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Immune-agonist combo has activity against several tumor types
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).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
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.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
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).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
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.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
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).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
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.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
AT ASCO 2017
Key clinical point: A combination of a GITR-agonist and anti-PD-1 agent was safe and produced partial responses in patients with heavily pretreated advanced cancers.
Major finding: Two patients with cancers that had progression on a PD-1 inhibitor had durable partial responses.
Data source: A phase I/IIa dose-finding and safety study of BMS986156 alone or in combination with nivolumab (Opdivo).
Disclosures: The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising for several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
Cirrhosis linked to increased risk of stroke
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.
After the data were adjusted to account for stroke risk factors, relevant comorbidities, and demographic traits, the annual incidence of any type of stroke was significantly higher with cirrhosis than without cirrhosis (hazard ratio, 1.4). The association was stronger for intracranial hemorrhage (HR, 1.9) and subarachnoid hemorrhage (HR, 2.4) than for ischemic stroke (HR, 1.3).
The results of several secondary and sensitivity analyses were consistent with those of the primary analysis, regardless of whether the cirrhosis was alcohol-related or the stroke was fatal. The association was strongest among patients who had decompensated cirrhosis and was not evident at all among patients who had mild liver disease, Dr. Parikh and his associates said (JAMA Neurol. 2017 Jun 5 [doi: 10.1001/jamaneurol.2017.0923).
This study was not designed to explore the reasons for an association between cirrhosis and stroke, but the investigators noted many possible explanations. First, “cirrhosis is accompanied by a mixed coagulopathy, with potential implications for hemorrhagic and thrombotic processes.” It has been linked to many bleeding complications, including, most recently, cerebral microhemorrhages detectable on brain MRI. In addition, the underlying causes of cirrhosis, including alcohol abuse, hepatitis infection, and metabolic disease, may also contribute to stroke risk.
Alternatively, clinicians caring for patients with cirrhosis “may limit the aggressiveness of stroke prevention” – for example, by limiting antithrombotic medications or statins – because they are mindful of the patient’s increased risk of bleeding and hepatic toxicity, the investigators said.
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.
After the data were adjusted to account for stroke risk factors, relevant comorbidities, and demographic traits, the annual incidence of any type of stroke was significantly higher with cirrhosis than without cirrhosis (hazard ratio, 1.4). The association was stronger for intracranial hemorrhage (HR, 1.9) and subarachnoid hemorrhage (HR, 2.4) than for ischemic stroke (HR, 1.3).
The results of several secondary and sensitivity analyses were consistent with those of the primary analysis, regardless of whether the cirrhosis was alcohol-related or the stroke was fatal. The association was strongest among patients who had decompensated cirrhosis and was not evident at all among patients who had mild liver disease, Dr. Parikh and his associates said (JAMA Neurol. 2017 Jun 5 [doi: 10.1001/jamaneurol.2017.0923).
This study was not designed to explore the reasons for an association between cirrhosis and stroke, but the investigators noted many possible explanations. First, “cirrhosis is accompanied by a mixed coagulopathy, with potential implications for hemorrhagic and thrombotic processes.” It has been linked to many bleeding complications, including, most recently, cerebral microhemorrhages detectable on brain MRI. In addition, the underlying causes of cirrhosis, including alcohol abuse, hepatitis infection, and metabolic disease, may also contribute to stroke risk.
Alternatively, clinicians caring for patients with cirrhosis “may limit the aggressiveness of stroke prevention” – for example, by limiting antithrombotic medications or statins – because they are mindful of the patient’s increased risk of bleeding and hepatic toxicity, the investigators said.
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.
After the data were adjusted to account for stroke risk factors, relevant comorbidities, and demographic traits, the annual incidence of any type of stroke was significantly higher with cirrhosis than without cirrhosis (hazard ratio, 1.4). The association was stronger for intracranial hemorrhage (HR, 1.9) and subarachnoid hemorrhage (HR, 2.4) than for ischemic stroke (HR, 1.3).
The results of several secondary and sensitivity analyses were consistent with those of the primary analysis, regardless of whether the cirrhosis was alcohol-related or the stroke was fatal. The association was strongest among patients who had decompensated cirrhosis and was not evident at all among patients who had mild liver disease, Dr. Parikh and his associates said (JAMA Neurol. 2017 Jun 5 [doi: 10.1001/jamaneurol.2017.0923).
This study was not designed to explore the reasons for an association between cirrhosis and stroke, but the investigators noted many possible explanations. First, “cirrhosis is accompanied by a mixed coagulopathy, with potential implications for hemorrhagic and thrombotic processes.” It has been linked to many bleeding complications, including, most recently, cerebral microhemorrhages detectable on brain MRI. In addition, the underlying causes of cirrhosis, including alcohol abuse, hepatitis infection, and metabolic disease, may also contribute to stroke risk.
Alternatively, clinicians caring for patients with cirrhosis “may limit the aggressiveness of stroke prevention” – for example, by limiting antithrombotic medications or statins – because they are mindful of the patient’s increased risk of bleeding and hepatic toxicity, the investigators said.
FROM JAMA NEUROLOGY
Key clinical point: Cirrhosis was associated with an increased risk of stroke, especially hemorrhagic stroke, in a large nationally representative cohort study.
Major finding: The annual incidence of any type of stroke was significantly higher with cirrhosis than without cirrhosis (HR, 1.4), and this association was stronger for intracranial hemorrhage (HR, 1.9) and subarachnoid hemorrhage (HR, 2.4) than for ischemic stroke (HR, 1.3).
Data source: A retrospective cohort study involving a nationally representative sample of 1.6 million Medicare patients.
Disclosures: This study was supported by the National Institute of Neurological Disorders and Stroke and the Florence Gould Endowment for Discovery in Stroke. Dr. Parikh and his associates reported having no relevant financial disclosures.
VIDEO: Phase III results show promise for erenumab as migraine prevention drug
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.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT AAN 2017
Female predisposition to anxiety disorders may have prenatal origin
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.
The findings shed new light on the relationship between testosterone and anxiety disorders, according to Ms. Jin, a doctoral student at the University of Texas, Austin. The hormone previously has been linked to reduced levels of anxiety, an observation consistent with the lower prevalence of anxiety disorders in men. However, it has been unclear whether prenatal exposure to testosterone, which encourages organizational effects, or the activational effects of postnatal exposure to the hormone is most protective against anxiety disorders.
Ms. Jin found that prenatal testosterone exposure as reflected in a low 2D:4D ratio was associated with a lower level of repetitive negative thinking as measured using the Perseverative Thinking Questionnaire but only in the female students.
She reported having no financial conflicts of interest regarding her study.
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.
The findings shed new light on the relationship between testosterone and anxiety disorders, according to Ms. Jin, a doctoral student at the University of Texas, Austin. The hormone previously has been linked to reduced levels of anxiety, an observation consistent with the lower prevalence of anxiety disorders in men. However, it has been unclear whether prenatal exposure to testosterone, which encourages organizational effects, or the activational effects of postnatal exposure to the hormone is most protective against anxiety disorders.
