NEWPORT BEACH, CALIF. – In medical school you may have been taught that herpes zoster infection primarily impacts elderly patients, but the burden of disease is shifting – along with the understanding of herpes zoster itself.

“Herpes zoster is a disease that can lull us into a false sense of security because we see it all the time,” Iris Ahronowitz, MD, said at the annual meeting of the Pacific Dermatologic Association. “But our understanding of how to manage this disease is still very much a work in progress.”

She noted that while 50% of people will acquire herpes zoster by the time they reach 85 years of age due to diminishing cell-mediated immunity, the major burden of disease impacts immunocompromised patients of all ages. HIV patients and solid-organ transplant recipients are well known to face an increased risk of acquiring herpes zoster, but the most overwhelming risk is seen in leukemia patients, who have rates as high as 100-fold that of the general population.

“More recent data on stem cell transplant patients show that about 50% of them will get zoster,” added Dr. Ahronowitz, a dermatologist at the University of Southern California, Los Angeles. “Most of that’s happening within the first year and a half after their transplant.”

Several recent epidemiologic studies in the medical literature have reported herpes zoster in patients who are not traditionally believed to be immunosuppressed, such as those with lupus, dermatomyositis, rheumatoid arthritis, asthma, and atopic dermatitis. “It begs the question: is it the disease or is it the treatment?” Dr. Ahronowitz said. “We don’t know the answer to that yet. In dermatomyositis and lupus, use of antimalarials has been found to be most associated with the risk of herpes zoster. Other studies looking at one disease are so heterogeneous, some saying that it’s one medication, some saying that it’s another. There’s no cohesive message yet about which medications cause the highest risk of zoster.”

Herpes zoster was originally believed to be far less transmissible than varicella. “Later it was thought that the only way that you can get VZV [varicella zoster virus] from a zoster patient was by direct contact with vesicle fluid,” Dr. Ahronowitz said. “That turns out to be wrong as well.” One study of pediatric patients found similar rates of secondary varicella cases from varicella and herpes zoster cases (15% vs. 9%, respectively), regardless of anatomic location of zoster (J Infect Dis. 2012; 205[9]:1336-41).

Another report that called into question prevailing beliefs about the disease involved an immunocompetent patient in a long-term care facility who developed localized herpes zoster (J Infect Dis. 2008;197[5]:646-53). That individual turned out to be “patient zero” in a varicella outbreak in the facility, even though the person’s lesions had been covered by gauze and clothing at all times. “The next patient who got infected was one of the health care workers who had never been in the room at the same time as the patient but who had changed the patient’s bed linens,” said Dr. Ahronowitz, who was not involved with the study. “Environmental samples were collected from the patient’s room and were contaminated with VZV DNA.”

She went on to note that VZV DNA has been found in vesicle fluid, serum, peripheral blood mononuclear cells, and saliva. One randomized, controlled trial found that hydrocolloid dressings are superior to traditional gauze and paper dressings in preventing the excretion of aerosolized VZV DNA from skin lesions of patients with localized herpes zoster (J Infect Dis. 2004;189[6]:1009-12). Using hydrocolloid dressings to cover lesions “does seem to make a difference,” she said. “Because of all this new data coming out, I think it’s time to reconsider isolation precautions in all hospitalized patients with herpes zoster, because the consequences of VZV transmission within a hospital where there are other patients nearby who have low immune systems could be absolutely devastating.”

The impact of herpes zoster infection on the central nervous system can be significant, including cranial nerve palsy, encephalitis, encephalopathy, and aseptic meningitis. “Patients can have long-lasting residual neurologic deficits from this at 6 months or longer despite appropriate treatment,” she said. “No correlation between CSF viral load and neurologic sequelae has been found at 3 months.”

More recent research has found an association between herpes zoster infection and an increased risk of stroke – up to threefold in some cases. “That risk doesn’t normalize until 6 months after the infection,” Dr. Ahronowitz said. “We’re even seeing it in kids, who have two times the risk of stroke in the first 6 months after VZV infection.” MI risk also seems to be elevated as a secondary outcome (a 1.7-fold increase in the first week of infection).

“There have also been recent reports of VZV antigen/DNA found in the vessel wall of patients with giant cell arteritis and granulomatous arteritis of the aorta,” she said. “This is an evolving story about zoster that we never knew about.”

Drug-induced hypersensitivity syndrome (DIHS) is also associated with CNS manifestations, but they resolve much faster, unlike those of CNS zoster. “As long as you take away the offending medication and put them on steroids they will recover very quickly,” she said. At least one case in the medical literature to date has reported DIHS in association with VZV (Acta Derm Venereol. 2015;95[4]:503-4).

The zoster vaccine (Zostavax, Merck & Co.) is currently indicated in patients aged 60 years and older, but since it is a live attenuated vaccine, it is contraindicated in many patients who could most benefit from it, including those with primary immunodeficiency disorders, those with a hematologic malignancy, those who have had a hematopoietic stem cell transplant within the last 2 years, pregnant patients, and patients taking high-dose steroids or anti–tumor necrosis factor biologics.

“There is an inactivated vaccine in the works being tested, and that is showing good efficacy,” Dr. Ahronowitz said. “Hopefully we’ll be able to prevaccinate patients, even young patients, prior to immune suppression.”

She reported having no relevant disclosures.

[email protected]

NEWPORT BEACH, CALIF. – In medical school you may have been taught that herpes zoster infection primarily impacts elderly patients, but the burden of disease is shifting – along with the understanding of herpes zoster itself.

“Herpes zoster is a disease that can lull us into a false sense of security because we see it all the time,” Iris Ahronowitz, MD, said at the annual meeting of the Pacific Dermatologic Association. “But our understanding of how to manage this disease is still very much a work in progress.”

She noted that while 50% of people will acquire herpes zoster by the time they reach 85 years of age due to diminishing cell-mediated immunity, the major burden of disease impacts immunocompromised patients of all ages. HIV patients and solid-organ transplant recipients are well known to face an increased risk of acquiring herpes zoster, but the most overwhelming risk is seen in leukemia patients, who have rates as high as 100-fold that of the general population.

“More recent data on stem cell transplant patients show that about 50% of them will get zoster,” added Dr. Ahronowitz, a dermatologist at the University of Southern California, Los Angeles. “Most of that’s happening within the first year and a half after their transplant.”

Several recent epidemiologic studies in the medical literature have reported herpes zoster in patients who are not traditionally believed to be immunosuppressed, such as those with lupus, dermatomyositis, rheumatoid arthritis, asthma, and atopic dermatitis. “It begs the question: is it the disease or is it the treatment?” Dr. Ahronowitz said. “We don’t know the answer to that yet. In dermatomyositis and lupus, use of antimalarials has been found to be most associated with the risk of herpes zoster. Other studies looking at one disease are so heterogeneous, some saying that it’s one medication, some saying that it’s another. There’s no cohesive message yet about which medications cause the highest risk of zoster.”

Herpes zoster was originally believed to be far less transmissible than varicella. “Later it was thought that the only way that you can get VZV [varicella zoster virus] from a zoster patient was by direct contact with vesicle fluid,” Dr. Ahronowitz said. “That turns out to be wrong as well.” One study of pediatric patients found similar rates of secondary varicella cases from varicella and herpes zoster cases (15% vs. 9%, respectively), regardless of anatomic location of zoster (J Infect Dis. 2012; 205[9]:1336-41).

Another report that called into question prevailing beliefs about the disease involved an immunocompetent patient in a long-term care facility who developed localized herpes zoster (J Infect Dis. 2008;197[5]:646-53). That individual turned out to be “patient zero” in a varicella outbreak in the facility, even though the person’s lesions had been covered by gauze and clothing at all times. “The next patient who got infected was one of the health care workers who had never been in the room at the same time as the patient but who had changed the patient’s bed linens,” said Dr. Ahronowitz, who was not involved with the study. “Environmental samples were collected from the patient’s room and were contaminated with VZV DNA.”

She went on to note that VZV DNA has been found in vesicle fluid, serum, peripheral blood mononuclear cells, and saliva. One randomized, controlled trial found that hydrocolloid dressings are superior to traditional gauze and paper dressings in preventing the excretion of aerosolized VZV DNA from skin lesions of patients with localized herpes zoster (J Infect Dis. 2004;189[6]:1009-12). Using hydrocolloid dressings to cover lesions “does seem to make a difference,” she said. “Because of all this new data coming out, I think it’s time to reconsider isolation precautions in all hospitalized patients with herpes zoster, because the consequences of VZV transmission within a hospital where there are other patients nearby who have low immune systems could be absolutely devastating.”

The impact of herpes zoster infection on the central nervous system can be significant, including cranial nerve palsy, encephalitis, encephalopathy, and aseptic meningitis. “Patients can have long-lasting residual neurologic deficits from this at 6 months or longer despite appropriate treatment,” she said. “No correlation between CSF viral load and neurologic sequelae has been found at 3 months.”

