CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.

The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.

[email protected]

CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.

The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.

[email protected]

CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.

The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.

[email protected]

CHICAGO – Genomic testing for all cancer patients was shown to be feasible and productive in a recent study, with a trend toward longer survival among those patients who received recommended targeted treatment.

Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).

“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.

[email protected]
On Twitter @karioakes

CHICAGO – Genomic testing for all cancer patients was shown to be feasible and productive in a recent study, with a trend toward longer survival among those patients who received recommended targeted treatment.

Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).

“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.

[email protected]
On Twitter @karioakes

CHICAGO – Genomic testing for all cancer patients was shown to be feasible and productive in a recent study, with a trend toward longer survival among those patients who received recommended targeted treatment.

Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).

“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.

[email protected]
On Twitter @karioakes

CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.

The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).

Safe and well tolerated

There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.

“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.

The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.

In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.

The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.

Early promise

Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.

For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.

CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.

The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).

Safe and well tolerated

There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.

“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.

The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.

In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.

The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.

Early promise

Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.

For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.

CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.

The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).

Safe and well tolerated

There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.

“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.

The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.

In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.

The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.

Early promise

Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.

For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.

Cirrhosis of any kind was associated with an increased risk of stroke, especially hemorrhagic stroke, in a large nationally representative cohort study reported online June 5 in JAMA Neurology.

Cirrhosis is known to be associated with “extrahepatic hemorrhagic and thrombotic processes, such as GI bleeding and venous thromboembolism. [But] the cerebrovascular complications of cirrhosis are comparatively less well understood.” Previous studies of the association with stroke have been small and have yielded conflicting results, with some finding a reduced incidence of stroke and others finding an increase among cirrhosis patients, said Neal S. Parikh, MD, of the Fell Family Brain and Mind Research Institute and Weill Cornell Medicine, both in New York, and his associates.

Cirrhosis of any kind was associated with an increased risk of stroke, especially hemorrhagic stroke, in a large nationally representative cohort study reported online June 5 in JAMA Neurology.

Cirrhosis is known to be associated with “extrahepatic hemorrhagic and thrombotic processes, such as GI bleeding and venous thromboembolism. [But] the cerebrovascular complications of cirrhosis are comparatively less well understood.” Previous studies of the association with stroke have been small and have yielded conflicting results, with some finding a reduced incidence of stroke and others finding an increase among cirrhosis patients, said Neal S. Parikh, MD, of the Fell Family Brain and Mind Research Institute and Weill Cornell Medicine, both in New York, and his associates.

Cirrhosis of any kind was associated with an increased risk of stroke, especially hemorrhagic stroke, in a large nationally representative cohort study reported online June 5 in JAMA Neurology.

Cirrhosis is known to be associated with “extrahepatic hemorrhagic and thrombotic processes, such as GI bleeding and venous thromboembolism. [But] the cerebrovascular complications of cirrhosis are comparatively less well understood.” Previous studies of the association with stroke have been small and have yielded conflicting results, with some finding a reduced incidence of stroke and others finding an increase among cirrhosis patients, said Neal S. Parikh, MD, of the Fell Family Brain and Mind Research Institute and Weill Cornell Medicine, both in New York, and his associates.

BOSTON – Two phase III trials of the investigational monoclonal antibody erenumab show promising results in reducing – but not eliminating – days affected by migraines and related disruptions in daily life with limited side effects, representing “an entirely new way forward” in migraine prevention, according to Peter Goadsby, MD.

In May, shortly after the results were released at the annual meeting of the American Academy of Neurology, Amgen filed regulatory documents for erenumab with the Food and Drug Administration.

Erenumab, also known as AMG 334, “is going to be the first mechanism-specific, migraine-targeted preventive treatment approach ever,” Dr. Goadsby, a University of California, San Francisco, neurologist, predicted at the annual meeting of the American Academy of Neurology. Erenumab is a fully human monoclonal antibody that is designed to block the calcitonin gene-related peptide (CGRP) receptor, which is linked to migraine.

Several drug makers are investigating CGRP-modulating treatments for migraine. Results suggest that the medications are “effective for episodic and migraine patients,” said Amaal Starling, MD, of the Mayo Clinic, Scottsdale, Ariz., who spoke about the drugs in a plenary session at the meeting. “They have rapid onset of efficacy, minimal side effects, and infrequent administration. All of these things may improve adherence.”

Dr. Goadsby is the lead author of the study reporting phase III results from the 24-week STRIVE trial, which tested two monthly subcutaneous doses of erenumab (70 mg and 140 mg) against placebo in a 1:1:1 ratio in 955 patients. The patients all had suffered from episodic migraine for at least a year.

“STRIVE has shown that the 70-mg and 140-mg doses are better than placebo at the regulatory endpoint and clinically relevant endpoints,” Dr. Goadsby said, “and there are improvements in function, everyday activities, and physical impairment. The overall frequency of adverse and serious events were comparable, even the same.”

The participants reported an average of 8.3 monthly migraine days (MMDs) at the beginning of the study. At the end, the number declined significantly by an average of 3.2 days (70-mg dose), 3.7 days (140-mg dose), and 1.8 days (placebo; P less than .001).

Half of those in the 140-mg group achieved at least a 50% reduction in MMDs, compared with 43% and 27% for the 70-mg and placebo groups, respectively (P less than .001).

The researchers also examined changes in scores regarding Physical Impairment (PI) and Impact on Everyday Activities (EA) as determined by the Migraine Physical Function Impact Diary. PI scores improved by 4.2, 4.8, and 2.4 points in the 70-mg, 140-mg, and placebo groups, respectively. EA scores improved by 5.5, 5.9, and 3.3 points, respectively (P less than .001).

The study authors reported that tolerability was similar for placebo and the drug. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and sinusitis.

The researchers at the AAN meeting also released the results of a second study known as ARISE, led by David W. Dodick, MD, of the Mayo Clinic, Phoenix, Ariz. This double-blind, 12-week trial randomly assigned 577 adults with episodic migraine to a monthly subcutaneous dose of a placebo or 70 mg of erenumab.

The patients reported an average of 8.3 MMDs at the beginning of the trial. Those who took the medication reported an average 2.9 fewer MMDs while those who took the placebo reported 1.8 fewer MMDs (P less than .001) at 9-12 weeks.

Forty percent of those who took the drug saw a decrease of at least half in MMDs, compared with 30% of those who took placebo (odds ratio, 1.6; P = .010).

The PI levels declined by at least 5 points in 27% of placebo patients and 33% of erenumab patients (P = .13). EA levels declined by at least 5 points in 36% of placebo patients and 40% of erenumab patients (P = .26)

There were similar levels of adverse events in both drug and placebo groups, led by upper respiratory tract infection, injection site pain, and nasopharyngitis.

The Mayo Clinic’s Dr. Starling said anti-CGRP medications may dramatically improve the world of preventive migraine treatments, which are recommended for a third of migraine patients. Only about 3%-13% use them, she said.

In the future, it may be possible to be able to identify and target “super-responders” whose MMDs dip by 75% or more in some cases.

But there are questions, she said. The drugs’ specific mechanism for blocking migraine is not yet clear, and it’s also not clear if the CGRP antagonists could push patients at risk of TIA or cardiac angina to have a stroke instead.

Dr. Starling discussed some of the implications of the CGRP antagonists in development in a video interview.

Both studies were funded by Amgen. Dr. Goadsby reported numerous grants and personal fees from multiple drug makers, including Amgen. Dr. Starling reported support from Amgen, eNeura, and Eli Lilly. Dr. Dodick disclosed many relationships with pharmaceutical companies developing or marketing drugs for headache and migraine, including Amgen.

BOSTON – Two phase III trials of the investigational monoclonal antibody erenumab show promising results in reducing – but not eliminating – days affected by migraines and related disruptions in daily life with limited side effects, representing “an entirely new way forward” in migraine prevention, according to Peter Goadsby, MD.

In May, shortly after the results were released at the annual meeting of the American Academy of Neurology, Amgen filed regulatory documents for erenumab with the Food and Drug Administration.

Erenumab, also known as AMG 334, “is going to be the first mechanism-specific, migraine-targeted preventive treatment approach ever,” Dr. Goadsby, a University of California, San Francisco, neurologist, predicted at the annual meeting of the American Academy of Neurology. Erenumab is a fully human monoclonal antibody that is designed to block the calcitonin gene-related peptide (CGRP) receptor, which is linked to migraine.

Several drug makers are investigating CGRP-modulating treatments for migraine. Results suggest that the medications are “effective for episodic and migraine patients,” said Amaal Starling, MD, of the Mayo Clinic, Scottsdale, Ariz., who spoke about the drugs in a plenary session at the meeting. “They have rapid onset of efficacy, minimal side effects, and infrequent administration. All of these things may improve adherence.”