Ms. Jin found that prenatal testosterone exposure as reflected in a low 2D:4D ratio was associated with a lower level of repetitive negative thinking as measured using the Perseverative Thinking Questionnaire but only in the female students.
She reported having no financial conflicts of interest regarding her study.
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.
The findings shed new light on the relationship between testosterone and anxiety disorders, according to Ms. Jin, a doctoral student at the University of Texas, Austin. The hormone previously has been linked to reduced levels of anxiety, an observation consistent with the lower prevalence of anxiety disorders in men. However, it has been unclear whether prenatal exposure to testosterone, which encourages organizational effects, or the activational effects of postnatal exposure to the hormone is most protective against anxiety disorders.
Ms. Jin found that prenatal testosterone exposure as reflected in a low 2D:4D ratio was associated with a lower level of repetitive negative thinking as measured using the Perseverative Thinking Questionnaire but only in the female students.
She reported having no financial conflicts of interest regarding her study.
AT THE ANXIETY AND DEPRESSION CONFERENCE 2017
Key clinical point:
Major finding: The higher the ratio of the length of the index finger to the ring finger on the left hand, the greater the predisposition to repetitive negative thinking in women but not in men.
Data source: This cross-sectional study correlated the 2D:4D digit ratio to levels of repetitive negative thinking in 103 college students.
Disclosures: The presenter reported having no financial conflicts regarding her study.
What’s Eating You? Chiggers
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
- McClain D, Dana AN, Goldenberg G. Mite infestations. Dermatol Ther. 2009;22:327-346.
- Lane RP, Crosskey RW. Medical Insects and Arachnids. London, England: Chapman & Hall; 1993.
- Gasser R, Wyniger R. Distribution and control of Trombiculidae with special reference to Trombicula autumnalis [article in German]. Acta Trop. 1955;12:308-326.
- Jones BM. The penetration of the host tissue by the harvest mite, Trombicula autumnalis Shaw. Parasitology. 1950;40:247-260.
- Farkas J. Concerning the predilected localisation of the manifestations of trombidiosis. predilected localisation and its relation to the ways of invasion [article in German]. Dermatol Monatsschr. 1979;165:858-861.
- Jones JG. Chiggers. Am Fam Physician. 1987;36:149-152.
- Shatrov AB. Stylostome formation in trombiculid mites (Acariformes: Trombiculidae). Exp Appl Acarol. 2009;49:261-280.
- Potts J. Eradication of ectoparasites in children. how to treat infestations of lice, scabies, and chiggers. Postgrad Med. 2001;110:57-59, 63-64.
- Elston DM. Arthropods and infestations. Infectious Diseases of the Skin. Boca Raton, FL; CRC Press; 2009:112-116.
- Smith GA, Sharma V, Knapp JF, et al. The summer penile syndrome: seasonal acute hypersensitivity reaction caused by chigger bites on the penis. Pediatr Emerg Care. 1998;14:116-118.
- Young GD, Evans S. Safety of DEET and permethrin in the prevention of arthropod attack. Military Med. 1998;163:324-330.
- Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. 2003;16:429-436.
- Panpanich R, Garner P. Antibiotics for treating scrub typhus. Cochrane Database Syst Rev. 2000;2:CD002150.
- Fernández-Soto P, Pérez-Sánchez R, Encinas-Grandes A. Molecular detection of Ehrlichia phagocytophila genogroup organisms in larvae of Neotrombicula autumnalis (Acari: Trombiculidae) captured in Spain. J Parasitol. 2001;87:1482-1483.
- Literak I, Stekolnikov AA, Sychra O, et al. Larvae of chigger mites Neotrombicula spp. (Acari: Trombiculidae) exhibited Borrelia but no Anaplasma infections: a field study including birds from the Czech Carpathians as hosts of chiggers. Exp Appl Acarol. 2008;44:307-314.
- Kampen H, Schöler A, Metzen M, et al. Neotrombicula autumnalis (Acari, Trombiculidae) as a vector for Borrelia burgdorferi sensu lato? Exp Appl Acarol. 2004;33:93-102.
- Houck MA, Qin H, Roberts HR. Hantavirus transmission: potential role of ectoparasites. Vector Borne Zoonotic Dis. 2001;1:75-79.
- Yu XJ, Tesh RB. The role of mites in the transmission and maintenance of Hantaan virus (Hantavirus: Bunyaviridae). J Infect Dis. 2014;210:1693-1699.
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
- McClain D, Dana AN, Goldenberg G. Mite infestations. Dermatol Ther. 2009;22:327-346.
- Lane RP, Crosskey RW. Medical Insects and Arachnids. London, England: Chapman & Hall; 1993.
- Gasser R, Wyniger R. Distribution and control of Trombiculidae with special reference to Trombicula autumnalis [article in German]. Acta Trop. 1955;12:308-326.
- Jones BM. The penetration of the host tissue by the harvest mite, Trombicula autumnalis Shaw. Parasitology. 1950;40:247-260.
- Farkas J. Concerning the predilected localisation of the manifestations of trombidiosis. predilected localisation and its relation to the ways of invasion [article in German]. Dermatol Monatsschr. 1979;165:858-861.
- Jones JG. Chiggers. Am Fam Physician. 1987;36:149-152.
- Shatrov AB. Stylostome formation in trombiculid mites (Acariformes: Trombiculidae). Exp Appl Acarol. 2009;49:261-280.
- Potts J. Eradication of ectoparasites in children. how to treat infestations of lice, scabies, and chiggers. Postgrad Med. 2001;110:57-59, 63-64.
- Elston DM. Arthropods and infestations. Infectious Diseases of the Skin. Boca Raton, FL; CRC Press; 2009:112-116.
- Smith GA, Sharma V, Knapp JF, et al. The summer penile syndrome: seasonal acute hypersensitivity reaction caused by chigger bites on the penis. Pediatr Emerg Care. 1998;14:116-118.
- Young GD, Evans S. Safety of DEET and permethrin in the prevention of arthropod attack. Military Med. 1998;163:324-330.
- Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. 2003;16:429-436.
- Panpanich R, Garner P. Antibiotics for treating scrub typhus. Cochrane Database Syst Rev. 2000;2:CD002150.
- Fernández-Soto P, Pérez-Sánchez R, Encinas-Grandes A. Molecular detection of Ehrlichia phagocytophila genogroup organisms in larvae of Neotrombicula autumnalis (Acari: Trombiculidae) captured in Spain. J Parasitol. 2001;87:1482-1483.
- Literak I, Stekolnikov AA, Sychra O, et al. Larvae of chigger mites Neotrombicula spp. (Acari: Trombiculidae) exhibited Borrelia but no Anaplasma infections: a field study including birds from the Czech Carpathians as hosts of chiggers. Exp Appl Acarol. 2008;44:307-314.
- Kampen H, Schöler A, Metzen M, et al. Neotrombicula autumnalis (Acari, Trombiculidae) as a vector for Borrelia burgdorferi sensu lato? Exp Appl Acarol. 2004;33:93-102.
- Houck MA, Qin H, Roberts HR. Hantavirus transmission: potential role of ectoparasites. Vector Borne Zoonotic Dis. 2001;1:75-79.