More recent research has found an association between herpes zoster infection and an increased risk of stroke – up to threefold in some cases. “That risk doesn’t normalize until 6 months after the infection,” Dr. Ahronowitz said. “We’re even seeing it in kids, who have two times the risk of stroke in the first 6 months after VZV infection.” MI risk also seems to be elevated as a secondary outcome (a 1.7-fold increase in the first week of infection).

“There have also been recent reports of VZV antigen/DNA found in the vessel wall of patients with giant cell arteritis and granulomatous arteritis of the aorta,” she said. “This is an evolving story about zoster that we never knew about.”

Drug-induced hypersensitivity syndrome (DIHS) is also associated with CNS manifestations, but they resolve much faster, unlike those of CNS zoster. “As long as you take away the offending medication and put them on steroids they will recover very quickly,” she said. At least one case in the medical literature to date has reported DIHS in association with VZV (Acta Derm Venereol. 2015;95[4]:503-4).

The zoster vaccine (Zostavax, Merck & Co.) is currently indicated in patients aged 60 years and older, but since it is a live attenuated vaccine, it is contraindicated in many patients who could most benefit from it, including those with primary immunodeficiency disorders, those with a hematologic malignancy, those who have had a hematopoietic stem cell transplant within the last 2 years, pregnant patients, and patients taking high-dose steroids or anti–tumor necrosis factor biologics.

“There is an inactivated vaccine in the works being tested, and that is showing good efficacy,” Dr. Ahronowitz said. “Hopefully we’ll be able to prevaccinate patients, even young patients, prior to immune suppression.”

She reported having no relevant disclosures.

[email protected]

NEWPORT BEACH, CALIF. – In medical school you may have been taught that herpes zoster infection primarily impacts elderly patients, but the burden of disease is shifting – along with the understanding of herpes zoster itself.

“Herpes zoster is a disease that can lull us into a false sense of security because we see it all the time,” Iris Ahronowitz, MD, said at the annual meeting of the Pacific Dermatologic Association. “But our understanding of how to manage this disease is still very much a work in progress.”

She noted that while 50% of people will acquire herpes zoster by the time they reach 85 years of age due to diminishing cell-mediated immunity, the major burden of disease impacts immunocompromised patients of all ages. HIV patients and solid-organ transplant recipients are well known to face an increased risk of acquiring herpes zoster, but the most overwhelming risk is seen in leukemia patients, who have rates as high as 100-fold that of the general population.

“More recent data on stem cell transplant patients show that about 50% of them will get zoster,” added Dr. Ahronowitz, a dermatologist at the University of Southern California, Los Angeles. “Most of that’s happening within the first year and a half after their transplant.”

Several recent epidemiologic studies in the medical literature have reported herpes zoster in patients who are not traditionally believed to be immunosuppressed, such as those with lupus, dermatomyositis, rheumatoid arthritis, asthma, and atopic dermatitis. “It begs the question: is it the disease or is it the treatment?” Dr. Ahronowitz said. “We don’t know the answer to that yet. In dermatomyositis and lupus, use of antimalarials has been found to be most associated with the risk of herpes zoster. Other studies looking at one disease are so heterogeneous, some saying that it’s one medication, some saying that it’s another. There’s no cohesive message yet about which medications cause the highest risk of zoster.”

Herpes zoster was originally believed to be far less transmissible than varicella. “Later it was thought that the only way that you can get VZV [varicella zoster virus] from a zoster patient was by direct contact with vesicle fluid,” Dr. Ahronowitz said. “That turns out to be wrong as well.” One study of pediatric patients found similar rates of secondary varicella cases from varicella and herpes zoster cases (15% vs. 9%, respectively), regardless of anatomic location of zoster (J Infect Dis. 2012; 205[9]:1336-41).

Another report that called into question prevailing beliefs about the disease involved an immunocompetent patient in a long-term care facility who developed localized herpes zoster (J Infect Dis. 2008;197[5]:646-53). That individual turned out to be “patient zero” in a varicella outbreak in the facility, even though the person’s lesions had been covered by gauze and clothing at all times. “The next patient who got infected was one of the health care workers who had never been in the room at the same time as the patient but who had changed the patient’s bed linens,” said Dr. Ahronowitz, who was not involved with the study. “Environmental samples were collected from the patient’s room and were contaminated with VZV DNA.”

She went on to note that VZV DNA has been found in vesicle fluid, serum, peripheral blood mononuclear cells, and saliva. One randomized, controlled trial found that hydrocolloid dressings are superior to traditional gauze and paper dressings in preventing the excretion of aerosolized VZV DNA from skin lesions of patients with localized herpes zoster (J Infect Dis. 2004;189[6]:1009-12). Using hydrocolloid dressings to cover lesions “does seem to make a difference,” she said. “Because of all this new data coming out, I think it’s time to reconsider isolation precautions in all hospitalized patients with herpes zoster, because the consequences of VZV transmission within a hospital where there are other patients nearby who have low immune systems could be absolutely devastating.”

The impact of herpes zoster infection on the central nervous system can be significant, including cranial nerve palsy, encephalitis, encephalopathy, and aseptic meningitis. “Patients can have long-lasting residual neurologic deficits from this at 6 months or longer despite appropriate treatment,” she said. “No correlation between CSF viral load and neurologic sequelae has been found at 3 months.”

More recent research has found an association between herpes zoster infection and an increased risk of stroke – up to threefold in some cases. “That risk doesn’t normalize until 6 months after the infection,” Dr. Ahronowitz said. “We’re even seeing it in kids, who have two times the risk of stroke in the first 6 months after VZV infection.” MI risk also seems to be elevated as a secondary outcome (a 1.7-fold increase in the first week of infection).

“There have also been recent reports of VZV antigen/DNA found in the vessel wall of patients with giant cell arteritis and granulomatous arteritis of the aorta,” she said. “This is an evolving story about zoster that we never knew about.”

Drug-induced hypersensitivity syndrome (DIHS) is also associated with CNS manifestations, but they resolve much faster, unlike those of CNS zoster. “As long as you take away the offending medication and put them on steroids they will recover very quickly,” she said. At least one case in the medical literature to date has reported DIHS in association with VZV (Acta Derm Venereol. 2015;95[4]:503-4).

The zoster vaccine (Zostavax, Merck & Co.) is currently indicated in patients aged 60 years and older, but since it is a live attenuated vaccine, it is contraindicated in many patients who could most benefit from it, including those with primary immunodeficiency disorders, those with a hematologic malignancy, those who have had a hematopoietic stem cell transplant within the last 2 years, pregnant patients, and patients taking high-dose steroids or anti–tumor necrosis factor biologics.

“There is an inactivated vaccine in the works being tested, and that is showing good efficacy,” Dr. Ahronowitz said. “Hopefully we’ll be able to prevaccinate patients, even young patients, prior to immune suppression.”

She reported having no relevant disclosures.

[email protected]

Neuroscientists cautioned patients about the dangers of self-administered transcranial direct current stimulation (tDCS) in an open letter published July 7 in Annals of Neurology. “We perceive an ethical obligation to draw the attention of both professionals and ‘do it yourself’ (DIY) users to some of these issues,” said Michael D. Fox, MD, PhD, Assistant Professor of Neurology at Harvard Medical School in Boston. The open letter, written by four neuroscientists and signed by 39 colleagues, addresses several less commonly recognized complications of self-administered brain stimulation.

Noninvasive electrical brain stimulation may help ameliorate symptoms of anxiety and depression; however, neuroscientists say that much about this technique remains unknown and could present potential risks for DIY users. “We have never formally studied tDCS at the frequencies many DIY users experiment with—for example, stimulating daily for months or longer. Because we know that stimulation from just a few sessions can be quite lasting, we infer that changes induced by these protocols may be even more so,” said Dr. Fox.

A further consideration is that tDCS affects more of the brain than people may think. Although electrodes are normally placed in specific scalp locations to target specific parts of the brain, stimulation extends beyond the regions beneath the electrodes and can result in unintended altering of brain functions.

Self-administered brain stimulation may have a different impact on neurons that are active during stimulation versus neurons that are inactive during stimulation, according to the neurologists. “Because of this feature, the cognitive or behavioral activity occurring while tDCS is applied will modify the effects,” said Dr. Fox. Stimulation may affect the brain differently depending on whether it is applied while the subject is watching TV, sleeping, or performing other daily tasks, he added.

In addition, while some cognitive abilities may be enhanced with tDCS, other abilities may be impacted negatively. “Such cognitive tradeoffs could develop over time and only become recognizable long after the stimulation,” said Dr. Fox. Also, small changes in tDCS settings such as current amplitude and electrode activity could result in negative effects on brain function, said the neurologists.