Dr. Goadsby is the lead author of the study reporting phase III results from the 24-week STRIVE trial, which tested two monthly subcutaneous doses of erenumab (70 mg and 140 mg) against placebo in a 1:1:1 ratio in 955 patients. The patients all had suffered from episodic migraine for at least a year.

“STRIVE has shown that the 70-mg and 140-mg doses are better than placebo at the regulatory endpoint and clinically relevant endpoints,” Dr. Goadsby said, “and there are improvements in function, everyday activities, and physical impairment. The overall frequency of adverse and serious events were comparable, even the same.”

The participants reported an average of 8.3 monthly migraine days (MMDs) at the beginning of the study. At the end, the number declined significantly by an average of 3.2 days (70-mg dose), 3.7 days (140-mg dose), and 1.8 days (placebo; P less than .001).

Half of those in the 140-mg group achieved at least a 50% reduction in MMDs, compared with 43% and 27% for the 70-mg and placebo groups, respectively (P less than .001).

The researchers also examined changes in scores regarding Physical Impairment (PI) and Impact on Everyday Activities (EA) as determined by the Migraine Physical Function Impact Diary. PI scores improved by 4.2, 4.8, and 2.4 points in the 70-mg, 140-mg, and placebo groups, respectively. EA scores improved by 5.5, 5.9, and 3.3 points, respectively (P less than .001).

The study authors reported that tolerability was similar for placebo and the drug. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and sinusitis.

The researchers at the AAN meeting also released the results of a second study known as ARISE, led by David W. Dodick, MD, of the Mayo Clinic, Phoenix, Ariz. This double-blind, 12-week trial randomly assigned 577 adults with episodic migraine to a monthly subcutaneous dose of a placebo or 70 mg of erenumab.

The patients reported an average of 8.3 MMDs at the beginning of the trial. Those who took the medication reported an average 2.9 fewer MMDs while those who took the placebo reported 1.8 fewer MMDs (P less than .001) at 9-12 weeks.

Forty percent of those who took the drug saw a decrease of at least half in MMDs, compared with 30% of those who took placebo (odds ratio, 1.6; P = .010).

The PI levels declined by at least 5 points in 27% of placebo patients and 33% of erenumab patients (P = .13). EA levels declined by at least 5 points in 36% of placebo patients and 40% of erenumab patients (P = .26)

There were similar levels of adverse events in both drug and placebo groups, led by upper respiratory tract infection, injection site pain, and nasopharyngitis.

The Mayo Clinic’s Dr. Starling said anti-CGRP medications may dramatically improve the world of preventive migraine treatments, which are recommended for a third of migraine patients. Only about 3%-13% use them, she said.

In the future, it may be possible to be able to identify and target “super-responders” whose MMDs dip by 75% or more in some cases.

But there are questions, she said. The drugs’ specific mechanism for blocking migraine is not yet clear, and it’s also not clear if the CGRP antagonists could push patients at risk of TIA or cardiac angina to have a stroke instead.

Dr. Starling discussed some of the implications of the CGRP antagonists in development in a video interview.

Both studies were funded by Amgen. Dr. Goadsby reported numerous grants and personal fees from multiple drug makers, including Amgen. Dr. Starling reported support from Amgen, eNeura, and Eli Lilly. Dr. Dodick disclosed many relationships with pharmaceutical companies developing or marketing drugs for headache and migraine, including Amgen.

BOSTON – Two phase III trials of the investigational monoclonal antibody erenumab show promising results in reducing – but not eliminating – days affected by migraines and related disruptions in daily life with limited side effects, representing “an entirely new way forward” in migraine prevention, according to Peter Goadsby, MD.

In May, shortly after the results were released at the annual meeting of the American Academy of Neurology, Amgen filed regulatory documents for erenumab with the Food and Drug Administration.

Erenumab, also known as AMG 334, “is going to be the first mechanism-specific, migraine-targeted preventive treatment approach ever,” Dr. Goadsby, a University of California, San Francisco, neurologist, predicted at the annual meeting of the American Academy of Neurology. Erenumab is a fully human monoclonal antibody that is designed to block the calcitonin gene-related peptide (CGRP) receptor, which is linked to migraine.

Several drug makers are investigating CGRP-modulating treatments for migraine. Results suggest that the medications are “effective for episodic and migraine patients,” said Amaal Starling, MD, of the Mayo Clinic, Scottsdale, Ariz., who spoke about the drugs in a plenary session at the meeting. “They have rapid onset of efficacy, minimal side effects, and infrequent administration. All of these things may improve adherence.”

Dr. Goadsby is the lead author of the study reporting phase III results from the 24-week STRIVE trial, which tested two monthly subcutaneous doses of erenumab (70 mg and 140 mg) against placebo in a 1:1:1 ratio in 955 patients. The patients all had suffered from episodic migraine for at least a year.

“STRIVE has shown that the 70-mg and 140-mg doses are better than placebo at the regulatory endpoint and clinically relevant endpoints,” Dr. Goadsby said, “and there are improvements in function, everyday activities, and physical impairment. The overall frequency of adverse and serious events were comparable, even the same.”

The participants reported an average of 8.3 monthly migraine days (MMDs) at the beginning of the study. At the end, the number declined significantly by an average of 3.2 days (70-mg dose), 3.7 days (140-mg dose), and 1.8 days (placebo; P less than .001).

Half of those in the 140-mg group achieved at least a 50% reduction in MMDs, compared with 43% and 27% for the 70-mg and placebo groups, respectively (P less than .001).

The researchers also examined changes in scores regarding Physical Impairment (PI) and Impact on Everyday Activities (EA) as determined by the Migraine Physical Function Impact Diary. PI scores improved by 4.2, 4.8, and 2.4 points in the 70-mg, 140-mg, and placebo groups, respectively. EA scores improved by 5.5, 5.9, and 3.3 points, respectively (P less than .001).

The study authors reported that tolerability was similar for placebo and the drug. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and sinusitis.

The researchers at the AAN meeting also released the results of a second study known as ARISE, led by David W. Dodick, MD, of the Mayo Clinic, Phoenix, Ariz. This double-blind, 12-week trial randomly assigned 577 adults with episodic migraine to a monthly subcutaneous dose of a placebo or 70 mg of erenumab.

The patients reported an average of 8.3 MMDs at the beginning of the trial. Those who took the medication reported an average 2.9 fewer MMDs while those who took the placebo reported 1.8 fewer MMDs (P less than .001) at 9-12 weeks.

Forty percent of those who took the drug saw a decrease of at least half in MMDs, compared with 30% of those who took placebo (odds ratio, 1.6; P = .010).

The PI levels declined by at least 5 points in 27% of placebo patients and 33% of erenumab patients (P = .13). EA levels declined by at least 5 points in 36% of placebo patients and 40% of erenumab patients (P = .26)

There were similar levels of adverse events in both drug and placebo groups, led by upper respiratory tract infection, injection site pain, and nasopharyngitis.

The Mayo Clinic’s Dr. Starling said anti-CGRP medications may dramatically improve the world of preventive migraine treatments, which are recommended for a third of migraine patients. Only about 3%-13% use them, she said.

In the future, it may be possible to be able to identify and target “super-responders” whose MMDs dip by 75% or more in some cases.

But there are questions, she said. The drugs’ specific mechanism for blocking migraine is not yet clear, and it’s also not clear if the CGRP antagonists could push patients at risk of TIA or cardiac angina to have a stroke instead.

Dr. Starling discussed some of the implications of the CGRP antagonists in development in a video interview.

Both studies were funded by Amgen. Dr. Goadsby reported numerous grants and personal fees from multiple drug makers, including Amgen. Dr. Starling reported support from Amgen, eNeura, and Eli Lilly. Dr. Dodick disclosed many relationships with pharmaceutical companies developing or marketing drugs for headache and migraine, including Amgen.

SAN FRANCISCO – Why are anxiety disorders twice as prevalent in women as in men? As in Hawaiian hula dancing, the expressive hands may tell the tale.

The ratio of the length of the index finger to ring finger – known as the 2D:4D ratio – is a physical trait that remains stable across the lifetimes of males and females. It’s also a reliable indicator of prenatal exposure to androgens. In female college students, the higher the 2D:4D ratio, the greater their level of ruminative thinking, which is known to be both a risk factor and maintenance factor for anxiety, Ellie Shuo Jin reported at the annual conference of the Anxiety and Depression Association of America.

Bruce Jancin/Frontline Medical News

[email protected]

SAN FRANCISCO – Why are anxiety disorders twice as prevalent in women as in men? As in Hawaiian hula dancing, the expressive hands may tell the tale.

The ratio of the length of the index finger to ring finger – known as the 2D:4D ratio – is a physical trait that remains stable across the lifetimes of males and females. It’s also a reliable indicator of prenatal exposure to androgens. In female college students, the higher the 2D:4D ratio, the greater their level of ruminative thinking, which is known to be both a risk factor and maintenance factor for anxiety, Ellie Shuo Jin reported at the annual conference of the Anxiety and Depression Association of America.