- Yu XJ, Tesh RB. The role of mites in the transmission and maintenance of Hantaan virus (Hantavirus: Bunyaviridae). J Infect Dis. 2014;210:1693-1699.
- McClain D, Dana AN, Goldenberg G. Mite infestations. Dermatol Ther. 2009;22:327-346.
- Lane RP, Crosskey RW. Medical Insects and Arachnids. London, England: Chapman & Hall; 1993.
- Gasser R, Wyniger R. Distribution and control of Trombiculidae with special reference to Trombicula autumnalis [article in German]. Acta Trop. 1955;12:308-326.
- Jones BM. The penetration of the host tissue by the harvest mite, Trombicula autumnalis Shaw. Parasitology. 1950;40:247-260.
- Farkas J. Concerning the predilected localisation of the manifestations of trombidiosis. predilected localisation and its relation to the ways of invasion [article in German]. Dermatol Monatsschr. 1979;165:858-861.
- Jones JG. Chiggers. Am Fam Physician. 1987;36:149-152.
- Shatrov AB. Stylostome formation in trombiculid mites (Acariformes: Trombiculidae). Exp Appl Acarol. 2009;49:261-280.
- Potts J. Eradication of ectoparasites in children. how to treat infestations of lice, scabies, and chiggers. Postgrad Med. 2001;110:57-59, 63-64.
- Elston DM. Arthropods and infestations. Infectious Diseases of the Skin. Boca Raton, FL; CRC Press; 2009:112-116.
- Smith GA, Sharma V, Knapp JF, et al. The summer penile syndrome: seasonal acute hypersensitivity reaction caused by chigger bites on the penis. Pediatr Emerg Care. 1998;14:116-118.
- Young GD, Evans S. Safety of DEET and permethrin in the prevention of arthropod attack. Military Med. 1998;163:324-330.
- Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. 2003;16:429-436.
- Panpanich R, Garner P. Antibiotics for treating scrub typhus. Cochrane Database Syst Rev. 2000;2:CD002150.
- Fernández-Soto P, Pérez-Sánchez R, Encinas-Grandes A. Molecular detection of Ehrlichia phagocytophila genogroup organisms in larvae of Neotrombicula autumnalis (Acari: Trombiculidae) captured in Spain. J Parasitol. 2001;87:1482-1483.
- Literak I, Stekolnikov AA, Sychra O, et al. Larvae of chigger mites Neotrombicula spp. (Acari: Trombiculidae) exhibited Borrelia but no Anaplasma infections: a field study including birds from the Czech Carpathians as hosts of chiggers. Exp Appl Acarol. 2008;44:307-314.
- Kampen H, Schöler A, Metzen M, et al. Neotrombicula autumnalis (Acari, Trombiculidae) as a vector for Borrelia burgdorferi sensu lato? Exp Appl Acarol. 2004;33:93-102.
- Houck MA, Qin H, Roberts HR. Hantavirus transmission: potential role of ectoparasites. Vector Borne Zoonotic Dis. 2001;1:75-79.
- Yu XJ, Tesh RB. The role of mites in the transmission and maintenance of Hantaan virus (Hantavirus: Bunyaviridae). J Infect Dis. 2014;210:1693-1699.
Practice Points
- The classic clinical presentation of chigger bites includes severe pruritus, cutaneous swelling, and erythematous papules and papulovesicles appearing in groups, most commonly affecting the legs and waistline.
- Because itching generally subsides within 72 hours of the chigger bite and cutaneous lesions typically heal within 1 to 2 weeks, treatment is focused on symptomatic relief.
- Symptomatic relief may be achieved by means of topical antipruritics or oral antihistamines as well as potent topical corticosteroids or an intralesional triamcinolone acetonide injection in severe cases.
NOTCH1 mutation predicts reduced ofatumumab efficacy in CLL
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.
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.
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.
AT iwCLL MEETING
Key clinical point:
Major finding: Ofatumumab was beneficial in patients with NOTCH1 wild-type, but not in patients with NOTCH1 mutation (hazard ratios, 0.64 and 0.86, respectively).
Data source: A mutation analysis of 325 DNA samples from patients in the phase III COMPLEMENT 2 trial.
Disclosures: Dr. Tausch reported receiving research support from Novartis.
For Americans, less salt is still too much
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.
Total food and beverage purchases also were down from 1,328 g/day in 2000 to 1,134 in 2014, and the total sodium content of those purchases followed suit, dropping from 2,363 mg/day in 2000 to 1,967 mg/day in 2014. The decline in total purchases, however, was driven largely by beverages, which fell 21% from 2000 to 2014, while packaged food purchases fell by only 2%, the investigators reported (JAMA Intern Med. 2017 June 5. doi: 10.1001/jamainternmed.2017.1407).
Median sodium density was down significantly from 1,712 to 1,628 mg of sodium per 1,000 kcal, but by 2014, only 1.2% of the 172,042 households included in the study were purchasing the optimal level of 1,100 mg per 1,000 kcal, based on the DASH-Sodium trial and the Health Eating Index-2010, Dr. Poti and her associates said.
“Additional studies are needed to examine whether decreases in sodium from packaged foods were offset by increases in sodium from away-from-home sources,” they said, and since “there were no major shifts in the amount purchased for key food groups … sodium declines may relate mainly to reformulation.”
The study was funded by the Robert Wood Johnson Foundation, the National Institutes of Health, and the Carolina Population Center at the University of North Carolina. One of the investigators is supported by a National Health and Medical Research Council of Australia Early Career Fellowship. The investigators did not report any conflicts of interest.
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.
Total food and beverage purchases also were down from 1,328 g/day in 2000 to 1,134 in 2014, and the total sodium content of those purchases followed suit, dropping from 2,363 mg/day in 2000 to 1,967 mg/day in 2014. The decline in total purchases, however, was driven largely by beverages, which fell 21% from 2000 to 2014, while packaged food purchases fell by only 2%, the investigators reported (JAMA Intern Med. 2017 June 5. doi: 10.1001/jamainternmed.2017.1407).
Median sodium density was down significantly from 1,712 to 1,628 mg of sodium per 1,000 kcal, but by 2014, only 1.2% of the 172,042 households included in the study were purchasing the optimal level of 1,100 mg per 1,000 kcal, based on the DASH-Sodium trial and the Health Eating Index-2010, Dr. Poti and her associates said.
“Additional studies are needed to examine whether decreases in sodium from packaged foods were offset by increases in sodium from away-from-home sources,” they said, and since “there were no major shifts in the amount purchased for key food groups … sodium declines may relate mainly to reformulation.”
The study was funded by the Robert Wood Johnson Foundation, the National Institutes of Health, and the Carolina Population Center at the University of North Carolina. One of the investigators is supported by a National Health and Medical Research Council of Australia Early Career Fellowship. The investigators did not report any conflicts of interest.
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.