The authors emphasized that the response to tDCS is unpredictable; subjects respond differently to changes in cortical excitability. For example, age, gender, hormones, cognitive ability, and head anatomy can modify the effects of tDCS in the brain. “Up to 30% of experimental subjects respond with changes in cortical excitability in the opposite direction from other subjects using identical tDCS settings,” said Dr. Fox.

“We encourage consideration of these issues and involvement of health care providers in making decisions regarding DIY brain stimulation,” said Dr. Fox. He and his coauthors recommended that parents weigh the risks before using this device for children, especially since minors are not able to fully assess the potential dangers of tDCS.

—Erica Robinson

Neuroscientists cautioned patients about the dangers of self-administered transcranial direct current stimulation (tDCS) in an open letter published July 7 in Annals of Neurology. “We perceive an ethical obligation to draw the attention of both professionals and ‘do it yourself’ (DIY) users to some of these issues,” said Michael D. Fox, MD, PhD, Assistant Professor of Neurology at Harvard Medical School in Boston. The open letter, written by four neuroscientists and signed by 39 colleagues, addresses several less commonly recognized complications of self-administered brain stimulation.

Noninvasive electrical brain stimulation may help ameliorate symptoms of anxiety and depression; however, neuroscientists say that much about this technique remains unknown and could present potential risks for DIY users. “We have never formally studied tDCS at the frequencies many DIY users experiment with—for example, stimulating daily for months or longer. Because we know that stimulation from just a few sessions can be quite lasting, we infer that changes induced by these protocols may be even more so,” said Dr. Fox.

A further consideration is that tDCS affects more of the brain than people may think. Although electrodes are normally placed in specific scalp locations to target specific parts of the brain, stimulation extends beyond the regions beneath the electrodes and can result in unintended altering of brain functions.

Self-administered brain stimulation may have a different impact on neurons that are active during stimulation versus neurons that are inactive during stimulation, according to the neurologists. “Because of this feature, the cognitive or behavioral activity occurring while tDCS is applied will modify the effects,” said Dr. Fox. Stimulation may affect the brain differently depending on whether it is applied while the subject is watching TV, sleeping, or performing other daily tasks, he added.

In addition, while some cognitive abilities may be enhanced with tDCS, other abilities may be impacted negatively. “Such cognitive tradeoffs could develop over time and only become recognizable long after the stimulation,” said Dr. Fox. Also, small changes in tDCS settings such as current amplitude and electrode activity could result in negative effects on brain function, said the neurologists.

The authors emphasized that the response to tDCS is unpredictable; subjects respond differently to changes in cortical excitability. For example, age, gender, hormones, cognitive ability, and head anatomy can modify the effects of tDCS in the brain. “Up to 30% of experimental subjects respond with changes in cortical excitability in the opposite direction from other subjects using identical tDCS settings,” said Dr. Fox.

“We encourage consideration of these issues and involvement of health care providers in making decisions regarding DIY brain stimulation,” said Dr. Fox. He and his coauthors recommended that parents weigh the risks before using this device for children, especially since minors are not able to fully assess the potential dangers of tDCS.

—Erica Robinson

Neuroscientists cautioned patients about the dangers of self-administered transcranial direct current stimulation (tDCS) in an open letter published July 7 in Annals of Neurology. “We perceive an ethical obligation to draw the attention of both professionals and ‘do it yourself’ (DIY) users to some of these issues,” said Michael D. Fox, MD, PhD, Assistant Professor of Neurology at Harvard Medical School in Boston. The open letter, written by four neuroscientists and signed by 39 colleagues, addresses several less commonly recognized complications of self-administered brain stimulation.

Noninvasive electrical brain stimulation may help ameliorate symptoms of anxiety and depression; however, neuroscientists say that much about this technique remains unknown and could present potential risks for DIY users. “We have never formally studied tDCS at the frequencies many DIY users experiment with—for example, stimulating daily for months or longer. Because we know that stimulation from just a few sessions can be quite lasting, we infer that changes induced by these protocols may be even more so,” said Dr. Fox.

A further consideration is that tDCS affects more of the brain than people may think. Although electrodes are normally placed in specific scalp locations to target specific parts of the brain, stimulation extends beyond the regions beneath the electrodes and can result in unintended altering of brain functions.

Self-administered brain stimulation may have a different impact on neurons that are active during stimulation versus neurons that are inactive during stimulation, according to the neurologists. “Because of this feature, the cognitive or behavioral activity occurring while tDCS is applied will modify the effects,” said Dr. Fox. Stimulation may affect the brain differently depending on whether it is applied while the subject is watching TV, sleeping, or performing other daily tasks, he added.

In addition, while some cognitive abilities may be enhanced with tDCS, other abilities may be impacted negatively. “Such cognitive tradeoffs could develop over time and only become recognizable long after the stimulation,” said Dr. Fox. Also, small changes in tDCS settings such as current amplitude and electrode activity could result in negative effects on brain function, said the neurologists.

The authors emphasized that the response to tDCS is unpredictable; subjects respond differently to changes in cortical excitability. For example, age, gender, hormones, cognitive ability, and head anatomy can modify the effects of tDCS in the brain. “Up to 30% of experimental subjects respond with changes in cortical excitability in the opposite direction from other subjects using identical tDCS settings,” said Dr. Fox.

“We encourage consideration of these issues and involvement of health care providers in making decisions regarding DIY brain stimulation,” said Dr. Fox. He and his coauthors recommended that parents weigh the risks before using this device for children, especially since minors are not able to fully assess the potential dangers of tDCS.

—Erica Robinson

NEWPORT BEACH, CALIF. – Offering photodynamic therapy is a smart move for any dermatology practice, but also it requires common sense. That starts with making sure you treat only appropriate candidates.

“They can’t be intimidated by the thought of light or looking red, and you have to go into depth ahead of time as far as managing reactions, as well as long-term expectations,” Neal Bhatia, MD, said at the annual meeting of the Pacific Dermatologic Association. That includes reviewing any oral medications they’re taking, as well as topical products they may be using on their face or scalp.

“I like to do this treatment on Fridays so it gives patients the weekend to stay indoors for the next 48 hours, which is really what they need to optimize the response rate,” said Dr. Bhatia, director of clinical dermatology at Therapeutics Clinical Research in San Diego. “The other part of this is managing your staff. Make sure they have enough time to check in on the patients while they’re incubating away from light, as well as to review the post-treatment plan. And make sure they have a comfortable chair. Some patients might feel claustrophobic if you lay them down and put the light above them. Others might like to lay down for the procedure versus sitting down.”

His checklist for treatment day includes a reminder for patients to bring a wide-brimmed hat to shield the treated lesions from ambient light, as well as a book, computer, or paperwork to pass the time. He also advises putting together a take-home bag for patients that includes topical anesthetics, moisturizers, and sunscreen. In his clinical experience, prior to photodynamic therapy (PDT), there is no reason for patients to discontinue medications that are sensitizing in the UV spectrum such as antibiotics, diuretics, anti-hypertensives, since PDT works in the 410-417 nm range. “If you are concerned, you can hold the drugs the day before [the procedure], the day of, and maybe the day after, but that’s really all you need,” he said.

Dr. Bhatia discussed combinations with 5-fluorouracil (5-FU) before and after PDT, imiquimod plus aminolevulinic acid–PDT (ALA-PDT), and ingenol mebutate plus ALA-PDT. Antihistamines may play a role in helping to reduce the anticipated ALA-PDT response (J Invest Dermatol. 2006;126[10]:2296-301). Dr. Bhatia explained that the edema component is generated by mast cell release and can be uncoupled using selected H1-antihistamines, which can provide symptom relief without compromising efficacy. “Some studies talk about reducing erythema and edema based on the presence of mast cells and the surge of mast cells within first 48 to 72 hours,” he said. “Symptomatic relief is going to mean a lot to that patient who’s getting red, feeling itchy, and feeling swollen, but we don’t want to stop the reaction pattern and the efficacy by undoing what we’ve created as a response.”

It may seem counterintuitive, but direct tissue cooling after PDT appears to have a negative impact on perforin conversion, “to the point where it actually reduces the efficacy and treatment when you do direct tissue cooling,” Dr. Bhatia said. One study showed found significantly less resolution of actinic keratosis (AK) lesions treated with direct tissue cooling, compared with those who did not receive tissue cooling (J Photochem Photobiol B. 2011;103:1-7). In addition, there was a failure of conversion and optimization of the accumulated protoporphyrin IX when direct tissue cooling was used.

“That’s not to say a handheld fan or a fan in the room or aerating, making sure they have enough oxygen around the treatment area [isn’t useful],” Dr. Bhatia said. “I’m talking about the direct tissue cooling that we use with the pulsed laser device, or the Zimmer cooler. You get better conversion when you have a warming device, compared with contact cooling.”