Bruce Jancin/Frontline Medical News

[email protected]

SAN FRANCISCO – Why are anxiety disorders twice as prevalent in women as in men? As in Hawaiian hula dancing, the expressive hands may tell the tale.

The ratio of the length of the index finger to ring finger – known as the 2D:4D ratio – is a physical trait that remains stable across the lifetimes of males and females. It’s also a reliable indicator of prenatal exposure to androgens. In female college students, the higher the 2D:4D ratio, the greater their level of ruminative thinking, which is known to be both a risk factor and maintenance factor for anxiety, Ellie Shuo Jin reported at the annual conference of the Anxiety and Depression Association of America.

Bruce Jancin/Frontline Medical News

[email protected]

Identifying Characteristics and Disease Transmission

Chiggers belong to the Trombiculidae family of mites and also are referred to as harvest mites, harvest bugs, harvest lice, mower’s mites, and redbugs.¹ The term chigger specifically describes the larval stage of this mite’s life cycle, as it is the only stage responsible for chigger bites. The nymph and adult phases feed on vegetable matter. Trombiculid mites are most often found in forests, grassy areas, gardens, and moist areas of soil near bodies of water. Trombicula alfreddugesi is the most common species in the United States, and these mites mainly live in the southeastern and south central regions of the country. Conversely, Trombicula autumnalis is most predominant in Western Europe and East Asia.¹

The life cycle of the mite includes the egg, larval, nymphal, and adult stages.² Due to their need for air humidity greater than 80%, mites lay their eggs on low leaves, blades of grass, or on the ground. They spend most of their lives on vegetation no more than 30 cm above ground level.³ Eggs remain dormant for approximately 6 days until the hatching of the prelarvae, which have 6 legs and are nonfeeding. It takes another 6 days for the prelarvae to mature into larvae. Measuring 0.15 to 0.3 mm in length, mite larvae are a mere fraction of the size of adult mites, which generally are 1 to 2 mm in length, and are bright red or brown-red in color (Figure 1).

The biting larvae have many acceptable hosts including turtles, toads, birds, small mammals, and humans, which act as accidental hosts. Larvae remain on vegetation waiting for a suitable host to pass by so they may attach to its skin and remain there for several days. In the exploration for an ideal area to begin feeding (eg, thin epidermis,⁴ localized increased air humidity⁵), larvae can travel extensively on the skin; however, they often are stopped by tight-fitting sections of clothing (eg, waistbands), so bites are mostly found in clusters. To feed, mite larvae latch onto the skin using chelicerae, jawlike appendages found in the front of the mouth in arachnids.⁶ They then inject digestive enzymes that liquefy epidermal cells on direct contact, which results in the formation of a stylostome from which the mites may suck up lymph fluid and broken down tissue.⁷ Although the actual initial bite is painless, this feeding process leads to the localized inflammation and irritation noticed by infested patients.⁸

The classic clinical presentation includes severe pruritus and cutaneous swelling as well as erythema caused by the combination of several factors, such as enzyme-induced cellular mechanical damage, human immune response, and sometimes a superimposed bacterial infection. Papules and papulovesicles appear in groups, most commonly affecting the legs and waistline (Figure 2).⁹ Itching generally occurs within hours of larval latching and subsides within 72 hours. Cutaneous lesions typically take 1 to 2 weeks to heal. In some rare cases, patients may react with urticarial, bullous, or morbilliform eruptions, and the inflammation and pruritus can last for weeks.⁶ Summer penile syndrome has been noted in boys who display a local hypersensitivity to chigger bites.¹⁰ This syndrome represents a triad of penile swelling, dysuria, and pruritus, which lasts for a few days to a few weeks.

Disease Management

Because the lesions are self-healing, treatment is focused on symptomatic relief of itching by means of topical antipruritics (eg, camphor and menthol, pramoxine lotion) or oral antihistamines (eg, diphenhydramine, hydroxyzine). Potent topical corticosteroids may be used to alleviate inflammation and pruritus, especially when occluded under plastic wrap to increase absorption. In severe cases, an intralesional triamcinolone acetonide (2.5–5 mg/mL) injection may be required.⁹ The best practice, however, is to take preventative measures to avoid becoming a host for the mites. Patients should take special care when traveling in infested areas by completely covering their skin, tucking pant cuffs into their socks, and applying products containing DEET (N,N-diethyl-meta-toluamide or N,N-diethyl-3-methylbenzamide) to the skin and clothing. The odds of prevention are increased even further when clothing also is treated with permethrin.¹¹

In parts of Asia and Australia, these mites may transmit Orientia tsutsugamushi, the organism responsible for scrub typhus, through their saliva during a bite.¹² Scrub typhus is associated with an eschar, as well as fever, intense headache, and diffuse myalgia. It responds well to treatment with doxycycline 100 mg twice daily.¹³ Studies investigating genetic material found in trombiculid mites across the globe have detected Ehrlichia-specific DNA in Spain,¹⁴Borrelia-specific DNA in the Czech Republic,^15,16 and Hantavirus-specific RNA in Texas.¹⁷ There is evidence that the mites play a role in maintenance of zoonotic reservoirs, while humans are infected via ingestion or inhalation of infectious rodent extreta.¹⁸

Identifying Characteristics and Disease Transmission

Chiggers belong to the Trombiculidae family of mites and also are referred to as harvest mites, harvest bugs, harvest lice, mower’s mites, and redbugs.¹ The term chigger specifically describes the larval stage of this mite’s life cycle, as it is the only stage responsible for chigger bites. The nymph and adult phases feed on vegetable matter. Trombiculid mites are most often found in forests, grassy areas, gardens, and moist areas of soil near bodies of water. Trombicula alfreddugesi is the most common species in the United States, and these mites mainly live in the southeastern and south central regions of the country. Conversely, Trombicula autumnalis is most predominant in Western Europe and East Asia.¹

The life cycle of the mite includes the egg, larval, nymphal, and adult stages.² Due to their need for air humidity greater than 80%, mites lay their eggs on low leaves, blades of grass, or on the ground. They spend most of their lives on vegetation no more than 30 cm above ground level.³ Eggs remain dormant for approximately 6 days until the hatching of the prelarvae, which have 6 legs and are nonfeeding. It takes another 6 days for the prelarvae to mature into larvae. Measuring 0.15 to 0.3 mm in length, mite larvae are a mere fraction of the size of adult mites, which generally are 1 to 2 mm in length, and are bright red or brown-red in color (Figure 1).

The biting larvae have many acceptable hosts including turtles, toads, birds, small mammals, and humans, which act as accidental hosts. Larvae remain on vegetation waiting for a suitable host to pass by so they may attach to its skin and remain there for several days. In the exploration for an ideal area to begin feeding (eg, thin epidermis,⁴ localized increased air humidity⁵), larvae can travel extensively on the skin; however, they often are stopped by tight-fitting sections of clothing (eg, waistbands), so bites are mostly found in clusters. To feed, mite larvae latch onto the skin using chelicerae, jawlike appendages found in the front of the mouth in arachnids.⁶ They then inject digestive enzymes that liquefy epidermal cells on direct contact, which results in the formation of a stylostome from which the mites may suck up lymph fluid and broken down tissue.⁷ Although the actual initial bite is painless, this feeding process leads to the localized inflammation and irritation noticed by infested patients.⁸

The classic clinical presentation includes severe pruritus and cutaneous swelling as well as erythema caused by the combination of several factors, such as enzyme-induced cellular mechanical damage, human immune response, and sometimes a superimposed bacterial infection. Papules and papulovesicles appear in groups, most commonly affecting the legs and waistline (Figure 2).⁹ Itching generally occurs within hours of larval latching and subsides within 72 hours. Cutaneous lesions typically take 1 to 2 weeks to heal. In some rare cases, patients may react with urticarial, bullous, or morbilliform eruptions, and the inflammation and pruritus can last for weeks.⁶ Summer penile syndrome has been noted in boys who display a local hypersensitivity to chigger bites.¹⁰ This syndrome represents a triad of penile swelling, dysuria, and pruritus, which lasts for a few days to a few weeks.