Total food and beverage purchases also were down from 1,328 g/day in 2000 to 1,134 in 2014, and the total sodium content of those purchases followed suit, dropping from 2,363 mg/day in 2000 to 1,967 mg/day in 2014. The decline in total purchases, however, was driven largely by beverages, which fell 21% from 2000 to 2014, while packaged food purchases fell by only 2%, the investigators reported (JAMA Intern Med. 2017 June 5. doi: 10.1001/jamainternmed.2017.1407).
Median sodium density was down significantly from 1,712 to 1,628 mg of sodium per 1,000 kcal, but by 2014, only 1.2% of the 172,042 households included in the study were purchasing the optimal level of 1,100 mg per 1,000 kcal, based on the DASH-Sodium trial and the Health Eating Index-2010, Dr. Poti and her associates said.
“Additional studies are needed to examine whether decreases in sodium from packaged foods were offset by increases in sodium from away-from-home sources,” they said, and since “there were no major shifts in the amount purchased for key food groups … sodium declines may relate mainly to reformulation.”
The study was funded by the Robert Wood Johnson Foundation, the National Institutes of Health, and the Carolina Population Center at the University of North Carolina. One of the investigators is supported by a National Health and Medical Research Council of Australia Early Career Fellowship. The investigators did not report any conflicts of interest.
FROM JAMA INTERNAL MEDICINE
Narrowband UVB Treatment Increases Serum 25-Hydroxyvitamin D Levels in Patients With Chronic Plaque Psoriasis
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 Eskisehir, 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.
- Şavk E. Immunology of Photo(chemo)therapy. Turkderm. 2010;44(suppl 2):62-66.
- Ferahbaş A. Phototherapy modalities and protocols. Turkderm. 2010;44(suppl 2):67-72.
- Ibbotson SH, Bilsland D, Cox NH, et al. An update and guidance on narrowband ultraviolet B phototherapy: a British Photodermatology Group Workshop report. Br J Dermatol. 2004;151:283-297.
- Norval M, Björn LO, de Gruijl FR. Is the action spectrum for the UV-induced production of previtamin D3 in human skin correct? Photochem Photobiol Sci. 2010;9:11-17.
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
- McKenzie RL, Liley JB, Björn LO. UV radiation: balancing risks and benefits. Photochem Photobiol. 2009;85:88-98.
- Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353-373.
- May E, Asadullah K, Zügel U. Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs. Curr Drug Targets Inflamm Allergy. 2004;3:377-393.
- Reichrath J. Vitamin D and the skin: an ancient friend, revisited. Exp Dermatol. 2007;16:618-625.
- Fu LW, Vender R. Systemic role for vitamin D in the treatment of psoriasis and metabolic syndrome. Dermatol Res Pract. 2011;2011:276079.
- Gisondi P, Rossini M, Di Cesare A, et al. Vitamin D status in patients with chronic plaque psoriasis. Br J Dermatol. 2012;166:505-510.
- Orgaz-Molina J, Buendía-Eisman A, Arrabal-Polo MA, et al. Deficiency of serum concentration of 25-hydroxyvitamin D in psoriatic patients: a case-control study. J Am Acad Dermatol. 2012;67:931-938.
- Osmancevic A, Landin-Wilhelmsen K, Larkö O, et al. UVB therapy increases 25 (OH) vitamin D syntheses in postmenopausal women with psoriasis. Photodermatol Photoimmunol Photomed. 2007;23:172-178.
- Ryan C, Moran B, McKenna MJ, et al. The effect of narrowband UV-B treatment for psoriasis on vitamin D status during wintertime in Ireland. Arch Dermatol. 2010;146:836-842.
- Vahavihu K, Ala-Houhala M, Peric M, et al. Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis. Br J Dermatol. 2010;163:321-328.
- Lesiak A, Narbutt J, Pawlaczyk M, et al. Vitamin D serum level changes in psoriatic patients treated with narrowband ultraviolet B phototherapy are related to the season of the irradiation. Photodermatol Photoimmunol Photomed. 2011;27:304-310.
- Osmancevic A, Landin-Wilhelmsen K, Larko O, et al.Vitamin D production in psoriasis patients increases less with narrowband than with broadband ultraviolet B phototherapy. Photodermatol Photoimmunol Photomed. 2009;25:119-123.
- Romaní J, Caixàs A, Carrascosa JM, et al. Effect of narrowband ultraviolet B therapy on inflammatory markers and body fat composition in moderate to severe psoriasis. Br J Dermatol. 2012;166:1237-1244.
- Diehl JW, Chiu MW. Effects of ambient sunlight and photoprotection on vitamin D status. Dermatol Ther. 2010;23:48-60.
- Armas LA, Dowell S, Akhter M, et al. Ultraviolet-B radiation increases serum 25-hydroxyvitamin D levels: the effect of UVB dose and skin color. J Am Acad Dermatol. 2007;57:588-593.
- Olds WJ, McKinley AR, Moore MR, et al. In vitro model of vitamin D3 (cholecalciferol) synthesis by UV radiation: dose-response relationships. J Photochem Photobiol B. 2008;93:88-93.
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 Eskisehir, 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 Eskisehir, 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.
- Şavk E. Immunology of Photo(chemo)therapy. Turkderm. 2010;44(suppl 2):62-66.
- Ferahbaş A. Phototherapy modalities and protocols. Turkderm. 2010;44(suppl 2):67-72.
- Ibbotson SH, Bilsland D, Cox NH, et al. An update and guidance on narrowband ultraviolet B phototherapy: a British Photodermatology Group Workshop report. Br J Dermatol. 2004;151:283-297.
- Norval M, Björn LO, de Gruijl FR. Is the action spectrum for the UV-induced production of previtamin D3 in human skin correct? Photochem Photobiol Sci. 2010;9:11-17.
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
- McKenzie RL, Liley JB, Björn LO. UV radiation: balancing risks and benefits. Photochem Photobiol. 2009;85:88-98.
- Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353-373.
- May E, Asadullah K, Zügel U. Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs. Curr Drug Targets Inflamm Allergy. 2004;3:377-393.
- Reichrath J. Vitamin D and the skin: an ancient friend, revisited. Exp Dermatol. 2007;16:618-625.
- Fu LW, Vender R. Systemic role for vitamin D in the treatment of psoriasis and metabolic syndrome. Dermatol Res Pract. 2011;2011:276079.
- Gisondi P, Rossini M, Di Cesare A, et al. Vitamin D status in patients with chronic plaque psoriasis. Br J Dermatol. 2012;166:505-510.
- Orgaz-Molina J, Buendía-Eisman A, Arrabal-Polo MA, et al. Deficiency of serum concentration of 25-hydroxyvitamin D in psoriatic patients: a case-control study. J Am Acad Dermatol. 2012;67:931-938.
- Osmancevic A, Landin-Wilhelmsen K, Larkö O, et al. UVB therapy increases 25 (OH) vitamin D syntheses in postmenopausal women with psoriasis. Photodermatol Photoimmunol Photomed. 2007;23:172-178.
- Ryan C, Moran B, McKenna MJ, et al. The effect of narrowband UV-B treatment for psoriasis on vitamin D status during wintertime in Ireland. Arch Dermatol. 2010;146:836-842.