Dr. Bhatia predicted that in the future, microneedle pre-treatment of human skin is going to gain popularity as a PDT adjunct. On early study of microneedling found that it improved 5-ALA and 5-MAL–induced protoporphyrin IX production for topical photodynamic therapy without increasing pain or erythema (Pharm Res. 2010;27[10]:2213-20). “I think that’s very important,” he said.

Dr. Bhatia disclosed having affiliations with Biofrontera and Dusa, the two main manufacturers of PDT in the United States.

[email protected]

NEWPORT BEACH, CALIF. – Offering photodynamic therapy is a smart move for any dermatology practice, but also it requires common sense. That starts with making sure you treat only appropriate candidates.

“They can’t be intimidated by the thought of light or looking red, and you have to go into depth ahead of time as far as managing reactions, as well as long-term expectations,” Neal Bhatia, MD, said at the annual meeting of the Pacific Dermatologic Association. That includes reviewing any oral medications they’re taking, as well as topical products they may be using on their face or scalp.

“I like to do this treatment on Fridays so it gives patients the weekend to stay indoors for the next 48 hours, which is really what they need to optimize the response rate,” said Dr. Bhatia, director of clinical dermatology at Therapeutics Clinical Research in San Diego. “The other part of this is managing your staff. Make sure they have enough time to check in on the patients while they’re incubating away from light, as well as to review the post-treatment plan. And make sure they have a comfortable chair. Some patients might feel claustrophobic if you lay them down and put the light above them. Others might like to lay down for the procedure versus sitting down.”

His checklist for treatment day includes a reminder for patients to bring a wide-brimmed hat to shield the treated lesions from ambient light, as well as a book, computer, or paperwork to pass the time. He also advises putting together a take-home bag for patients that includes topical anesthetics, moisturizers, and sunscreen. In his clinical experience, prior to photodynamic therapy (PDT), there is no reason for patients to discontinue medications that are sensitizing in the UV spectrum such as antibiotics, diuretics, anti-hypertensives, since PDT works in the 410-417 nm range. “If you are concerned, you can hold the drugs the day before [the procedure], the day of, and maybe the day after, but that’s really all you need,” he said.

Dr. Bhatia discussed combinations with 5-fluorouracil (5-FU) before and after PDT, imiquimod plus aminolevulinic acid–PDT (ALA-PDT), and ingenol mebutate plus ALA-PDT. Antihistamines may play a role in helping to reduce the anticipated ALA-PDT response (J Invest Dermatol. 2006;126[10]:2296-301). Dr. Bhatia explained that the edema component is generated by mast cell release and can be uncoupled using selected H1-antihistamines, which can provide symptom relief without compromising efficacy. “Some studies talk about reducing erythema and edema based on the presence of mast cells and the surge of mast cells within first 48 to 72 hours,” he said. “Symptomatic relief is going to mean a lot to that patient who’s getting red, feeling itchy, and feeling swollen, but we don’t want to stop the reaction pattern and the efficacy by undoing what we’ve created as a response.”

It may seem counterintuitive, but direct tissue cooling after PDT appears to have a negative impact on perforin conversion, “to the point where it actually reduces the efficacy and treatment when you do direct tissue cooling,” Dr. Bhatia said. One study showed found significantly less resolution of actinic keratosis (AK) lesions treated with direct tissue cooling, compared with those who did not receive tissue cooling (J Photochem Photobiol B. 2011;103:1-7). In addition, there was a failure of conversion and optimization of the accumulated protoporphyrin IX when direct tissue cooling was used.

“That’s not to say a handheld fan or a fan in the room or aerating, making sure they have enough oxygen around the treatment area [isn’t useful],” Dr. Bhatia said. “I’m talking about the direct tissue cooling that we use with the pulsed laser device, or the Zimmer cooler. You get better conversion when you have a warming device, compared with contact cooling.”

Dr. Bhatia predicted that in the future, microneedle pre-treatment of human skin is going to gain popularity as a PDT adjunct. On early study of microneedling found that it improved 5-ALA and 5-MAL–induced protoporphyrin IX production for topical photodynamic therapy without increasing pain or erythema (Pharm Res. 2010;27[10]:2213-20). “I think that’s very important,” he said.

Dr. Bhatia disclosed having affiliations with Biofrontera and Dusa, the two main manufacturers of PDT in the United States.

[email protected]

NEWPORT BEACH, CALIF. – Offering photodynamic therapy is a smart move for any dermatology practice, but also it requires common sense. That starts with making sure you treat only appropriate candidates.

“They can’t be intimidated by the thought of light or looking red, and you have to go into depth ahead of time as far as managing reactions, as well as long-term expectations,” Neal Bhatia, MD, said at the annual meeting of the Pacific Dermatologic Association. That includes reviewing any oral medications they’re taking, as well as topical products they may be using on their face or scalp.

“I like to do this treatment on Fridays so it gives patients the weekend to stay indoors for the next 48 hours, which is really what they need to optimize the response rate,” said Dr. Bhatia, director of clinical dermatology at Therapeutics Clinical Research in San Diego. “The other part of this is managing your staff. Make sure they have enough time to check in on the patients while they’re incubating away from light, as well as to review the post-treatment plan. And make sure they have a comfortable chair. Some patients might feel claustrophobic if you lay them down and put the light above them. Others might like to lay down for the procedure versus sitting down.”

His checklist for treatment day includes a reminder for patients to bring a wide-brimmed hat to shield the treated lesions from ambient light, as well as a book, computer, or paperwork to pass the time. He also advises putting together a take-home bag for patients that includes topical anesthetics, moisturizers, and sunscreen. In his clinical experience, prior to photodynamic therapy (PDT), there is no reason for patients to discontinue medications that are sensitizing in the UV spectrum such as antibiotics, diuretics, anti-hypertensives, since PDT works in the 410-417 nm range. “If you are concerned, you can hold the drugs the day before [the procedure], the day of, and maybe the day after, but that’s really all you need,” he said.

Dr. Bhatia discussed combinations with 5-fluorouracil (5-FU) before and after PDT, imiquimod plus aminolevulinic acid–PDT (ALA-PDT), and ingenol mebutate plus ALA-PDT. Antihistamines may play a role in helping to reduce the anticipated ALA-PDT response (J Invest Dermatol. 2006;126[10]:2296-301). Dr. Bhatia explained that the edema component is generated by mast cell release and can be uncoupled using selected H1-antihistamines, which can provide symptom relief without compromising efficacy. “Some studies talk about reducing erythema and edema based on the presence of mast cells and the surge of mast cells within first 48 to 72 hours,” he said. “Symptomatic relief is going to mean a lot to that patient who’s getting red, feeling itchy, and feeling swollen, but we don’t want to stop the reaction pattern and the efficacy by undoing what we’ve created as a response.”

It may seem counterintuitive, but direct tissue cooling after PDT appears to have a negative impact on perforin conversion, “to the point where it actually reduces the efficacy and treatment when you do direct tissue cooling,” Dr. Bhatia said. One study showed found significantly less resolution of actinic keratosis (AK) lesions treated with direct tissue cooling, compared with those who did not receive tissue cooling (J Photochem Photobiol B. 2011;103:1-7). In addition, there was a failure of conversion and optimization of the accumulated protoporphyrin IX when direct tissue cooling was used.

“That’s not to say a handheld fan or a fan in the room or aerating, making sure they have enough oxygen around the treatment area [isn’t useful],” Dr. Bhatia said. “I’m talking about the direct tissue cooling that we use with the pulsed laser device, or the Zimmer cooler. You get better conversion when you have a warming device, compared with contact cooling.”

Dr. Bhatia predicted that in the future, microneedle pre-treatment of human skin is going to gain popularity as a PDT adjunct. On early study of microneedling found that it improved 5-ALA and 5-MAL–induced protoporphyrin IX production for topical photodynamic therapy without increasing pain or erythema (Pharm Res. 2010;27[10]:2213-20). “I think that’s very important,” he said.

Dr. Bhatia disclosed having affiliations with Biofrontera and Dusa, the two main manufacturers of PDT in the United States.

[email protected]

Patients with multiple system atrophy (MSA) have decreased levels of plasma coenzyme Q10 (CoQ10), regardless of their COQ2 genotype, according to a study published in the August issue of JAMA Neurology. This finding, researchers said, supports the hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

It has been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of CoQ10, are associated with MSA. However, little is known about blood levels of CoQ10 in patients with or without COQ2 mutations or about the role of CoQ10 in the pathogenesis of MSA.

To explore whether there are associations between levels of CoQ10 in the blood and MSA, Jun Mitsui, MD, PhD, a neurogeneticist at the University of Tokyo, and colleagues compared the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls.

The study included 44 Japanese patients with MSA (mean age, 63.7) and, for comparison, 39 Japanese control patients (mean age, 60.3).