Disease Management

Because the lesions are self-healing, treatment is focused on symptomatic relief of itching by means of topical antipruritics (eg, camphor and menthol, pramoxine lotion) or oral antihistamines (eg, diphenhydramine, hydroxyzine). Potent topical corticosteroids may be used to alleviate inflammation and pruritus, especially when occluded under plastic wrap to increase absorption. In severe cases, an intralesional triamcinolone acetonide (2.5–5 mg/mL) injection may be required.⁹ The best practice, however, is to take preventative measures to avoid becoming a host for the mites. Patients should take special care when traveling in infested areas by completely covering their skin, tucking pant cuffs into their socks, and applying products containing DEET (N,N-diethyl-meta-toluamide or N,N-diethyl-3-methylbenzamide) to the skin and clothing. The odds of prevention are increased even further when clothing also is treated with permethrin.¹¹

In parts of Asia and Australia, these mites may transmit Orientia tsutsugamushi, the organism responsible for scrub typhus, through their saliva during a bite.¹² Scrub typhus is associated with an eschar, as well as fever, intense headache, and diffuse myalgia. It responds well to treatment with doxycycline 100 mg twice daily.¹³ Studies investigating genetic material found in trombiculid mites across the globe have detected Ehrlichia-specific DNA in Spain,¹⁴Borrelia-specific DNA in the Czech Republic,^15,16 and Hantavirus-specific RNA in Texas.¹⁷ There is evidence that the mites play a role in maintenance of zoonotic reservoirs, while humans are infected via ingestion or inhalation of infectious rodent extreta.¹⁸

Identifying Characteristics and Disease Transmission

Chiggers belong to the Trombiculidae family of mites and also are referred to as harvest mites, harvest bugs, harvest lice, mower’s mites, and redbugs.¹ The term chigger specifically describes the larval stage of this mite’s life cycle, as it is the only stage responsible for chigger bites. The nymph and adult phases feed on vegetable matter. Trombiculid mites are most often found in forests, grassy areas, gardens, and moist areas of soil near bodies of water. Trombicula alfreddugesi is the most common species in the United States, and these mites mainly live in the southeastern and south central regions of the country. Conversely, Trombicula autumnalis is most predominant in Western Europe and East Asia.¹

The life cycle of the mite includes the egg, larval, nymphal, and adult stages.² Due to their need for air humidity greater than 80%, mites lay their eggs on low leaves, blades of grass, or on the ground. They spend most of their lives on vegetation no more than 30 cm above ground level.³ Eggs remain dormant for approximately 6 days until the hatching of the prelarvae, which have 6 legs and are nonfeeding. It takes another 6 days for the prelarvae to mature into larvae. Measuring 0.15 to 0.3 mm in length, mite larvae are a mere fraction of the size of adult mites, which generally are 1 to 2 mm in length, and are bright red or brown-red in color (Figure 1).

The biting larvae have many acceptable hosts including turtles, toads, birds, small mammals, and humans, which act as accidental hosts. Larvae remain on vegetation waiting for a suitable host to pass by so they may attach to its skin and remain there for several days. In the exploration for an ideal area to begin feeding (eg, thin epidermis,⁴ localized increased air humidity⁵), larvae can travel extensively on the skin; however, they often are stopped by tight-fitting sections of clothing (eg, waistbands), so bites are mostly found in clusters. To feed, mite larvae latch onto the skin using chelicerae, jawlike appendages found in the front of the mouth in arachnids.⁶ They then inject digestive enzymes that liquefy epidermal cells on direct contact, which results in the formation of a stylostome from which the mites may suck up lymph fluid and broken down tissue.⁷ Although the actual initial bite is painless, this feeding process leads to the localized inflammation and irritation noticed by infested patients.⁸

The classic clinical presentation includes severe pruritus and cutaneous swelling as well as erythema caused by the combination of several factors, such as enzyme-induced cellular mechanical damage, human immune response, and sometimes a superimposed bacterial infection. Papules and papulovesicles appear in groups, most commonly affecting the legs and waistline (Figure 2).⁹ Itching generally occurs within hours of larval latching and subsides within 72 hours. Cutaneous lesions typically take 1 to 2 weeks to heal. In some rare cases, patients may react with urticarial, bullous, or morbilliform eruptions, and the inflammation and pruritus can last for weeks.⁶ Summer penile syndrome has been noted in boys who display a local hypersensitivity to chigger bites.¹⁰ This syndrome represents a triad of penile swelling, dysuria, and pruritus, which lasts for a few days to a few weeks.

Disease Management

Because the lesions are self-healing, treatment is focused on symptomatic relief of itching by means of topical antipruritics (eg, camphor and menthol, pramoxine lotion) or oral antihistamines (eg, diphenhydramine, hydroxyzine). Potent topical corticosteroids may be used to alleviate inflammation and pruritus, especially when occluded under plastic wrap to increase absorption. In severe cases, an intralesional triamcinolone acetonide (2.5–5 mg/mL) injection may be required.⁹ The best practice, however, is to take preventative measures to avoid becoming a host for the mites. Patients should take special care when traveling in infested areas by completely covering their skin, tucking pant cuffs into their socks, and applying products containing DEET (N,N-diethyl-meta-toluamide or N,N-diethyl-3-methylbenzamide) to the skin and clothing. The odds of prevention are increased even further when clothing also is treated with permethrin.¹¹

In parts of Asia and Australia, these mites may transmit Orientia tsutsugamushi, the organism responsible for scrub typhus, through their saliva during a bite.¹² Scrub typhus is associated with an eschar, as well as fever, intense headache, and diffuse myalgia. It responds well to treatment with doxycycline 100 mg twice daily.¹³ Studies investigating genetic material found in trombiculid mites across the globe have detected Ehrlichia-specific DNA in Spain,¹⁴Borrelia-specific DNA in the Czech Republic,^15,16 and Hantavirus-specific RNA in Texas.¹⁷ There is evidence that the mites play a role in maintenance of zoonotic reservoirs, while humans are infected via ingestion or inhalation of infectious rodent extreta.¹⁸

NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.

Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).

The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.

The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.

Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.

“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.

In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.

However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.

CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.

Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).

Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.

With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).

This effect was not explained by CD20 expression levels, Dr. Tausch said.

The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.

“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.

Dr. Tausch reported receiving research support from Novartis.

[email protected]

NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.

Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).

The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.

The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.

Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.

“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.

In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.

However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.

CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.

Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).

Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.

With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).

This effect was not explained by CD20 expression levels, Dr. Tausch said.

The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.

“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.

Dr. Tausch reported receiving research support from Novartis.

[email protected]

NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.

Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).

The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.

The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.

Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.

“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.

In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.

However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.

CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.

Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).

Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.

With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).

This effect was not explained by CD20 expression levels, Dr. Tausch said.

The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.

“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.

Dr. Tausch reported receiving research support from Novartis.

[email protected]

Americans are buying less packaged food and beverages these days, and they’re getting less salt in the food that they do buy, but very few are getting the optimal sodium density in their purchases, according to a study involving more than 170,000 households.

First, salt content: In 2014, the households taking part in the Nielsen Homescan Consumer Panel were getting 361 mg of salt per 100 g of packaged food purchased, which is 12% less than the 411 mg per 100 g of food purchased in 2000. Overall sodium content, which includes beverages, dropped from 192 mg/100 g to 186 mg/100 g, said Jennifer M. Poti, PhD, of the University of North Carolina at Chapel Hill, and her associates.

[email protected]

Americans are buying less packaged food and beverages these days, and they’re getting less salt in the food that they do buy, but very few are getting the optimal sodium density in their purchases, according to a study involving more than 170,000 households.

First, salt content: In 2014, the households taking part in the Nielsen Homescan Consumer Panel were getting 361 mg of salt per 100 g of packaged food purchased, which is 12% less than the 411 mg per 100 g of food purchased in 2000. Overall sodium content, which includes beverages, dropped from 192 mg/100 g to 186 mg/100 g, said Jennifer M. Poti, PhD, of the University of North Carolina at Chapel Hill, and her associates.

[email protected]

Americans are buying less packaged food and beverages these days, and they’re getting less salt in the food that they do buy, but very few are getting the optimal sodium density in their purchases, according to a study involving more than 170,000 households.

First, salt content: In 2014, the households taking part in the Nielsen Homescan Consumer Panel were getting 361 mg of salt per 100 g of packaged food purchased, which is 12% less than the 411 mg per 100 g of food purchased in 2000. Overall sodium content, which includes beverages, dropped from 192 mg/100 g to 186 mg/100 g, said Jennifer M. Poti, PhD, of the University of North Carolina at Chapel Hill, and her associates.

[email protected]

Psoriasis is a chronic, inflammatory, T-cell–mediated skin disease. Phototherapy, which consists of light used at various wavelengths, is a well-established treatment method for psoriasis vulgaris. Although successful results have been obtained with phototherapy in psoriasis, its mechanism of action is not fully understood. UV light has been shown to have an effect on T-lymphocyte function as well as various components of the natural and acquired immune response. It also has a suppressive effect on the immune system caused by many independent effects.¹ Phototherapy currently is available using broadband UVB (290–320 nm), narrowband UVB (NB-UVB)(311–313 nm), 308-nm excimer laser, UVA1 (340–400 nm), psoralen plus UVA, and photopheresis.² Narrowband UVB treatment with light sources that peak at 311 to 313 nm have been used with high efficacy and a low side-effect profile, becoming the standard phototherapy method for chronic plaque-type psoriasis.³

More than 90% of vitamin D synthesis is formed in the skin following UV exposure, and the wavelengths and the solar spectrum that stimulate vitamin D synthesis have been a focus of research.⁴ 7-Dehydrocholesterol (provitamin D₃) is first converted to previtamin D₃. Although the necessary UV wavelength for previtamin D₃ synthesis is 295 to 300 nm, it is known that production stops below 260 nm and above 315 nm.^4-6 Previtamin D₃ is unstable and is quickly converted to vitamin D₃ in the skinand then to the biologically active form of 1,25-dihydroxyvitamin D₃ (calcitriol) following hydroxylation in the liver and kidneys. Calcitriol shows its effect by binding to the special nuclear receptor for vitamin D.⁷ Many tissues including the keratinocytes, dendritic cells, melanocytes, and sebocytes in the skin have been shown to possess the enzymatic mechanism necessary for 1,25-dihydroxyvitamin D₃ production. Vitamin D also is known to have paracrine, autocrine, and intracrine effects on immunomodulation, cell proliferation, differentiation, and apoptosis, in addition to its role in calcium metabolism.^5-9 Topical vitamin D and its analogues are used effectively and safely in psoriasis treatment with these effects.¹⁰ A correlation between low serum vitamin D levels and chronic inflammation severity has been shown in psoriasis patients in some studies.^11,12

In this study, we sought to evaluate the effect of NB-UVB on vitamin D status and related metabolic markers in patients with psoriasis.