- Vahavihu K, Ala-Houhala M, Peric M, et al. Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis. Br J Dermatol. 2010;163:321-328.
- Lesiak A, Narbutt J, Pawlaczyk M, et al. Vitamin D serum level changes in psoriatic patients treated with narrowband ultraviolet B phototherapy are related to the season of the irradiation. Photodermatol Photoimmunol Photomed. 2011;27:304-310.
- Osmancevic A, Landin-Wilhelmsen K, Larko O, et al.Vitamin D production in psoriasis patients increases less with narrowband than with broadband ultraviolet B phototherapy. Photodermatol Photoimmunol Photomed. 2009;25:119-123.
- Romaní J, Caixàs A, Carrascosa JM, et al. Effect of narrowband ultraviolet B therapy on inflammatory markers and body fat composition in moderate to severe psoriasis. Br J Dermatol. 2012;166:1237-1244.
- Diehl JW, Chiu MW. Effects of ambient sunlight and photoprotection on vitamin D status. Dermatol Ther. 2010;23:48-60.
- Armas LA, Dowell S, Akhter M, et al. Ultraviolet-B radiation increases serum 25-hydroxyvitamin D levels: the effect of UVB dose and skin color. J Am Acad Dermatol. 2007;57:588-593.
- Olds WJ, McKinley AR, Moore MR, et al. In vitro model of vitamin D3 (cholecalciferol) synthesis by UV radiation: dose-response relationships. J Photochem Photobiol B. 2008;93:88-93.
- Şavk E. Immunology of Photo(chemo)therapy. Turkderm. 2010;44(suppl 2):62-66.
- Ferahbaş A. Phototherapy modalities and protocols. Turkderm. 2010;44(suppl 2):67-72.
- Ibbotson SH, Bilsland D, Cox NH, et al. An update and guidance on narrowband ultraviolet B phototherapy: a British Photodermatology Group Workshop report. Br J Dermatol. 2004;151:283-297.
- Norval M, Björn LO, de Gruijl FR. Is the action spectrum for the UV-induced production of previtamin D3 in human skin correct? Photochem Photobiol Sci. 2010;9:11-17.
- Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
- McKenzie RL, Liley JB, Björn LO. UV radiation: balancing risks and benefits. Photochem Photobiol. 2009;85:88-98.
- Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353-373.
- May E, Asadullah K, Zügel U. Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs. Curr Drug Targets Inflamm Allergy. 2004;3:377-393.
- Reichrath J. Vitamin D and the skin: an ancient friend, revisited. Exp Dermatol. 2007;16:618-625.
- Fu LW, Vender R. Systemic role for vitamin D in the treatment of psoriasis and metabolic syndrome. Dermatol Res Pract. 2011;2011:276079.
- Gisondi P, Rossini M, Di Cesare A, et al. Vitamin D status in patients with chronic plaque psoriasis. Br J Dermatol. 2012;166:505-510.
- Orgaz-Molina J, Buendía-Eisman A, Arrabal-Polo MA, et al. Deficiency of serum concentration of 25-hydroxyvitamin D in psoriatic patients: a case-control study. J Am Acad Dermatol. 2012;67:931-938.
- Osmancevic A, Landin-Wilhelmsen K, Larkö O, et al. UVB therapy increases 25 (OH) vitamin D syntheses in postmenopausal women with psoriasis. Photodermatol Photoimmunol Photomed. 2007;23:172-178.
- Ryan C, Moran B, McKenna MJ, et al. The effect of narrowband UV-B treatment for psoriasis on vitamin D status during wintertime in Ireland. Arch Dermatol. 2010;146:836-842.
- Vahavihu K, Ala-Houhala M, Peric M, et al. Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis. Br J Dermatol. 2010;163:321-328.
- Lesiak A, Narbutt J, Pawlaczyk M, et al. Vitamin D serum level changes in psoriatic patients treated with narrowband ultraviolet B phototherapy are related to the season of the irradiation. Photodermatol Photoimmunol Photomed. 2011;27:304-310.
- Osmancevic A, Landin-Wilhelmsen K, Larko O, et al.Vitamin D production in psoriasis patients increases less with narrowband than with broadband ultraviolet B phototherapy. Photodermatol Photoimmunol Photomed. 2009;25:119-123.
- Romaní J, Caixàs A, Carrascosa JM, et al. Effect of narrowband ultraviolet B therapy on inflammatory markers and body fat composition in moderate to severe psoriasis. Br J Dermatol. 2012;166:1237-1244.
- Diehl JW, Chiu MW. Effects of ambient sunlight and photoprotection on vitamin D status. Dermatol Ther. 2010;23:48-60.
- Armas LA, Dowell S, Akhter M, et al. Ultraviolet-B radiation increases serum 25-hydroxyvitamin D levels: the effect of UVB dose and skin color. J Am Acad Dermatol. 2007;57:588-593.
- Olds WJ, McKinley AR, Moore MR, et al. In vitro model of vitamin D3 (cholecalciferol) synthesis by UV radiation: dose-response relationships. J Photochem Photobiol B. 2008;93:88-93.
Practice Points
- The 25-hydroxyvitamin D (25[OH]D) levels are increased by narrowband UVB (NB-UVB) treatment in psoriasis patients.
- The number of sessions of NB-UVB is associated with increased 25(OH)D levels.
Leukocytoclastic Vasculitis Resolution With Topical Dapsone
Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.1 Numerous etiologies have been described, but the disease commonly remains idiopathic.2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.
Case Report
A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).
Comment
Established therapies for LCV carry serious side-effect profiles, which can preclude their use.5 Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.5 Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.7 It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.8,9 A case of methemoglobinemia due to topical dapsone has been reported.10 Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.
Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.
Conclusion
Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.
- Koutkia P, Mylonakis E, Rounds S, et al. Leucocytoclastic vasculitis: an update for the clinician. Scand J Rheumatol. 2001;30:315-322.
- Af Ekenstam E, Callen JP. Cutaneous leukocytoclastic vasculitis. clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120:484-489.
- Gyselbrecht L, de Keyser F, Ongenae K, et al. Etiological factors and underlying conditions in patientswith leucocytoclastic vasculitis. Clin Exp Rheumatol. 1996;14:665-668.
- Sais G, Vidaller A, Jucglà A, et al. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. results of a prospective, randomized controlled trial. Arch Dermatol. 1995;131:1399-1402.
- Sunderkotter C, Bonsmann G, Sindrilaru A, et al. Management of leukocytoclastic vasculitis: clinical review. J Dermatol Treat. 2005;16:193-206.
- Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45:420-434.
- Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol. 2009;10:221-227.
- Frieling GW, Williams NL, Lim SJ, et al. Novel use of topical dapsone 5% gel for erythema elevatum diutinum: safer and effective. J Drugs Dermatol. 2013;12:481-484.
- Handler MZ, Hamilton H, Aires D. Treatment of peristomal pyoderma gangrenosum with topical crushed dapsone. J Drugs Dermatol. 2011;10:1059-1061.
- Swartzentruber GS, Yanta JH, Pizon AF. Methemoglobi-nemia as a complication of topical dapsone. N Engl J Med. 2015;372:491-492.
Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.1 Numerous etiologies have been described, but the disease commonly remains idiopathic.2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.
Case Report
A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).
Comment
Established therapies for LCV carry serious side-effect profiles, which can preclude their use.5 Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.5 Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.7 It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.8,9 A case of methemoglobinemia due to topical dapsone has been reported.10 Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.
Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.
Conclusion
Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.
Leukocytoclastic vasculitis (LCV) is a disease characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.1 Numerous etiologies have been described, but the disease commonly remains idiopathic.2,3 Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment. Chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids. These agents are effective but carry risks of serious side effects.4,5 These side effects and/or medical contraindications prevent some patients from taking systemic medications for LCV. We present a case of LCV that resolved after treatment with topical dapsone, highlighting a potential new treatment ofLCV with a markedly better side-effect profile.
Case Report
A 60-year-old woman with recent upper respiratory tract and sinus infections presented to our dermatology clinic with painful palpable purpura on the bilateral shins, thighs, and dorsal aspects of the feet of several months’ duration (Figure, A). Her primary care provider initiated treatment with amoxicillin and doxycycline for the infections. When the rash developed approximately 1.5 weeks following initiation of her symptoms, the patient was referred to the dermatology and rheumatology departments at our institution. The treating dermatologist (M.B.T.) obtained a 4-mm punch biopsy from the right lower leg and LCV was shown on histology. The patient completed a 14-day course of doxycycline and amoxicillin without resolution of the eruption. After an extensive investigation, the treating rheumatologist concluded that the LCV was idiopathic or secondary to an infection or drug exposure. The rheumatologist started the patient on oral prednisone for the chronic symptomatic LCV, but she was intolerant of this medication and discontinued it after 1 week. Our dermatology clinic started her on triamcinolone cream 0.1% twice daily, but she continued to experience new and worsening lesions. At her follow-up appointment 1 month later, triamcinolone cream was discontinued and dapsone gel 5% twice daily was started. She experienced resolution of her previously recalcitrant LCV within 3 weeks (Figure, B).
Comment
Established therapies for LCV carry serious side-effect profiles, which can preclude their use.5 Therefore, a topical therapeutic alternative for LCV would be ideal. Systemic prednisone is the first-line therapy for chronic and/or symptomatic LCV, but its side effects include suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, osteonecrosis, and glucose intolerance.5 Colchicine therapy carries risks for blood dyscrasia, immunosuppression, and gastrointestinal tract upset. Systemic dapsone also is an effective therapy for chronic and/or symptomatic LCV.5,6 However, systemic dapsone requires glucose-6-phosphate dehydrogenase deficiency screening and routine monitoring of blood counts, and it also carries the risk for serious adverse effects including neuropathy, blood dyscrasia, and hypersensitivity syndrome.5,6 Topical dapsone may provide similar efficacy with far fewer adverse effects and has proven to be a safe treatment of acne, even when used in patients with glucose-6-phosphate dehydrogenase deficiency. It displays low systemic absorption and does not accumulate over time once a steady state is reached.7 It also has been shown to be beneficial in other vasculopathies such as erythema elevatum diutinum and in other neutrophilic inflammatory disorders such as pyoderma gangrenosum.8,9 A case of methemoglobinemia due to topical dapsone has been reported.10 Although this effect is rare, clinicians should be aware of such adverse effects when using medications for off-label purposes.
Leukocytoclastic vasculitis can spontaneously resolve; however, our patient’s disease was chronic for several months, and she continued to develop new lesions without signs of resolution. After initiating topical dapsone, she experienced resolution within 3 weeks.
Conclusion
Topical dapsone is a novel approach for treating LCV. Given this drug’s favorable side-effect profile compared to the currently available therapeutic alternatives, we believe it is a reasonable option in select patients. Further investigation is needed to prove its efficacy, but it could be an ideal alternative for patients with contraindications to traditional therapies and/or for those unable to tolerate systemic therapy.
- Koutkia P, Mylonakis E, Rounds S, et al. Leucocytoclastic vasculitis: an update for the clinician. Scand J Rheumatol. 2001;30:315-322.
- Af Ekenstam E, Callen JP. Cutaneous leukocytoclastic vasculitis. clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120:484-489.
- Gyselbrecht L, de Keyser F, Ongenae K, et al. Etiological factors and underlying conditions in patientswith leucocytoclastic vasculitis. Clin Exp Rheumatol. 1996;14:665-668.
- Sais G, Vidaller A, Jucglà A, et al. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. results of a prospective, randomized controlled trial. Arch Dermatol. 1995;131:1399-1402.
- Sunderkotter C, Bonsmann G, Sindrilaru A, et al. Management of leukocytoclastic vasculitis: clinical review. J Dermatol Treat. 2005;16:193-206.
- Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45:420-434.
- Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol. 2009;10:221-227.
- Frieling GW, Williams NL, Lim SJ, et al. Novel use of topical dapsone 5% gel for erythema elevatum diutinum: safer and effective. J Drugs Dermatol. 2013;12:481-484.
- Handler MZ, Hamilton H, Aires D. Treatment of peristomal pyoderma gangrenosum with topical crushed dapsone. J Drugs Dermatol. 2011;10:1059-1061.
- Swartzentruber GS, Yanta JH, Pizon AF. Methemoglobi-nemia as a complication of topical dapsone. N Engl J Med. 2015;372:491-492.
- Koutkia P, Mylonakis E, Rounds S, et al. Leucocytoclastic vasculitis: an update for the clinician. Scand J Rheumatol. 2001;30:315-322.
- Af Ekenstam E, Callen JP. Cutaneous leukocytoclastic vasculitis. clinical and laboratory features of 82 patients seen in private practice. Arch Dermatol. 1984;120:484-489.
- Gyselbrecht L, de Keyser F, Ongenae K, et al. Etiological factors and underlying conditions in patientswith leucocytoclastic vasculitis. Clin Exp Rheumatol. 1996;14:665-668.
- Sais G, Vidaller A, Jucglà A, et al. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. results of a prospective, randomized controlled trial. Arch Dermatol. 1995;131:1399-1402.
- Sunderkotter C, Bonsmann G, Sindrilaru A, et al. Management of leukocytoclastic vasculitis: clinical review. J Dermatol Treat. 2005;16:193-206.
- Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45:420-434.
- Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol. 2009;10:221-227.
- Frieling GW, Williams NL, Lim SJ, et al. Novel use of topical dapsone 5% gel for erythema elevatum diutinum: safer and effective. J Drugs Dermatol. 2013;12:481-484.
- Handler MZ, Hamilton H, Aires D. Treatment of peristomal pyoderma gangrenosum with topical crushed dapsone. J Drugs Dermatol. 2011;10:1059-1061.
- Swartzentruber GS, Yanta JH, Pizon AF. Methemoglobi-nemia as a complication of topical dapsone. N Engl J Med. 2015;372:491-492.
Practice Points
- Leukocytoclastic vasculitis is characterized by inflammation of small vessels with characteristic clinical findings of petechiae and palpable purpura.