The authors reported that the mean plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 μg/mL vs 0.72 μg/mL). The mean plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 μg/mL and 0.49 μg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the plasma levels of CoQ10 were significantly associated with MSA.

“Prospective cohort studies are warranted to determine the longitudinal effects of plasma levels of CoQ10 on the development of MSA. Furthermore, future clinical trials of supplementation with CoQ10 in patients with MSA are required to confirm our hypothesis,” Dr. Mitsui and colleagues said.

In an accompanying editorial, Sheng-Han Kuo, MD, and Catarina M. Quinzii, MD, both of Columbia University in New York, said, “The recent discoveries of COQ2 mutations in rare patients with MSA and of CoQ10 deficiency in the brain and blood of patients with MSA may lead to mechanism-based and rational therapies for MSA, a rapidly progressive disorder in need of a disease-modifying therapy.”

—Glenn S. Williams

Patients with multiple system atrophy (MSA) have decreased levels of plasma coenzyme Q10 (CoQ10), regardless of their COQ2 genotype, according to a study published in the August issue of JAMA Neurology. This finding, researchers said, supports the hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

It has been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of CoQ10, are associated with MSA. However, little is known about blood levels of CoQ10 in patients with or without COQ2 mutations or about the role of CoQ10 in the pathogenesis of MSA.

To explore whether there are associations between levels of CoQ10 in the blood and MSA, Jun Mitsui, MD, PhD, a neurogeneticist at the University of Tokyo, and colleagues compared the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls.

The study included 44 Japanese patients with MSA (mean age, 63.7) and, for comparison, 39 Japanese control patients (mean age, 60.3).

The authors reported that the mean plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 μg/mL vs 0.72 μg/mL). The mean plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 μg/mL and 0.49 μg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the plasma levels of CoQ10 were significantly associated with MSA.

“Prospective cohort studies are warranted to determine the longitudinal effects of plasma levels of CoQ10 on the development of MSA. Furthermore, future clinical trials of supplementation with CoQ10 in patients with MSA are required to confirm our hypothesis,” Dr. Mitsui and colleagues said.

In an accompanying editorial, Sheng-Han Kuo, MD, and Catarina M. Quinzii, MD, both of Columbia University in New York, said, “The recent discoveries of COQ2 mutations in rare patients with MSA and of CoQ10 deficiency in the brain and blood of patients with MSA may lead to mechanism-based and rational therapies for MSA, a rapidly progressive disorder in need of a disease-modifying therapy.”

—Glenn S. Williams

Patients with multiple system atrophy (MSA) have decreased levels of plasma coenzyme Q10 (CoQ10), regardless of their COQ2 genotype, according to a study published in the August issue of JAMA Neurology. This finding, researchers said, supports the hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

It has been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of CoQ10, are associated with MSA. However, little is known about blood levels of CoQ10 in patients with or without COQ2 mutations or about the role of CoQ10 in the pathogenesis of MSA.

To explore whether there are associations between levels of CoQ10 in the blood and MSA, Jun Mitsui, MD, PhD, a neurogeneticist at the University of Tokyo, and colleagues compared the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls.

The study included 44 Japanese patients with MSA (mean age, 63.7) and, for comparison, 39 Japanese control patients (mean age, 60.3).

The authors reported that the mean plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 μg/mL vs 0.72 μg/mL). The mean plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 μg/mL and 0.49 μg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the plasma levels of CoQ10 were significantly associated with MSA.

“Prospective cohort studies are warranted to determine the longitudinal effects of plasma levels of CoQ10 on the development of MSA. Furthermore, future clinical trials of supplementation with CoQ10 in patients with MSA are required to confirm our hypothesis,” Dr. Mitsui and colleagues said.

In an accompanying editorial, Sheng-Han Kuo, MD, and Catarina M. Quinzii, MD, both of Columbia University in New York, said, “The recent discoveries of COQ2 mutations in rare patients with MSA and of CoQ10 deficiency in the brain and blood of patients with MSA may lead to mechanism-based and rational therapies for MSA, a rapidly progressive disorder in need of a disease-modifying therapy.”

—Glenn S. Williams

Trusted by GIs for more than 15 years, the Digestive Diseases Self-Education Program^® (DDSEP), which is now in its eighth edition, builds upon prior success by incorporating a number of innovations and adaptations to deliver a diverse and highly engaging learning platform.

You can tailor your learning experience as you see fit with our app-based format and flexible options.

What’s new?

• Web and app based – Learn at your computer or on-the-go with your smart device. When and how you learn is up to you.

• Mock exams – Evaluate your exam readiness with American Board of Internal Medicine–style mock exams, each with 60 questions.

• Enhanced flexibility – Access all resources with DDSEP 8 Complete or customize your learning by purchasing individual chapters, questions only, or mock exams.

To purchase and learn more, visit the DDSEP 8 website.

Trusted by GIs for more than 15 years, the Digestive Diseases Self-Education Program^® (DDSEP), which is now in its eighth edition, builds upon prior success by incorporating a number of innovations and adaptations to deliver a diverse and highly engaging learning platform.

You can tailor your learning experience as you see fit with our app-based format and flexible options.

What’s new?

• Web and app based – Learn at your computer or on-the-go with your smart device. When and how you learn is up to you.

• Mock exams – Evaluate your exam readiness with American Board of Internal Medicine–style mock exams, each with 60 questions.

• Enhanced flexibility – Access all resources with DDSEP 8 Complete or customize your learning by purchasing individual chapters, questions only, or mock exams.

To purchase and learn more, visit the DDSEP 8 website.

Trusted by GIs for more than 15 years, the Digestive Diseases Self-Education Program^® (DDSEP), which is now in its eighth edition, builds upon prior success by incorporating a number of innovations and adaptations to deliver a diverse and highly engaging learning platform.

You can tailor your learning experience as you see fit with our app-based format and flexible options.

What’s new?

• Web and app based – Learn at your computer or on-the-go with your smart device. When and how you learn is up to you.

• Mock exams – Evaluate your exam readiness with American Board of Internal Medicine–style mock exams, each with 60 questions.

• Enhanced flexibility – Access all resources with DDSEP 8 Complete or customize your learning by purchasing individual chapters, questions only, or mock exams.

To purchase and learn more, visit the DDSEP 8 website.

When treating an acute hypertensive response in patients with intracerebral hemorrhage, intensive blood pressure treatment does not result in a lower rate of death or disability than standard blood pressure treatment, according to a study published online ahead of print June 22 in the New England Journal of Medicine.

Chronic hypertension is the greatest risk factor for intracerebral hemorrhage, and an acute hypertensive response is common among patients with intracerebral hemorrhage. Studies have suggested that controlling blood pressure early and aggressively in patients with acute intracerebral hemorrhage may reduce hematoma expansion and rates of subsequent death or disability, but optimal blood pressure targets and treatment windows have not been established.

To test whether intensive reduction of blood pressure (ie, targeting a systolic blood pressure of 110 mm Hg to 139 mm Hg) is superior to standard blood pressure reduction (ie, a target of 140 mm Hg to 179 mm Hg), Adnan I. Qureshi, MD, Professor of Neurology, Neurosurgery, and Radiology at the Zeenat Qureshi Stroke Research Center at the University of Minnesota in Minneapolis, and colleagues conducted the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial. The trial was conducted at 110 sites in the United States, Japan, China, Taiwan, South Korea, and Germany.

The investigators enrolled 1,000 patients with spontaneous supratentorial intracerebral hemorrhage who had a Glasgow Coma Scale score of five or more and at least one systolic blood pressure reading of 180 mm Hg or more between symptom onset and initiation of IV antihypertensive treatment.

Five hundred patients were assigned to intensive treatment, and 500 patients were assigned to standard treatment. Patients had a mean age of 61.9, 38% were women, and 56.2% were Asian. Patients had an average systolic blood pressure of 200.6 mm Hg at baseline.

Investigators administered IV nicardipine to lower blood pressure within four and a half hours following symptom onset, and researchers continued this treatment for the next 24 hours.

Investigators followed up with patients by telephone after a month and in person after three months. Death or disability (ie, modified Rankin scale score of 4 to 6) was the primary outcome.

The trial was designed to enroll 1,280 participants, but researchers stopped the trial early for futility after a prespecified interim analysis found that patients who received intensive treatment did not have a lower rate of death or disability than those who received standard treatment. The rate of death or disability was 38.7% in the intensive treatment group and 37.7% in the standard treatment group. "Our results do not support the notion that acute reduction to a target systolic blood pressure of 110 to 139 mm Hg in patients with intracerebral hemorrhage is more effective in improving functional outcome than a reduction to a target systolic blood pressure of 140 to 179 mm Hg," the researchers said.

