healthy development is in place. "Make sure they are learning social and emotional skills – kids with good people skills can deal with a bully," he said, adding that "catastrophizing" bullying doesn’t fix anything.

Focusing on the effects of bullying can perpetuate the problem. But focusing on what it is that prevents children from being traumatized by it can make a difference, he explained.

The media tend to focus on the catastrophes – the teens who commit suicide. The reality is that suicide rates in teens are about 20 per 100,000, but the attempt rates are 5,000 per 100,000, he said.

"You would think maybe half would complete [suicide] later on, but they don’t," he said, adding that what is stopping them is the social fabric and support systems that are necessary for healthy development.

"Kids with good emotional affect regulation aren’t going to be tripped up, stressed out, or traumatized by a bully," he said.

Physicians can help by encouraging patients to voice their protective factors, he added.

"A lot of the problems we see in children could be curtailed by pediatricians making sure they are in good protective villages, that they have an adult monitoring their behavior, and that they have good skills such as affect regulation. I know pediatricians are not social workers, but ... they have a huge responsibility to try to make sure children are in safe environments, and – equally importantly – in supportive environments that foster emotional, social, mental, and spiritual growth."

That responsibility has particular importance in a society where bullying is no longer defined simply by playground taunts.

The Josephson Institute survey showed that in the prior year, 52% of students had hit a person out of anger, 10% had taken a weapon to school, and 16% admitted to having been under the influence of drugs or alcohol while at school.

The combination of bullying along with these factors significantly increases the likelihood of retaliatory violence, and it’s not only the prevalence of bullying behavior and victimization that’s troublesome, according to Michael Josephson, founder and president of the Institute.

"The Internet has intensified the injury," he said in a statement on the findings.

"What’s posted on the Internet is permanent, and it spreads like a virus – there is no refuge. The difference between the impact of bullying today versus 20 years ago is the difference between getting into a fist fight and using a gun," he said.

Dr. Bell reported having no disclosures other than having been bullied himself as a child. Michael Josephson is founder and president of the Josephson Institute of Ethics.

Half of the respondents in a recent survey of more than 43,000 public and private high school students said they had bullied someone in the last year, and 47% said they had been the victim of bullying.

Moreover, 33% of the students surveyed said that violence is a big problem at their school, and 24% said they don’t feel very safe at school, according to the Josephson Institute Center for Youth Ethics, a Los Angeles–based nonprofit, nonpartisan organization that has conducted biannual studies of the ethics of American youth since 1992, and which administers a national values-based program for students titled "CHARACTER COUNTS!"

The problem of bullying, which has garnered a great deal of media attention in the wake of a number of bullying-related incidents – perhaps most notably the suicide of 18-year-old Rutgers University freshman Tyler Clementi in September, after his roommate used a webcam to stream video over the Internet of him during a gay sexual encounter – is one that requires the attention of parents and educators. In fact, on the day the Josephson Institute survey results were released, the U.S. Department of Education issued guidance "to support educators in combating bullying in schools by clarifying when student bullying may violate federal education antidiscrimination laws," according to a press release from the department, and by explaining educators’ legal obligations in regard to protecting students from harassment.

But the problem is one that physicians who care for children also should be addressing routinely, according to Dr. Carl C. Bell, clinical professor of psychiatry and public health, and director of the Institute for Juvenile Research at the University of Illinois at Chicago.

The American Academy of Pediatrics has an anticipatory guidance regarding violence prevention, and this also should apply to bullying, which is a form of violence, Dr. Bell said.

"It should be part of the standard protocol in the office," he said.

The goal should be to ensure that the social fabric that youngsters need for healthy development is in place. "Make sure they are learning social and emotional skills – kids with good people skills can deal with a bully," he said, adding that "catastrophizing" bullying doesn’t fix anything.

Focusing on the effects of bullying can perpetuate the problem. But focusing on what it is that prevents children from being traumatized by it can make a difference, he explained.

The media tend to focus on the catastrophes – the teens who commit suicide. The reality is that suicide rates in teens are about 20 per 100,000, but the attempt rates are 5,000 per 100,000, he said.

"You would think maybe half would complete [suicide] later on, but they don’t," he said, adding that what is stopping them is the social fabric and support systems that are necessary for healthy development.

"Kids with good emotional affect regulation aren’t going to be tripped up, stressed out, or traumatized by a bully," he said.

Physicians can help by encouraging patients to voice their protective factors, he added.

"A lot of the problems we see in children could be curtailed by pediatricians making sure they are in good protective villages, that they have an adult monitoring their behavior, and that they have good skills such as affect regulation. I know pediatricians are not social workers, but ... they have a huge responsibility to try to make sure children are in safe environments, and – equally importantly – in supportive environments that foster emotional, social, mental, and spiritual growth."

That responsibility has particular importance in a society where bullying is no longer defined simply by playground taunts.

The Josephson Institute survey showed that in the prior year, 52% of students had hit a person out of anger, 10% had taken a weapon to school, and 16% admitted to having been under the influence of drugs or alcohol while at school.

The combination of bullying along with these factors significantly increases the likelihood of retaliatory violence, and it’s not only the prevalence of bullying behavior and victimization that’s troublesome, according to Michael Josephson, founder and president of the Institute.

"The Internet has intensified the injury," he said in a statement on the findings.

"What’s posted on the Internet is permanent, and it spreads like a virus – there is no refuge. The difference between the impact of bullying today versus 20 years ago is the difference between getting into a fist fight and using a gun," he said.

Dr. Bell reported having no disclosures other than having been bullied himself as a child. Michael Josephson is founder and president of the Josephson Institute of Ethics.