- Leukocytoclastic vasculitis often spontaneously resolves within weeks and requires only symptomatic treatment, but chronic or severe disease can require systemic medical treatment with agents such as colchicine, dapsone, and corticosteroids.
Long-acting injectables may be best at preventing relapse in psychosis
SAN DIEGO – A new meta-analysis suggests that second-generation long-acting injectable antipsychotics (LAIs) are slightly better than oral antipsychotics at preventing relapse after a first psychotic incident.
The meta-analysis, released at the annual meeting of the American Psychiatric Association, is limited because it looks at only three studies. Still, study lead author Christine Tran-Boynes, DO, said the findings are useful for psychiatrists.
“For a long time, LAIs were associated with severely ill psychotic patients who were frequently hospitalized and not compliant with their oral meds,” Dr. Tran-Boynes, a resident at the University of Maryland, Baltimore, said in an interview. “The purpose of this paper is to change the perception of LAIs. They are not just a medication of last resort in those with severe, chronic psychosis but, instead, can be used in the early stages of psychosis as prophylaxis against relapse.”
Injectable antipsychotics are more commonly used in Europe, where “there also seemed to be a greater willingness among patients to receive this treatment,” said Peter F. Buckley, MD, dean of the medical school at Virginia Commonwealth University, Richmond.
The APA’s schizophrenia treatment guidelines recommend LAIs for patients with “recurrent relapses related to nonadherence” and patients who prefer the shots. Dr. Tran-Boynes notes that “the most common cause of relapse in patients with schizophrenia is partial adherence or nonadherence to oral antipsychotics. If LAIs can improve adherence in patients and monitoring of adherence for clinicians, they could have a role in preventing relapse during this critical period in psychosis.”
The meta-analysis examines three randomized controlled studies – two from 2015 and one from 2013 – that compare second-generation LAIs to first- and second-generation oral antipsychotics after first episodes of psychosis. Dr. Tran-Boynes said researchers could not find any studies comparing first-generation long-acting antipsychotics to oral antipsychotics.
The largest study had 769 participants; the others had 85 and 86. The subjects, all adults, had diagnoses of schizophrenia, schizoaffective disorder, or schizophreniform disorder. Their diagnoses must have been made within the previous 5 years.
According to the meta-analysis, relapses after first-episode psychosis were more likely (relative risk, 1.078; 95% confidence interval, 1.007-1.154; P = 0.012) in patients taking first- or second-generation oral antipsychotics, compared with those on second-generation LAIs.
“There was an 8% greater efficacy for LAIs preventing relapse after early psychosis, compared to oral antipsychotics,” Dr. Tran-Boynes said. She calculated the number needed to treat as 14.
The percentages of patients who did not relapse while taking second-generation LAIs ranged from 73% (31 of 42 patients randomized to an injectable risperidone arm over 24 months) to 95% (38 of 40 patients over a 12-month study, also of injectable risperidone), Dr. Tran-Boynes said.
When asked about the meta-analysis, Robert Rosenheck, MD, expressed concern.
“While well done, it is based on too few studies to give useful guidance to practice,” said Dr. Rosenheck, professor of psychiatry, epidemiology and public health at Yale University, New Haven, Conn.
Dr. Buckley also noted that the meta-analysis includes a small number of studies. “The effect is sizable for a first-episode population, but other studies to date are more mixed,” he added. “For instance, in a study among a more chronic schizophrenic population, we found no difference between a group receiving long-acting injectable risperidone and oral second-generation antipsychotics” (Schizophr Bull. 2015 Mar;41[2]:449-59).
What should psychiatrists know when they consider prescribing LAIs to prevent psychotic relapse? “If a patient expresses willingness to take an oral antipsychotic on a daily basis and/or has someone to monitor his medication intake, then prescribing an oral antipsychotic would be the ideal route,” Dr. Tran-Boynes said. “However, I would recommend LAIs to patients who have demonstrated poor compliance with previous medications in general, poor awareness of psychosis, poor awareness of need for treatment, poor availability of social support to ensure that the patient will take his/her medication daily, and/or if a patient expresses preference for LAIs.”
She cautioned that LAIs have disadvantages. Compared with oral antipsychotics, it’s harder to adjust patients’ dosages in response to side effects or when they improve, she said. LAIs are also more expensive in the short term, she said.
However, LAIs also may have produced fewer side effects, and there aren’t any questions about compliance, she said. In addition, “there’s less pain at the injection site with second-generation LAIs, compared to first-generation LAIs, due to the water-based solution of the former. The oil-based solutions that are characteristic of first-generation LAIs have been shown in studies to be very painful.”
Dr. Tran-Boynes and Dr. Rosenheck reported no relevant disclosures. Dr. Buckley disclosed that he is a research consultant for the National Institute of Mental Health.
SAN DIEGO – A new meta-analysis suggests that second-generation long-acting injectable antipsychotics (LAIs) are slightly better than oral antipsychotics at preventing relapse after a first psychotic incident.
The meta-analysis, released at the annual meeting of the American Psychiatric Association, is limited because it looks at only three studies. Still, study lead author Christine Tran-Boynes, DO, said the findings are useful for psychiatrists.
“For a long time, LAIs were associated with severely ill psychotic patients who were frequently hospitalized and not compliant with their oral meds,” Dr. Tran-Boynes, a resident at the University of Maryland, Baltimore, said in an interview. “The purpose of this paper is to change the perception of LAIs. They are not just a medication of last resort in those with severe, chronic psychosis but, instead, can be used in the early stages of psychosis as prophylaxis against relapse.”
Injectable antipsychotics are more commonly used in Europe, where “there also seemed to be a greater willingness among patients to receive this treatment,” said Peter F. Buckley, MD, dean of the medical school at Virginia Commonwealth University, Richmond.
The APA’s schizophrenia treatment guidelines recommend LAIs for patients with “recurrent relapses related to nonadherence” and patients who prefer the shots. Dr. Tran-Boynes notes that “the most common cause of relapse in patients with schizophrenia is partial adherence or nonadherence to oral antipsychotics. If LAIs can improve adherence in patients and monitoring of adherence for clinicians, they could have a role in preventing relapse during this critical period in psychosis.”
The meta-analysis examines three randomized controlled studies – two from 2015 and one from 2013 – that compare second-generation LAIs to first- and second-generation oral antipsychotics after first episodes of psychosis. Dr. Tran-Boynes said researchers could not find any studies comparing first-generation long-acting antipsychotics to oral antipsychotics.
The largest study had 769 participants; the others had 85 and 86. The subjects, all adults, had diagnoses of schizophrenia, schizoaffective disorder, or schizophreniform disorder. Their diagnoses must have been made within the previous 5 years.
According to the meta-analysis, relapses after first-episode psychosis were more likely (relative risk, 1.078; 95% confidence interval, 1.007-1.154; P = 0.012) in patients taking first- or second-generation oral antipsychotics, compared with those on second-generation LAIs.
“There was an 8% greater efficacy for LAIs preventing relapse after early psychosis, compared to oral antipsychotics,” Dr. Tran-Boynes said. She calculated the number needed to treat as 14.