Serious adverse events within 72 hours of randomization that were considered to be related to treatment were reported in 1.6% of patients in the intensive treatment group, compared with 1.2% of patients in the standard treatment group. The rate of renal adverse events within seven days was significantly higher in the intensive treatment group than in the standard treatment group (9% vs 4%).

The overall death and severe disability rate in this study was lower than that in previous stroke studies (38% vs 60%). This difference may be due to the inclusion of patients with relatively minor strokes in the current study. In addition, "we may have seen a global benefit of careful monitoring and standardized care for patients with acute cerebral hemorrhage," said Dr. Qureshi.

—Erica Robinson

When treating an acute hypertensive response in patients with intracerebral hemorrhage, intensive blood pressure treatment does not result in a lower rate of death or disability than standard blood pressure treatment, according to a study published online ahead of print June 22 in the New England Journal of Medicine.

Chronic hypertension is the greatest risk factor for intracerebral hemorrhage, and an acute hypertensive response is common among patients with intracerebral hemorrhage. Studies have suggested that controlling blood pressure early and aggressively in patients with acute intracerebral hemorrhage may reduce hematoma expansion and rates of subsequent death or disability, but optimal blood pressure targets and treatment windows have not been established.

To test whether intensive reduction of blood pressure (ie, targeting a systolic blood pressure of 110 mm Hg to 139 mm Hg) is superior to standard blood pressure reduction (ie, a target of 140 mm Hg to 179 mm Hg), Adnan I. Qureshi, MD, Professor of Neurology, Neurosurgery, and Radiology at the Zeenat Qureshi Stroke Research Center at the University of Minnesota in Minneapolis, and colleagues conducted the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial. The trial was conducted at 110 sites in the United States, Japan, China, Taiwan, South Korea, and Germany.

The investigators enrolled 1,000 patients with spontaneous supratentorial intracerebral hemorrhage who had a Glasgow Coma Scale score of five or more and at least one systolic blood pressure reading of 180 mm Hg or more between symptom onset and initiation of IV antihypertensive treatment.

Five hundred patients were assigned to intensive treatment, and 500 patients were assigned to standard treatment. Patients had a mean age of 61.9, 38% were women, and 56.2% were Asian. Patients had an average systolic blood pressure of 200.6 mm Hg at baseline.

Investigators administered IV nicardipine to lower blood pressure within four and a half hours following symptom onset, and researchers continued this treatment for the next 24 hours.

Investigators followed up with patients by telephone after a month and in person after three months. Death or disability (ie, modified Rankin scale score of 4 to 6) was the primary outcome.

The trial was designed to enroll 1,280 participants, but researchers stopped the trial early for futility after a prespecified interim analysis found that patients who received intensive treatment did not have a lower rate of death or disability than those who received standard treatment. The rate of death or disability was 38.7% in the intensive treatment group and 37.7% in the standard treatment group. "Our results do not support the notion that acute reduction to a target systolic blood pressure of 110 to 139 mm Hg in patients with intracerebral hemorrhage is more effective in improving functional outcome than a reduction to a target systolic blood pressure of 140 to 179 mm Hg," the researchers said.

Serious adverse events within 72 hours of randomization that were considered to be related to treatment were reported in 1.6% of patients in the intensive treatment group, compared with 1.2% of patients in the standard treatment group. The rate of renal adverse events within seven days was significantly higher in the intensive treatment group than in the standard treatment group (9% vs 4%).

The overall death and severe disability rate in this study was lower than that in previous stroke studies (38% vs 60%). This difference may be due to the inclusion of patients with relatively minor strokes in the current study. In addition, "we may have seen a global benefit of careful monitoring and standardized care for patients with acute cerebral hemorrhage," said Dr. Qureshi.

—Erica Robinson

When treating an acute hypertensive response in patients with intracerebral hemorrhage, intensive blood pressure treatment does not result in a lower rate of death or disability than standard blood pressure treatment, according to a study published online ahead of print June 22 in the New England Journal of Medicine.

Chronic hypertension is the greatest risk factor for intracerebral hemorrhage, and an acute hypertensive response is common among patients with intracerebral hemorrhage. Studies have suggested that controlling blood pressure early and aggressively in patients with acute intracerebral hemorrhage may reduce hematoma expansion and rates of subsequent death or disability, but optimal blood pressure targets and treatment windows have not been established.

To test whether intensive reduction of blood pressure (ie, targeting a systolic blood pressure of 110 mm Hg to 139 mm Hg) is superior to standard blood pressure reduction (ie, a target of 140 mm Hg to 179 mm Hg), Adnan I. Qureshi, MD, Professor of Neurology, Neurosurgery, and Radiology at the Zeenat Qureshi Stroke Research Center at the University of Minnesota in Minneapolis, and colleagues conducted the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-2) trial. The trial was conducted at 110 sites in the United States, Japan, China, Taiwan, South Korea, and Germany.

The investigators enrolled 1,000 patients with spontaneous supratentorial intracerebral hemorrhage who had a Glasgow Coma Scale score of five or more and at least one systolic blood pressure reading of 180 mm Hg or more between symptom onset and initiation of IV antihypertensive treatment.

Five hundred patients were assigned to intensive treatment, and 500 patients were assigned to standard treatment. Patients had a mean age of 61.9, 38% were women, and 56.2% were Asian. Patients had an average systolic blood pressure of 200.6 mm Hg at baseline.

Investigators administered IV nicardipine to lower blood pressure within four and a half hours following symptom onset, and researchers continued this treatment for the next 24 hours.

Investigators followed up with patients by telephone after a month and in person after three months. Death or disability (ie, modified Rankin scale score of 4 to 6) was the primary outcome.

The trial was designed to enroll 1,280 participants, but researchers stopped the trial early for futility after a prespecified interim analysis found that patients who received intensive treatment did not have a lower rate of death or disability than those who received standard treatment. The rate of death or disability was 38.7% in the intensive treatment group and 37.7% in the standard treatment group. "Our results do not support the notion that acute reduction to a target systolic blood pressure of 110 to 139 mm Hg in patients with intracerebral hemorrhage is more effective in improving functional outcome than a reduction to a target systolic blood pressure of 140 to 179 mm Hg," the researchers said.

Serious adverse events within 72 hours of randomization that were considered to be related to treatment were reported in 1.6% of patients in the intensive treatment group, compared with 1.2% of patients in the standard treatment group. The rate of renal adverse events within seven days was significantly higher in the intensive treatment group than in the standard treatment group (9% vs 4%).

The overall death and severe disability rate in this study was lower than that in previous stroke studies (38% vs 60%). This difference may be due to the inclusion of patients with relatively minor strokes in the current study. In addition, "we may have seen a global benefit of careful monitoring and standardized care for patients with acute cerebral hemorrhage," said Dr. Qureshi.

—Erica Robinson

Patients with rheumatoid arthritis have steadily made their initial clinical presentation with shorter and shorter symptom durations and less severe inflammation from the early 1990s into the 2010s, but this paradoxically has coincided with gradual increases in the severity of patient-reported outcome measures, according to findings from the Leiden Early Arthritis Cohort.

For 1,406 patients who met 2010 European League Against Rheumatism/American College of Rheumatology rheumatoid arthritis (RA) criteria during 1993-2015, investigators led by Wouter P. Nieuwenhuis, MD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center found that the symptom duration at initial presentation declined significantly from a median 138 days during 1993-1996 to 97 days during 2011-2015. Although the frequency of autoantibodies at presentation did not change significantly, the median number of swollen joints decreased from 12 to 6, median tender joints declined from 21 to 10, and median C-reactive protein levels dropped from 24 mg/L to 10 mg/L (all P values less than .001). All these measures declined steadily during the five time periods analyzed (1993-1996, 1997-2000, 2001-2005, 2006-2010, 2011-2015). Median scores on the Health Assessment Questionnaire, which measures functional disability, stayed the same in all five time periods.

©kgtoh/Thinkstock

In contrast, patient-reported outcomes measures (PROMs) on visual analog scales for pain, fatigue, and disease activity all rose significantly from 1993-1996 to 2011-2015.

“Presumably, the present findings are not specific for RA, but reflect a general increase in societal pressure posed upon the individual over the years (i.e., society has become more demanding), whereby smaller health problems, which might be less visible, could be experienced as more disabling. In parallel, patients may also have higher health expectations themselves. Both phenomena likely contribute to a shift of reference when reporting outcomes,” the researchers wrote.

They added that the current findings, in light of previous studies that found that PROMs are not responsive to changes in the severity of inflammation, “raise the question if it is known what PROMs actually measure. Furthermore, this may have consequences for the monitoring of RA using PROMs or composite scores (e.g., Disease Activity Score or Simple Disease Activity Index) for defining remission.”

Read the full study in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Aug 24. doi: 10.1136/annrheumdis-2016-209949).