Methods

This prospective, single-center study included patients living in or around Eskisehir, Turkey, who were 18 years of age or older and had been diagnosed with chronic plaque psoriasis with a psoriasis area and severity index (PASI) score of 5 or higher. Permission was granted by the local ethics committee. Patients provided written informed consent prior to enrollment. Patients were excluded if they were younger than 18 years; were pregnant or breastfeeding; stayed in open environments for more than 2 hours per day during the summer months (May through September); used drugs affecting calcium metabolism in the last 8 weeks (eg, barbiturates, anticonvulsants, corticosteroids, vitamin D supplements, bisphosphonates); used systemic treatment for psoriasis in the last 8 weeks; used phototherapy or sunbathing in the last 8 weeks; used topical vitamin D analogues in the last 4 weeks; or had a history of psoriatic arthritis and other inflammatory disorders, renal disease, known calcium metabolism disorders, granulomatous disorders, thyroid disease, diabetes mellitus, skin cancer, or abnormal photosensitivity and known lack of response or hypersensitivity to phototherapy.

Clinical Evaluation and Laboratory Studies
The participants’ age, gender, Fitzpatrick skin type, disease duration, dairy intake and vitamin supplement levels, hours of sun exposure per week, detailed medical history, and medications were obtained and documented in the medical records.

Serum 25(OH)D levels were measured using high-performance liquid chromatography/mass spectrometry, serum calcium and phosphorus levels using colorimetric analysis, serum alkaline phosphatase (ALP) levels using the enzymatic colorimetric method, and serum parathyroid hormone (PTH) levels using electrochemiluminescence at baseline and after PASI 75 was achieved with treatment. Vitamin D levels were classified in 3 groups: (1) deficient (<20 ng/mL); (2) inadequate (20–30 ng/mL); and (3) adequate (>30 ng/mL). The PASI scores at baseline and posttreatment were calculated by the same dermatologist (S.S.).

Treatment Protocol and Patient Follow-up
Narrowband UVB treatment was started at 70% of the minimal erythema dose (MED). Phototherapy was administered 3 times weekly for 6 months or until PASI 75 response was achieved. An increase of 20% to 30% from the prior dose was made according to the participants’ clinical status at each treatment session, and the dose was stabilized once the maximum dose was achieved according to skin type—up to 2000 mJ/cm² for Fitzpatrick skin types I and II, 3000 mJ/cm² for skin types III and IV, and 5000 mJ/cm² for skin types V and VI. Participants were allowed to use low- and moderate-potency topical corticosteroids and moisturizers containing urea during the course of treatment. The study physician (S.S.) clinically evaluated participants every 4 weeks for 6 months or until PASI 75 was achieved, and the clinical improvement was calculated as the percentage decrease in PASI score.

Statistical Analysis
The Shapiro-Wilk normalcy test was used for the continuous variables in the study. Variables with a normal distribution were analyzed with the paired t test and 1-way analysis of variance test and presented as mean (SD). Variables without a normal distribution were analyzed with the Wilcoxon t test and the Kruskal-Wallis test and presented as the median and 25th and 75th quartiles. The serum 25(OH)D levels were evaluated according to the seasons with the Kruskal-Wallis test. Categorical variables were expressed as frequency and percentages. The Pearson and Spearman correlation analysis and regression analysis were used to show the relationship between the variables (ie, age, Fitzpatrick skin type, PASI score, maximum NB-UVB dose, and number of sessions). The statistical significance level was set at P≤.05. Statistical analyses were performed using SPSS software version 21.

Results

A total of 49 participants (30 [61.22%] males; 19 [38.78%] females) were included in the study. The mean age (SD) was 40.27 (14.62) years (range, 19–74 years). Three (6.12%) participants were Fitzpatrick skin type I, 15 (30.61%) were skin type II, and 31 (63.27%) were skin type III.

The baseline median PASI score for the 49 participants was 10.20 (7.85–13.65). Baseline serum 25(OH)D levels were noted to be deficient in 40 participants (81.63%) and inadequate in 9 participants (18.37%). The distribution of the serum 25(OH)D levels of the participants according to the season was evaluated with the Kruskal-Wallis test and no association was found between serum 25(OH)D levels and seasonal changes (P=.685). Comparison of 25(OH)D basal values with Fitzpatrick skin type revealed a statistically significant relationship between skin type and vitamin D level (P=.024). The basal serum 25(OH)D levels were significantly lower in Fitzpatrick skin type II versus skin type I (P=.039).

Thirty-two (65.31%) participants achieved PASI 75 by the end of treatment. The baseline median PASI score (25th-75th quartiles) for the 32 patients was 10.45 (8.20-13.83) and the posttreatment PASI score was 1.95 (1.20-3.55), a statistically significant decrease following treatment (P<.001)(Table 1). Mean (SD) baseline serum 25(OH)D levels were 14.14 (6.70) ng/mL and posttreatment levels were 46.42 (15.51) ng/mL in these participants, which demonstrated a statistically significant increase during NB-UVB treatment (P<.001). None of the participants reached the toxicity levels (>80 ng/mL) for serum 25(OH)D. There were no significant changes in serum calcium or phosphorus levels posttreatment (Table 1), but statistically significant decreases in serum ALP and PTH levels were noted (P=.001 and P=.019, respectively)(Table 1).

Participants who completed the study (n=32) received an average (SD) of 30.09 (7.53) sessions of NB-UVB treatment and the mean (SD) MED was 611.88 (240.14) mJ/cm². The mean (SD) maximum dose was 2090.09 (341.78) mJ/cm² (Table 2).

Posttreatment serum 25(OH)D levels were compared with the number of NB-UVB phototherapy sessions and the maximum dose values. We found that the posttreatment serum 25(OH)D levels correlated with the number of sessions (P=.031) but not with the maximum dose (P=.498).

Using regression analysis, we also evaluated the effect of the increase in vitamin D levels—posttreatment serum 25(OH)D level minus baseline serum 25(OH)D levels—on the decrease in PASI scores—baseline PASI score minus posttreatment PASI score—and found no effect of serum 25(OH)D level increase on PASI decrease (P=.530). There was no correlation between increased serum 25(OH)D levels and age, Fitzpatrick skin type, or baseline PASI score.

Comment

The most effective UV wavelength for vitamin D synthesis is 295 to 300 nm, and therefore broadband UVB is frequently studied when determining the relationship between phototherapy and serum vitamin D levels.⁴ The current study demonstrated a statistically significant increase in serum 25(OH)D levels following NB-UVB treatment in patients with moderate to severe chronic plaque psoriasis (P<.001). This result supports other studies reporting that NB-UVB treatment in psoriasis patients increases serum 25(OH)D levels.^13-18

The main factor in the effective UVB level for vitamin D synthesis is the angle at which solar radiation reaches the earth, which is affected by the longitude, latitude, and time of day.¹⁹ For this reason, we planned to perform our study at a single center. Patients who stayed in open areas for more than 2 hours per day during the summer months (May through September) were excluded from the study to decrease the effect of seasonal changes on vitamin D levels. We evaluated the seasonal variation of vitamin D levels and found no relationship between seasonal changes and serum 25(OH)D levels. Therefore, the potential effect of seasonal changes on the vitamin D levels of study participants was excluded from the study.

The response to UV radiation changes according to age and Fitzpatrick skin type because 7-dehydrocholesterol levels decrease with age and melanin prevents the access of UVB photons to 7-dehydrocholesterol.²⁰ The basal serum 25(OH)D levels were deficient in 81.63% of participants and inadequate in 18.37%. In this study, we also observed that the basal serum 25(OH)D levels were significantly lower in patients with Fitzpatrick skin type II than in Fitzpatrick skin type I (P=.039). The mean (SD) serum 25(OH)D level at baseline was 14.14 (6.70) ng/mL and posttreatment was 46.42 (15.51) ng/mL in the 32 patients who completed the study. Serum 25(OH)D levels showed a statistically significant increase after NB-UVB treatment (P<.001). The increased serum 25(OH)D levels after NB-UVB phototherapy were not associated with Fitzpatrick skin type, which was consistent with the results of Osmancevic et al.¹⁷ The adjusted NB-UVB doses according to the different skin types might be responsible for this result in our study.