The percentages of patients who did not relapse while taking second-generation LAIs ranged from 73% (31 of 42 patients randomized to an injectable risperidone arm over 24 months) to 95% (38 of 40 patients over a 12-month study, also of injectable risperidone), Dr. Tran-Boynes said.
When asked about the meta-analysis, Robert Rosenheck, MD, expressed concern.
“While well done, it is based on too few studies to give useful guidance to practice,” said Dr. Rosenheck, professor of psychiatry, epidemiology and public health at Yale University, New Haven, Conn.
Dr. Buckley also noted that the meta-analysis includes a small number of studies. “The effect is sizable for a first-episode population, but other studies to date are more mixed,” he added. “For instance, in a study among a more chronic schizophrenic population, we found no difference between a group receiving long-acting injectable risperidone and oral second-generation antipsychotics” (Schizophr Bull. 2015 Mar;41[2]:449-59).
What should psychiatrists know when they consider prescribing LAIs to prevent psychotic relapse? “If a patient expresses willingness to take an oral antipsychotic on a daily basis and/or has someone to monitor his medication intake, then prescribing an oral antipsychotic would be the ideal route,” Dr. Tran-Boynes said. “However, I would recommend LAIs to patients who have demonstrated poor compliance with previous medications in general, poor awareness of psychosis, poor awareness of need for treatment, poor availability of social support to ensure that the patient will take his/her medication daily, and/or if a patient expresses preference for LAIs.”
She cautioned that LAIs have disadvantages. Compared with oral antipsychotics, it’s harder to adjust patients’ dosages in response to side effects or when they improve, she said. LAIs are also more expensive in the short term, she said.
However, LAIs also may have produced fewer side effects, and there aren’t any questions about compliance, she said. In addition, “there’s less pain at the injection site with second-generation LAIs, compared to first-generation LAIs, due to the water-based solution of the former. The oil-based solutions that are characteristic of first-generation LAIs have been shown in studies to be very painful.”
Dr. Tran-Boynes and Dr. Rosenheck reported no relevant disclosures. Dr. Buckley disclosed that he is a research consultant for the National Institute of Mental Health.
SAN DIEGO – A new meta-analysis suggests that second-generation long-acting injectable antipsychotics (LAIs) are slightly better than oral antipsychotics at preventing relapse after a first psychotic incident.
The meta-analysis, released at the annual meeting of the American Psychiatric Association, is limited because it looks at only three studies. Still, study lead author Christine Tran-Boynes, DO, said the findings are useful for psychiatrists.
“For a long time, LAIs were associated with severely ill psychotic patients who were frequently hospitalized and not compliant with their oral meds,” Dr. Tran-Boynes, a resident at the University of Maryland, Baltimore, said in an interview. “The purpose of this paper is to change the perception of LAIs. They are not just a medication of last resort in those with severe, chronic psychosis but, instead, can be used in the early stages of psychosis as prophylaxis against relapse.”
Injectable antipsychotics are more commonly used in Europe, where “there also seemed to be a greater willingness among patients to receive this treatment,” said Peter F. Buckley, MD, dean of the medical school at Virginia Commonwealth University, Richmond.
The APA’s schizophrenia treatment guidelines recommend LAIs for patients with “recurrent relapses related to nonadherence” and patients who prefer the shots. Dr. Tran-Boynes notes that “the most common cause of relapse in patients with schizophrenia is partial adherence or nonadherence to oral antipsychotics. If LAIs can improve adherence in patients and monitoring of adherence for clinicians, they could have a role in preventing relapse during this critical period in psychosis.”
The meta-analysis examines three randomized controlled studies – two from 2015 and one from 2013 – that compare second-generation LAIs to first- and second-generation oral antipsychotics after first episodes of psychosis. Dr. Tran-Boynes said researchers could not find any studies comparing first-generation long-acting antipsychotics to oral antipsychotics.
The largest study had 769 participants; the others had 85 and 86. The subjects, all adults, had diagnoses of schizophrenia, schizoaffective disorder, or schizophreniform disorder. Their diagnoses must have been made within the previous 5 years.
According to the meta-analysis, relapses after first-episode psychosis were more likely (relative risk, 1.078; 95% confidence interval, 1.007-1.154; P = 0.012) in patients taking first- or second-generation oral antipsychotics, compared with those on second-generation LAIs.
“There was an 8% greater efficacy for LAIs preventing relapse after early psychosis, compared to oral antipsychotics,” Dr. Tran-Boynes said. She calculated the number needed to treat as 14.
The percentages of patients who did not relapse while taking second-generation LAIs ranged from 73% (31 of 42 patients randomized to an injectable risperidone arm over 24 months) to 95% (38 of 40 patients over a 12-month study, also of injectable risperidone), Dr. Tran-Boynes said.
When asked about the meta-analysis, Robert Rosenheck, MD, expressed concern.
“While well done, it is based on too few studies to give useful guidance to practice,” said Dr. Rosenheck, professor of psychiatry, epidemiology and public health at Yale University, New Haven, Conn.
Dr. Buckley also noted that the meta-analysis includes a small number of studies. “The effect is sizable for a first-episode population, but other studies to date are more mixed,” he added. “For instance, in a study among a more chronic schizophrenic population, we found no difference between a group receiving long-acting injectable risperidone and oral second-generation antipsychotics” (Schizophr Bull. 2015 Mar;41[2]:449-59).
What should psychiatrists know when they consider prescribing LAIs to prevent psychotic relapse? “If a patient expresses willingness to take an oral antipsychotic on a daily basis and/or has someone to monitor his medication intake, then prescribing an oral antipsychotic would be the ideal route,” Dr. Tran-Boynes said. “However, I would recommend LAIs to patients who have demonstrated poor compliance with previous medications in general, poor awareness of psychosis, poor awareness of need for treatment, poor availability of social support to ensure that the patient will take his/her medication daily, and/or if a patient expresses preference for LAIs.”
She cautioned that LAIs have disadvantages. Compared with oral antipsychotics, it’s harder to adjust patients’ dosages in response to side effects or when they improve, she said. LAIs are also more expensive in the short term, she said.
However, LAIs also may have produced fewer side effects, and there aren’t any questions about compliance, she said. In addition, “there’s less pain at the injection site with second-generation LAIs, compared to first-generation LAIs, due to the water-based solution of the former. The oil-based solutions that are characteristic of first-generation LAIs have been shown in studies to be very painful.”
Dr. Tran-Boynes and Dr. Rosenheck reported no relevant disclosures. Dr. Buckley disclosed that he is a research consultant for the National Institute of Mental Health.
AT APA
Key clinical point: Second-generation long-acting injectable antipsychotics (LAIs) may be better than oral antipsychotics at preventing relapse after first episode of psychosis.
Major finding: Relapses after first-episode psychosis were more likely (RR, 1.078; 95% CI, 1.007-1.154; P = 0.012) in patients on first- and second-generation oral antipsychotics, compared with second-generation LAIs.
Data source: Meta-analysis of three randomized controlled trials with 940 total patients.
Disclosures: Dr. Tran-Boynes reported having no relevant disclosures.