[email protected]

Patients with rheumatoid arthritis have steadily made their initial clinical presentation with shorter and shorter symptom durations and less severe inflammation from the early 1990s into the 2010s, but this paradoxically has coincided with gradual increases in the severity of patient-reported outcome measures, according to findings from the Leiden Early Arthritis Cohort.

For 1,406 patients who met 2010 European League Against Rheumatism/American College of Rheumatology rheumatoid arthritis (RA) criteria during 1993-2015, investigators led by Wouter P. Nieuwenhuis, MD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center found that the symptom duration at initial presentation declined significantly from a median 138 days during 1993-1996 to 97 days during 2011-2015. Although the frequency of autoantibodies at presentation did not change significantly, the median number of swollen joints decreased from 12 to 6, median tender joints declined from 21 to 10, and median C-reactive protein levels dropped from 24 mg/L to 10 mg/L (all P values less than .001). All these measures declined steadily during the five time periods analyzed (1993-1996, 1997-2000, 2001-2005, 2006-2010, 2011-2015). Median scores on the Health Assessment Questionnaire, which measures functional disability, stayed the same in all five time periods.

©kgtoh/Thinkstock

In contrast, patient-reported outcomes measures (PROMs) on visual analog scales for pain, fatigue, and disease activity all rose significantly from 1993-1996 to 2011-2015.

“Presumably, the present findings are not specific for RA, but reflect a general increase in societal pressure posed upon the individual over the years (i.e., society has become more demanding), whereby smaller health problems, which might be less visible, could be experienced as more disabling. In parallel, patients may also have higher health expectations themselves. Both phenomena likely contribute to a shift of reference when reporting outcomes,” the researchers wrote.

They added that the current findings, in light of previous studies that found that PROMs are not responsive to changes in the severity of inflammation, “raise the question if it is known what PROMs actually measure. Furthermore, this may have consequences for the monitoring of RA using PROMs or composite scores (e.g., Disease Activity Score or Simple Disease Activity Index) for defining remission.”

Read the full study in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Aug 24. doi: 10.1136/annrheumdis-2016-209949).

[email protected]

Patients with rheumatoid arthritis have steadily made their initial clinical presentation with shorter and shorter symptom durations and less severe inflammation from the early 1990s into the 2010s, but this paradoxically has coincided with gradual increases in the severity of patient-reported outcome measures, according to findings from the Leiden Early Arthritis Cohort.

For 1,406 patients who met 2010 European League Against Rheumatism/American College of Rheumatology rheumatoid arthritis (RA) criteria during 1993-2015, investigators led by Wouter P. Nieuwenhuis, MD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center found that the symptom duration at initial presentation declined significantly from a median 138 days during 1993-1996 to 97 days during 2011-2015. Although the frequency of autoantibodies at presentation did not change significantly, the median number of swollen joints decreased from 12 to 6, median tender joints declined from 21 to 10, and median C-reactive protein levels dropped from 24 mg/L to 10 mg/L (all P values less than .001). All these measures declined steadily during the five time periods analyzed (1993-1996, 1997-2000, 2001-2005, 2006-2010, 2011-2015). Median scores on the Health Assessment Questionnaire, which measures functional disability, stayed the same in all five time periods.

©kgtoh/Thinkstock

In contrast, patient-reported outcomes measures (PROMs) on visual analog scales for pain, fatigue, and disease activity all rose significantly from 1993-1996 to 2011-2015.

“Presumably, the present findings are not specific for RA, but reflect a general increase in societal pressure posed upon the individual over the years (i.e., society has become more demanding), whereby smaller health problems, which might be less visible, could be experienced as more disabling. In parallel, patients may also have higher health expectations themselves. Both phenomena likely contribute to a shift of reference when reporting outcomes,” the researchers wrote.

They added that the current findings, in light of previous studies that found that PROMs are not responsive to changes in the severity of inflammation, “raise the question if it is known what PROMs actually measure. Furthermore, this may have consequences for the monitoring of RA using PROMs or composite scores (e.g., Disease Activity Score or Simple Disease Activity Index) for defining remission.”

Read the full study in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Aug 24. doi: 10.1136/annrheumdis-2016-209949).

[email protected]

TORONTO—Impairment in odor identification is a strong predictor of the transition to dementia, according to data described at the Alzheimer's Association International Conference. Entorhinal cortical thickness also predicts the transition to dementia, albeit to a lesser degree.

In addition, impaired odor identification, but not entorhinal cortical thickness, appears to predict cognitive decline. These results may provide indirect evidence that olfactory impairment precedes entorhinal cortical thinning, said Seonjoo Lee, PhD, Assistant Professor of Clinical Biostatistics in Psychiatry at Columbia University Mailman School of Public Health in New York.

The olfactory system undergoes structural and functional changes in the early stage of Alzheimer's disease. Dr. Lee and colleagues examined participants in the Washington Heights Community Aging Project II to determine whether the University of Pennsylvania Smell Identification Test (UPSIT) score predicts transition to dementia or cognitive decline. The investigators also sought to compare UPSIT score as a biomarker with entorhinal cortical thickness. Eligible participants were older than 65, did not have dementia, and underwent MRI and UPSIT at baseline. The researchers enrolled 397 subjects in the study and followed them for four years.

In all, 50 participants developed dementia during follow-up, including 49 people who developed Alzheimer's disease. Dr. Lee and colleagues measured average entorhinal cortical thickness using FreeSurfer and tested UPSIT and its interaction with entorhinal cortical thickness as the main effects.

The researchers measured participants' cognition by evaluating memory, language, and visuospatial cognition. They defined cognitive decline as a decline of one or more standard deviations in any of these cognitive domains during the four-year follow-up. In the examinations of incident dementia and cognitive decline, Dr. Lee and colleagues adjusted the data for age, gender, years of education, functional status, intracranial volume, and language of UPSIT administration.

UPSIT score, entorhinal cortical thickness, and these factors' interactions significantly predicted the transition to dementia. As UPSIT score declined, subjects were more likely to develop dementia. The same association was found for entorhinal cortical thickness. Among participants with olfactory impairment, thinning in the entorhinal cortex increased the risk of incident dementia.

In contrast, only UPSIT was a strong predictor of cognitive decline. Dr. Lee also found that entorhinal cortical thickness was significantly associated with UPSIT score only among subjects who transitioned to dementia. "This [result] confirmed that those two biomarkers are associated with each other for dementia," she said. The correlation also indicates that odor identification deficits are related to neurodegenerative changes in the entorhinal cortex during the progression of Alzheimer's disease, she added.

—Erik Greb

TORONTO—Impairment in odor identification is a strong predictor of the transition to dementia, according to data described at the Alzheimer's Association International Conference. Entorhinal cortical thickness also predicts the transition to dementia, albeit to a lesser degree.

In addition, impaired odor identification, but not entorhinal cortical thickness, appears to predict cognitive decline. These results may provide indirect evidence that olfactory impairment precedes entorhinal cortical thinning, said Seonjoo Lee, PhD, Assistant Professor of Clinical Biostatistics in Psychiatry at Columbia University Mailman School of Public Health in New York.

The olfactory system undergoes structural and functional changes in the early stage of Alzheimer's disease. Dr. Lee and colleagues examined participants in the Washington Heights Community Aging Project II to determine whether the University of Pennsylvania Smell Identification Test (UPSIT) score predicts transition to dementia or cognitive decline. The investigators also sought to compare UPSIT score as a biomarker with entorhinal cortical thickness. Eligible participants were older than 65, did not have dementia, and underwent MRI and UPSIT at baseline. The researchers enrolled 397 subjects in the study and followed them for four years.

In all, 50 participants developed dementia during follow-up, including 49 people who developed Alzheimer's disease. Dr. Lee and colleagues measured average entorhinal cortical thickness using FreeSurfer and tested UPSIT and its interaction with entorhinal cortical thickness as the main effects.

The researchers measured participants' cognition by evaluating memory, language, and visuospatial cognition. They defined cognitive decline as a decline of one or more standard deviations in any of these cognitive domains during the four-year follow-up. In the examinations of incident dementia and cognitive decline, Dr. Lee and colleagues adjusted the data for age, gender, years of education, functional status, intracranial volume, and language of UPSIT administration.

UPSIT score, entorhinal cortical thickness, and these factors' interactions significantly predicted the transition to dementia. As UPSIT score declined, subjects were more likely to develop dementia. The same association was found for entorhinal cortical thickness. Among participants with olfactory impairment, thinning in the entorhinal cortex increased the risk of incident dementia.

In contrast, only UPSIT was a strong predictor of cognitive decline. Dr. Lee also found that entorhinal cortical thickness was significantly associated with UPSIT score only among subjects who transitioned to dementia. "This [result] confirmed that those two biomarkers are associated with each other for dementia," she said. The correlation also indicates that odor identification deficits are related to neurodegenerative changes in the entorhinal cortex during the progression of Alzheimer's disease, she added.