Participant age did not have a significant effect on serum 25(OH)D levels, similar to other studies in the literature.^13,17 We believe that artificial UVB radiation at high doses can compensate for the 7-dehydrocholesterol that decreases in the skin with aging.

We observed no significant change in the serum calcium and phosphorus levels with NB-UVB treatment in our study. None of the participants had a metabolic disorder related to increased 25(OH)D levels. The serum ALP and PTH levels decreased significantly following treatment (P=.001 and P=.019, respectively), which may have been secondary to increased serum 25(OH)D levels.

Posttreatment serum 25(OH)D levels were compared with the number of NB-UVB phototherapy sessions and maximum dose values. The posttreatment serum 25(OH)D levels were found to be related to the number of sessions received, but this value was not correlated with the maximum dose received. The MED and maximum dose were determined according to the Fitzpatrick skin type of the participants. Therefore, increased serum 25(OH)D levels with an increased number of sessions was an expected result. Our observation is in accordance with the finding described by Ryan et al.¹⁴ On the other hand, an in vitro study conducted by Olds et al²¹ reported that the relationship between UV light and cholecalciferol synthesis was not linear.

We found that increased serum 25(OH)D levels after treatment were not correlated with the decrease in PASI score, similar to studies by Romaní et al¹⁸ and Ryan et al.¹⁴ These results suggest that the clinical improvement following NB-UVB treatment is independent of the increased serum 25(OH)D levels in psoriasis patients.

Conclusion

In conclusion, we found that the serum 25(OH)D levels that increase as a result of NB-UVB therapy for the treatment of chronic plaque psoriasis has no statistically significant relationship with the age, Fitzpatrick skin type, baseline PASI score, changes in PASI, or maximum dose, while a positive relationship is present between the serum 25(OH)D levels and the number of sessions of NB-UVB.

Psoriasis is a chronic, inflammatory, T-cell–mediated skin disease. Phototherapy, which consists of light used at various wavelengths, is a well-established treatment method for psoriasis vulgaris. Although successful results have been obtained with phototherapy in psoriasis, its mechanism of action is not fully understood. UV light has been shown to have an effect on T-lymphocyte function as well as various components of the natural and acquired immune response. It also has a suppressive effect on the immune system caused by many independent effects.¹ Phototherapy currently is available using broadband UVB (290–320 nm), narrowband UVB (NB-UVB)(311–313 nm), 308-nm excimer laser, UVA1 (340–400 nm), psoralen plus UVA, and photopheresis.² Narrowband UVB treatment with light sources that peak at 311 to 313 nm have been used with high efficacy and a low side-effect profile, becoming the standard phototherapy method for chronic plaque-type psoriasis.³

More than 90% of vitamin D synthesis is formed in the skin following UV exposure, and the wavelengths and the solar spectrum that stimulate vitamin D synthesis have been a focus of research.⁴ 7-Dehydrocholesterol (provitamin D₃) is first converted to previtamin D₃. Although the necessary UV wavelength for previtamin D₃ synthesis is 295 to 300 nm, it is known that production stops below 260 nm and above 315 nm.^4-6 Previtamin D₃ is unstable and is quickly converted to vitamin D₃ in the skinand then to the biologically active form of 1,25-dihydroxyvitamin D₃ (calcitriol) following hydroxylation in the liver and kidneys. Calcitriol shows its effect by binding to the special nuclear receptor for vitamin D.⁷ Many tissues including the keratinocytes, dendritic cells, melanocytes, and sebocytes in the skin have been shown to possess the enzymatic mechanism necessary for 1,25-dihydroxyvitamin D₃ production. Vitamin D also is known to have paracrine, autocrine, and intracrine effects on immunomodulation, cell proliferation, differentiation, and apoptosis, in addition to its role in calcium metabolism.^5-9 Topical vitamin D and its analogues are used effectively and safely in psoriasis treatment with these effects.¹⁰ A correlation between low serum vitamin D levels and chronic inflammation severity has been shown in psoriasis patients in some studies.^11,12

In this study, we sought to evaluate the effect of NB-UVB on vitamin D status and related metabolic markers in patients with psoriasis.

Methods

This prospective, single-center study included patients living in or around Eskisehir, Turkey, who were 18 years of age or older and had been diagnosed with chronic plaque psoriasis with a psoriasis area and severity index (PASI) score of 5 or higher. Permission was granted by the local ethics committee. Patients provided written informed consent prior to enrollment. Patients were excluded if they were younger than 18 years; were pregnant or breastfeeding; stayed in open environments for more than 2 hours per day during the summer months (May through September); used drugs affecting calcium metabolism in the last 8 weeks (eg, barbiturates, anticonvulsants, corticosteroids, vitamin D supplements, bisphosphonates); used systemic treatment for psoriasis in the last 8 weeks; used phototherapy or sunbathing in the last 8 weeks; used topical vitamin D analogues in the last 4 weeks; or had a history of psoriatic arthritis and other inflammatory disorders, renal disease, known calcium metabolism disorders, granulomatous disorders, thyroid disease, diabetes mellitus, skin cancer, or abnormal photosensitivity and known lack of response or hypersensitivity to phototherapy.

Clinical Evaluation and Laboratory Studies
The participants’ age, gender, Fitzpatrick skin type, disease duration, dairy intake and vitamin supplement levels, hours of sun exposure per week, detailed medical history, and medications were obtained and documented in the medical records.

Serum 25(OH)D levels were measured using high-performance liquid chromatography/mass spectrometry, serum calcium and phosphorus levels using colorimetric analysis, serum alkaline phosphatase (ALP) levels using the enzymatic colorimetric method, and serum parathyroid hormone (PTH) levels using electrochemiluminescence at baseline and after PASI 75 was achieved with treatment. Vitamin D levels were classified in 3 groups: (1) deficient (<20 ng/mL); (2) inadequate (20–30 ng/mL); and (3) adequate (>30 ng/mL). The PASI scores at baseline and posttreatment were calculated by the same dermatologist (S.S.).

Treatment Protocol and Patient Follow-up
Narrowband UVB treatment was started at 70% of the minimal erythema dose (MED). Phototherapy was administered 3 times weekly for 6 months or until PASI 75 response was achieved. An increase of 20% to 30% from the prior dose was made according to the participants’ clinical status at each treatment session, and the dose was stabilized once the maximum dose was achieved according to skin type—up to 2000 mJ/cm² for Fitzpatrick skin types I and II, 3000 mJ/cm² for skin types III and IV, and 5000 mJ/cm² for skin types V and VI. Participants were allowed to use low- and moderate-potency topical corticosteroids and moisturizers containing urea during the course of treatment. The study physician (S.S.) clinically evaluated participants every 4 weeks for 6 months or until PASI 75 was achieved, and the clinical improvement was calculated as the percentage decrease in PASI score.

Statistical Analysis
The Shapiro-Wilk normalcy test was used for the continuous variables in the study. Variables with a normal distribution were analyzed with the paired t test and 1-way analysis of variance test and presented as mean (SD). Variables without a normal distribution were analyzed with the Wilcoxon t test and the Kruskal-Wallis test and presented as the median and 25th and 75th quartiles. The serum 25(OH)D levels were evaluated according to the seasons with the Kruskal-Wallis test. Categorical variables were expressed as frequency and percentages. The Pearson and Spearman correlation analysis and regression analysis were used to show the relationship between the variables (ie, age, Fitzpatrick skin type, PASI score, maximum NB-UVB dose, and number of sessions). The statistical significance level was set at P≤.05. Statistical analyses were performed using SPSS software version 21.

Results

A total of 49 participants (30 [61.22%] males; 19 [38.78%] females) were included in the study. The mean age (SD) was 40.27 (14.62) years (range, 19–74 years). Three (6.12%) participants were Fitzpatrick skin type I, 15 (30.61%) were skin type II, and 31 (63.27%) were skin type III.

The baseline median PASI score for the 49 participants was 10.20 (7.85–13.65). Baseline serum 25(OH)D levels were noted to be deficient in 40 participants (81.63%) and inadequate in 9 participants (18.37%). The distribution of the serum 25(OH)D levels of the participants according to the season was evaluated with the Kruskal-Wallis test and no association was found between serum 25(OH)D levels and seasonal changes (P=.685). Comparison of 25(OH)D basal values with Fitzpatrick skin type revealed a statistically significant relationship between skin type and vitamin D level (P=.024). The basal serum 25(OH)D levels were significantly lower in Fitzpatrick skin type II versus skin type I (P=.039).

Thirty-two (65.31%) participants achieved PASI 75 by the end of treatment. The baseline median PASI score (25th-75th quartiles) for the 32 patients was 10.45 (8.20-13.83) and the posttreatment PASI score was 1.95 (1.20-3.55), a statistically significant decrease following treatment (P<.001)(Table 1). Mean (SD) baseline serum 25(OH)D levels were 14.14 (6.70) ng/mL and posttreatment levels were 46.42 (15.51) ng/mL in these participants, which demonstrated a statistically significant increase during NB-UVB treatment (P<.001). None of the participants reached the toxicity levels (>80 ng/mL) for serum 25(OH)D. There were no significant changes in serum calcium or phosphorus levels posttreatment (Table 1), but statistically significant decreases in serum ALP and PTH levels were noted (P=.001 and P=.019, respectively)(Table 1).

Participants who completed the study (n=32) received an average (SD) of 30.09 (7.53) sessions of NB-UVB treatment and the mean (SD) MED was 611.88 (240.14) mJ/cm². The mean (SD) maximum dose was 2090.09 (341.78) mJ/cm² (Table 2).

Posttreatment serum 25(OH)D levels were compared with the number of NB-UVB phototherapy sessions and the maximum dose values. We found that the posttreatment serum 25(OH)D levels correlated with the number of sessions (P=.031) but not with the maximum dose (P=.498).

Using regression analysis, we also evaluated the effect of the increase in vitamin D levels—posttreatment serum 25(OH)D level minus baseline serum 25(OH)D levels—on the decrease in PASI scores—baseline PASI score minus posttreatment PASI score—and found no effect of serum 25(OH)D level increase on PASI decrease (P=.530). There was no correlation between increased serum 25(OH)D levels and age, Fitzpatrick skin type, or baseline PASI score.

Comment

The most effective UV wavelength for vitamin D synthesis is 295 to 300 nm, and therefore broadband UVB is frequently studied when determining the relationship between phototherapy and serum vitamin D levels.⁴ The current study demonstrated a statistically significant increase in serum 25(OH)D levels following NB-UVB treatment in patients with moderate to severe chronic plaque psoriasis (P<.001). This result supports other studies reporting that NB-UVB treatment in psoriasis patients increases serum 25(OH)D levels.^13-18

The main factor in the effective UVB level for vitamin D synthesis is the angle at which solar radiation reaches the earth, which is affected by the longitude, latitude, and time of day.¹⁹ For this reason, we planned to perform our study at a single center. Patients who stayed in open areas for more than 2 hours per day during the summer months (May through September) were excluded from the study to decrease the effect of seasonal changes on vitamin D levels. We evaluated the seasonal variation of vitamin D levels and found no relationship between seasonal changes and serum 25(OH)D levels. Therefore, the potential effect of seasonal changes on the vitamin D levels of study participants was excluded from the study.

The response to UV radiation changes according to age and Fitzpatrick skin type because 7-dehydrocholesterol levels decrease with age and melanin prevents the access of UVB photons to 7-dehydrocholesterol.²⁰ The basal serum 25(OH)D levels were deficient in 81.63% of participants and inadequate in 18.37%. In this study, we also observed that the basal serum 25(OH)D levels were significantly lower in patients with Fitzpatrick skin type II than in Fitzpatrick skin type I (P=.039). The mean (SD) serum 25(OH)D level at baseline was 14.14 (6.70) ng/mL and posttreatment was 46.42 (15.51) ng/mL in the 32 patients who completed the study. Serum 25(OH)D levels showed a statistically significant increase after NB-UVB treatment (P<.001). The increased serum 25(OH)D levels after NB-UVB phototherapy were not associated with Fitzpatrick skin type, which was consistent with the results of Osmancevic et al.¹⁷ The adjusted NB-UVB doses according to the different skin types might be responsible for this result in our study.

Participant age did not have a significant effect on serum 25(OH)D levels, similar to other studies in the literature.^13,17 We believe that artificial UVB radiation at high doses can compensate for the 7-dehydrocholesterol that decreases in the skin with aging.

We observed no significant change in the serum calcium and phosphorus levels with NB-UVB treatment in our study. None of the participants had a metabolic disorder related to increased 25(OH)D levels. The serum ALP and PTH levels decreased significantly following treatment (P=.001 and P=.019, respectively), which may have been secondary to increased serum 25(OH)D levels.

Posttreatment serum 25(OH)D levels were compared with the number of NB-UVB phototherapy sessions and maximum dose values. The posttreatment serum 25(OH)D levels were found to be related to the number of sessions received, but this value was not correlated with the maximum dose received. The MED and maximum dose were determined according to the Fitzpatrick skin type of the participants. Therefore, increased serum 25(OH)D levels with an increased number of sessions was an expected result. Our observation is in accordance with the finding described by Ryan et al.¹⁴ On the other hand, an in vitro study conducted by Olds et al²¹ reported that the relationship between UV light and cholecalciferol synthesis was not linear.

We found that increased serum 25(OH)D levels after treatment were not correlated with the decrease in PASI score, similar to studies by Romaní et al¹⁸ and Ryan et al.¹⁴ These results suggest that the clinical improvement following NB-UVB treatment is independent of the increased serum 25(OH)D levels in psoriasis patients.

Conclusion

In conclusion, we found that the serum 25(OH)D levels that increase as a result of NB-UVB therapy for the treatment of chronic plaque psoriasis has no statistically significant relationship with the age, Fitzpatrick skin type, baseline PASI score, changes in PASI, or maximum dose, while a positive relationship is present between the serum 25(OH)D levels and the number of sessions of NB-UVB.

Psoriasis is a chronic, inflammatory, T-cell–mediated skin disease. Phototherapy, which consists of light used at various wavelengths, is a well-established treatment method for psoriasis vulgaris. Although successful results have been obtained with phototherapy in psoriasis, its mechanism of action is not fully understood. UV light has been shown to have an effect on T-lymphocyte function as well as various components of the natural and acquired immune response. It also has a suppressive effect on the immune system caused by many independent effects.¹ Phototherapy currently is available using broadband UVB (290–320 nm), narrowband UVB (NB-UVB)(311–313 nm), 308-nm excimer laser, UVA1 (340–400 nm), psoralen plus UVA, and photopheresis.² Narrowband UVB treatment with light sources that peak at 311 to 313 nm have been used with high efficacy and a low side-effect profile, becoming the standard phototherapy method for chronic plaque-type psoriasis.³

More than 90% of vitamin D synthesis is formed in the skin following UV exposure, and the wavelengths and the solar spectrum that stimulate vitamin D synthesis have been a focus of research.⁴ 7-Dehydrocholesterol (provitamin D₃) is first converted to previtamin D₃. Although the necessary UV wavelength for previtamin D₃ synthesis is 295 to 300 nm, it is known that production stops below 260 nm and above 315 nm.^4-6 Previtamin D₃ is unstable and is quickly converted to vitamin D₃ in the skinand then to the biologically active form of 1,25-dihydroxyvitamin D₃ (calcitriol) following hydroxylation in the liver and kidneys. Calcitriol shows its effect by binding to the special nuclear receptor for vitamin D.⁷ Many tissues including the keratinocytes, dendritic cells, melanocytes, and sebocytes in the skin have been shown to possess the enzymatic mechanism necessary for 1,25-dihydroxyvitamin D₃ production. Vitamin D also is known to have paracrine, autocrine, and intracrine effects on immunomodulation, cell proliferation, differentiation, and apoptosis, in addition to its role in calcium metabolism.^5-9 Topical vitamin D and its analogues are used effectively and safely in psoriasis treatment with these effects.¹⁰ A correlation between low serum vitamin D levels and chronic inflammation severity has been shown in psoriasis patients in some studies.^11,12

In this study, we sought to evaluate the effect of NB-UVB on vitamin D status and related metabolic markers in patients with psoriasis.

Methods

This prospective, single-center study included patients living in or around Eskisehir, Turkey, who were 18 years of age or older and had been diagnosed with chronic plaque psoriasis with a psoriasis area and severity index (PASI) score of 5 or higher. Permission was granted by the local ethics committee. Patients provided written informed consent prior to enrollment. Patients were excluded if they were younger than 18 years; were pregnant or breastfeeding; stayed in open environments for more than 2 hours per day during the summer months (May through September); used drugs affecting calcium metabolism in the last 8 weeks (eg, barbiturates, anticonvulsants, corticosteroids, vitamin D supplements, bisphosphonates); used systemic treatment for psoriasis in the last 8 weeks; used phototherapy or sunbathing in the last 8 weeks; used topical vitamin D analogues in the last 4 weeks; or had a history of psoriatic arthritis and other inflammatory disorders, renal disease, known calcium metabolism disorders, granulomatous disorders, thyroid disease, diabetes mellitus, skin cancer, or abnormal photosensitivity and known lack of response or hypersensitivity to phototherapy.

Clinical Evaluation and Laboratory Studies
The participants’ age, gender, Fitzpatrick skin type, disease duration, dairy intake and vitamin supplement levels, hours of sun exposure per week, detailed medical history, and medications were obtained and documented in the medical records.

Serum 25(OH)D levels were measured using high-performance liquid chromatography/mass spectrometry, serum calcium and phosphorus levels using colorimetric analysis, serum alkaline phosphatase (ALP) levels using the enzymatic colorimetric method, and serum parathyroid hormone (PTH) levels using electrochemiluminescence at baseline and after PASI 75 was achieved with treatment. Vitamin D levels were classified in 3 groups: (1) deficient (<20 ng/mL); (2) inadequate (20–30 ng/mL); and (3) adequate (>30 ng/mL). The PASI scores at baseline and posttreatment were calculated by the same dermatologist (S.S.).

Treatment Protocol and Patient Follow-up
Narrowband UVB treatment was started at 70% of the minimal erythema dose (MED). Phototherapy was administered 3 times weekly for 6 months or until PASI 75 response was achieved. An increase of 20% to 30% from the prior dose was made according to the participants’ clinical status at each treatment session, and the dose was stabilized once the maximum dose was achieved according to skin type—up to 2000 mJ/cm² for Fitzpatrick skin types I and II, 3000 mJ/cm² for skin types III and IV, and 5000 mJ/cm² for skin types V and VI. Participants were allowed to use low- and moderate-potency topical corticosteroids and moisturizers containing urea during the course of treatment. The study physician (S.S.) clinically evaluated participants every 4 weeks for 6 months or until PASI 75 was achieved, and the clinical improvement was calculated as the percentage decrease in PASI score.

Statistical Analysis
The Shapiro-Wilk normalcy test was used for the continuous variables in the study. Variables with a normal distribution were analyzed with the paired t test and 1-way analysis of variance test and presented as mean (SD). Variables without a normal distribution were analyzed with the Wilcoxon t test and the Kruskal-Wallis test and presented as the median and 25th and 75th quartiles. The serum 25(OH)D levels were evaluated according to the seasons with the Kruskal-Wallis test. Categorical variables were expressed as frequency and percentages. The Pearson and Spearman correlation analysis and regression analysis were used to show the relationship between the variables (ie, age, Fitzpatrick skin type, PASI score, maximum NB-UVB dose, and number of sessions). The statistical significance level was set at P≤.05. Statistical analyses were performed using SPSS software version 21.

Results

A total of 49 participants (30 [61.22%] males; 19 [38.78%] females) were included in the study. The mean age (SD) was 40.27 (14.62) years (range, 19–74 years). Three (6.12%) participants were Fitzpatrick skin type I, 15 (30.61%) were skin type II, and 31 (63.27%) were skin type III.

The baseline median PASI score for the 49 participants was 10.20 (7.85–13.65). Baseline serum 25(OH)D levels were noted to be deficient in 40 participants (81.63%) and inadequate in 9 participants (18.37%). The distribution of the serum 25(OH)D levels of the participants according to the season was evaluated with the Kruskal-Wallis test and no association was found between serum 25(OH)D levels and seasonal changes (P=.685). Comparison of 25(OH)D basal values with Fitzpatrick skin type revealed a statistically significant relationship between skin type and vitamin D level (P=.024). The basal serum 25(OH)D levels were significantly lower in Fitzpatrick skin type II versus skin type I (P=.039).

Thirty-two (65.31%) participants achieved PASI 75 by the end of treatment. The baseline median PASI score (25th-75th quartiles) for the 32 patients was 10.45 (8.20-13.83) and the posttreatment PASI score was 1.95 (1.20-3.55), a statistically significant decrease following treatment (P<.001)(Table 1). Mean (SD) baseline serum 25(OH)D levels were 14.14 (6.70) ng/mL and posttreatment levels were 46.42 (15.51) ng/mL in these participants, which demonstrated a statistically significant increase during NB-UVB treatment (P<.001). None of the participants reached the toxicity levels (>80 ng/mL) for serum 25(OH)D. There were no significant changes in serum calcium or phosphorus levels posttreatment (Table 1), but statistically significant decreases in serum ALP and PTH levels were noted (P=.001 and P=.019, respectively)(Table 1).

Participants who completed the study (n=32) received an average (SD) of 30.09 (7.53) sessions of NB-UVB treatment and the mean (SD) MED was 611.88 (240.14) mJ/cm². The mean (SD) maximum dose was 2090.09 (341.78) mJ/cm² (Table 2).

Posttreatment serum 25(OH)D levels were compared with the number of NB-UVB phototherapy sessions and the maximum dose values. We found that the posttreatment serum 25(OH)D levels correlated with the number of sessions (P=.031) but not with the maximum dose (P=.498).

Using regression analysis, we also evaluated the effect of the increase in vitamin D levels—posttreatment serum 25(OH)D level minus baseline serum 25(OH)D levels—on the decrease in PASI scores—baseline PASI score minus posttreatment PASI score—and found no effect of serum 25(OH)D level increase on PASI decrease (P=.530). There was no correlation between increased serum 25(OH)D levels and age, Fitzpatrick skin type, or baseline PASI score.

Comment

The most effective UV wavelength for vitamin D synthesis is 295 to 300 nm, and therefore broadband UVB is frequently studied when determining the relationship between phototherapy and serum vitamin D levels.⁴ The current study demonstrated a statistically significant increase in serum 25(OH)D levels following NB-UVB treatment in patients with moderate to severe chronic plaque psoriasis (P<.001). This result supports other studies reporting that NB-UVB treatment in psoriasis patients increases serum 25(OH)D levels.^13-18

The main factor in the effective UVB level for vitamin D synthesis is the angle at which solar radiation reaches the earth, which is affected by the longitude, latitude, and time of day.¹⁹ For this reason, we planned to perform our study at a single center. Patients who stayed in open areas for more than 2 hours per day during the summer months (May through September) were excluded from the study to decrease the effect of seasonal changes on vitamin D levels. We evaluated the seasonal variation of vitamin D levels and found no relationship between seasonal changes and serum 25(OH)D levels. Therefore, the potential effect of seasonal changes on the vitamin D levels of study participants was excluded from the study.

The response to UV radiation changes according to age and Fitzpatrick skin type because 7-dehydrocholesterol levels decrease with age and melanin prevents the access of UVB photons to 7-dehydrocholesterol.²⁰ The basal serum 25(OH)D levels were deficient in 81.63% of participants and inadequate in 18.37%. In this study, we also observed that the basal serum 25(OH)D levels were significantly lower in patients with Fitzpatrick skin type II than in Fitzpatrick skin type I (P=.039). The mean (SD) serum 25(OH)D level at baseline was 14.14 (6.70) ng/mL and posttreatment was 46.42 (15.51) ng/mL in the 32 patients who completed the study. Serum 25(OH)D levels showed a statistically significant increase after NB-UVB treatment (P<.001). The increased serum 25(OH)D levels after NB-UVB phototherapy were not associated with Fitzpatrick skin type, which was consistent with the results of Osmancevic et al.¹⁷ The adjusted NB-UVB doses according to the different skin types might be responsible for this result in our study.

Participant age did not have a significant effect on serum 25(OH)D levels, similar to other studies in the literature.^13,17 We believe that artificial UVB radiation at high doses can compensate for the 7-dehydrocholesterol that decreases in the skin with aging.

We observed no significant change in the serum calcium and phosphorus levels with NB-UVB treatment in our study. None of the participants had a metabolic disorder related to increased 25(OH)D levels. The serum ALP and PTH levels decreased significantly following treatment (P=.001 and P=.019, respectively), which may have been secondary to increased serum 25(OH)D levels.

Posttreatment serum 25(OH)D levels were compared with the number of NB-UVB phototherapy sessions and maximum dose values. The posttreatment serum 25(OH)D levels were found to be related to the number of sessions received, but this value was not correlated with the maximum dose received. The MED and maximum dose were determined according to the Fitzpatrick skin type of the participants. Therefore, increased serum 25(OH)D levels with an increased number of sessions was an expected result. Our observation is in accordance with the finding described by Ryan et al.¹⁴ On the other hand, an in vitro study conducted by Olds et al²¹ reported that the relationship between UV light and cholecalciferol synthesis was not linear.

We found that increased serum 25(OH)D levels after treatment were not correlated with the decrease in PASI score, similar to studies by Romaní et al¹⁸ and Ryan et al.¹⁴ These results suggest that the clinical improvement following NB-UVB treatment is independent of the increased serum 25(OH)D levels in psoriasis patients.

Conclusion

In conclusion, we found that the serum 25(OH)D levels that increase as a result of NB-UVB therapy for the treatment of chronic plaque psoriasis has no statistically significant relationship with the age, Fitzpatrick skin type, baseline PASI score, changes in PASI, or maximum dose, while a positive relationship is present between the serum 25(OH)D levels and the number of sessions of NB-UVB.