—Erik Greb

TORONTO—Impairment in odor identification is a strong predictor of the transition to dementia, according to data described at the Alzheimer's Association International Conference. Entorhinal cortical thickness also predicts the transition to dementia, albeit to a lesser degree.

In addition, impaired odor identification, but not entorhinal cortical thickness, appears to predict cognitive decline. These results may provide indirect evidence that olfactory impairment precedes entorhinal cortical thinning, said Seonjoo Lee, PhD, Assistant Professor of Clinical Biostatistics in Psychiatry at Columbia University Mailman School of Public Health in New York.

The olfactory system undergoes structural and functional changes in the early stage of Alzheimer's disease. Dr. Lee and colleagues examined participants in the Washington Heights Community Aging Project II to determine whether the University of Pennsylvania Smell Identification Test (UPSIT) score predicts transition to dementia or cognitive decline. The investigators also sought to compare UPSIT score as a biomarker with entorhinal cortical thickness. Eligible participants were older than 65, did not have dementia, and underwent MRI and UPSIT at baseline. The researchers enrolled 397 subjects in the study and followed them for four years.

In all, 50 participants developed dementia during follow-up, including 49 people who developed Alzheimer's disease. Dr. Lee and colleagues measured average entorhinal cortical thickness using FreeSurfer and tested UPSIT and its interaction with entorhinal cortical thickness as the main effects.

The researchers measured participants' cognition by evaluating memory, language, and visuospatial cognition. They defined cognitive decline as a decline of one or more standard deviations in any of these cognitive domains during the four-year follow-up. In the examinations of incident dementia and cognitive decline, Dr. Lee and colleagues adjusted the data for age, gender, years of education, functional status, intracranial volume, and language of UPSIT administration.

UPSIT score, entorhinal cortical thickness, and these factors' interactions significantly predicted the transition to dementia. As UPSIT score declined, subjects were more likely to develop dementia. The same association was found for entorhinal cortical thickness. Among participants with olfactory impairment, thinning in the entorhinal cortex increased the risk of incident dementia.

In contrast, only UPSIT was a strong predictor of cognitive decline. Dr. Lee also found that entorhinal cortical thickness was significantly associated with UPSIT score only among subjects who transitioned to dementia. "This [result] confirmed that those two biomarkers are associated with each other for dementia," she said. The correlation also indicates that odor identification deficits are related to neurodegenerative changes in the entorhinal cortex during the progression of Alzheimer's disease, she added.

—Erik Greb

CHICAGO – A new model of gastroesophageal reflux disease (GERD) paints it as a disease caused by inflammatory molecules, rather than a reaction to an acid-inflicted wound.

And rather than esophagitis due to GERD being a top-down process, from surface epithelium to submucosa, multiple lines of evidence now suggest it is a bottom-up phenomenon sparked by activation of a hypoxia-inducible factor that occurs when esophageal epithelium is exposed to acidic bile salts, Rhonda Souza, MD, said at the meeting sponsored by the American Gastroenterological Association.

Michele G. Sullivan/Frontline Medical News

“We’re proposing that reflux is a cytokine-mediated injury,” said Dr. Souza of the University of Texas Southwestern Medical Center, Dallas, and the Dallas VA Medical Center. “The reflux of acid and bile doesn’t destroy the epithelial cells directly, but induces them to produce proinflammatory cytokines. These cytokines attract lymphocytes first, which induce the basal cell proliferation characteristic of GERD. Ultimately, it’s these inflammatory cells that mediate the epithelial injury – not the direct caustic effects of gastric acid.”

Dr. Souza and her colleagues, including Dr. Stuart Spechler and Dr. Kerry Dunbar, also of UT Southwestern and the Dallas VA Medical Center, have been building this case for several years, beginning with a surgical rat model of GERD. Their histologic findings in this model have been recapitulated in human cell lines and, most recently, in a clinical trial of 12 patients (JAMA. 2016. doi:10.1001/jama.2016.5657).

The rat model, published in 2009 (Gastroenterology. 2009. doi:10.1053/j.gastro.2009.07.055) provided one of the first very early looks at the pathogenesis of acute GERD.

Rats underwent esophagoduodenostomy, a procedure that left the stomach in place so that both gastric and duodenal contents could reflux into the esophagus, thus ensuring immediate esophageal exposure to acid and bile acids. But the investigators were puzzled as to why it took weeks to see changes in the esophageal surface. “The epithelial mucosa stayed intact for far longer than it should have – up to 3 weeks – if acid simply caused a caustic injury as the mechanism of cell death and replacement,” Dr. Souza said.

What she did see, however, was a rapid migration of T cells into the submucosa. “By postoperative week 3, we observed profound basal cell and papillary hyperplasia, but the surface cells were still intact, so this hyperplasia was not due to the death of surface cells.”

The team proceeded to an in vitro model using esophageal squamous cell lines established from endoscopic biopsies obtained from GERD patients. When the squamous cells were exposed in culture to acidic bile salts, the cells ramped up their production of several proinflammatory cytokines, including interleukin-8 and interleukin-1b. The production of proinflammatory cytokines released into the surrounding media were potent recruitment signals for lymphocytes.

The researchers saw this same signaling response in their rat model. “We saw a dramatic increase in IL-8 by postoperative week 2. It was in the intracellular spaces between cells at the epithelial surface and in the cell cytoplasm, and we also saw it in the submucosa and in the lamina propria.”

Acute reflux esophagitis has been almost impossible to observe in humans, Dr. Souza said, because most patients don’t seek medical attention until they’ve had months or years of acid reflux symptoms. By then, the injury response to gastroesophageal reflux has become chronic and well established.

The human study, published in May, confirmed the findings in the rat model. It comprised 12 patients with severe GERD who had been on twice-daily proton pump inhibitor (PPI) therapy for at least 1 month. Successful PPI treatment heals reflux esophagitis rapidly, and healing was endoscopically confirmed at baseline in all these patients. Then, however, they gave up their medication so that the damage would begin again. Dr. Souza and her colleagues could travel back in time, clinically speaking, and track the histopatholgic changes as they occurred. Within 2 weeks, esophagitis had reappeared in every patient: Three had the least-severe LA (Los Angeles) grade A, four had LA grade B, and five had LA grade C esophagitis, with extensive mucosal breaks.

“We know from older studies that within 6 months of going off of PPIs, most patients with reflux esophagitis develop it again, but we weren’t sure we would get this response within 2 weeks. It was surprising that not only did everyone get it, but that a few were so severe,” Dr. Souza said.

Biopsies at weeks 1 and 2 showed the same kind of inflammatory signaling seen in the rats. Again, the responding cells were almost exclusively lymphocytes; neutrophils and eosinophils were very rare or absent in all specimens. The team also observed basal cell and papillary hyperplasia and areas of spongiosis, even though the surface cells were still intact.

The lymphocyte-predominant response is the key to this new pathogenic theory, Dr. Souza wrote in her JAMA paper.

“If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily.”

She also suggested that PPIs may be healing esophagitis not simply by preventing acid reflux, but by exerting anti-inflammatory properties.

“Cytokines like IL-8 may also have proliferative effects which might have contributed to esophageal basal cell and papillary hyperplasia observed in the absence of surface erosions. In esophageal epithelial cells in culture, PPIs inhibit secretion of IL-8 through acid-independent mechanisms. This observation raises the interesting possibility that anti-inflammatory PPI effects, independent of their effects on acid inhibition, might contribute to GERD healing by PPIs.”

Dr. Souza said she continues to investigate, focusing now on how the initial insult of acidic bile salts on esophageal epithelium stimulates this inflammatory response. The key may be in a small protein called hypoxia-inducible factor-2 alpha (HIF-2a), one of a family of transcription factors that enable cells to respond to hypoxic stress.

Under normal oxygen conditions, HIF proteins are low, their levels regulated by an enzyme called prolyl hydroxylase. This enzyme is inactivated under hypoxic conditions, or in the presence of reactive oxygen species. HIF factors then rise and, among other functions, stimulate a strong inflammatory response. Inflamed tissues like those seen in esophagitis are frequently hypoxic, Dr. Souza said, and this state could be activating HIFs.

She examined HIF levels in her 12-patient cohort. These results were presented earlier this year at the Digestive Disease Weekmeeting in San Diego.

“At weeks 1 and 2, we found large associations between HIF-2a and increases in a number of proinflammatory cytokines including IL-8 and intercellular adhesion molecule–1,” a protein that facilitates leukocyte migration. Preliminary studies of HIF-2a inhibition in esophageal squamous cells in culture exposed to acidic bile salts show promising results as a potential therapeutic strategy to reduce proinflammatory cytokine expression. It is conceivable that anti-inflammatory therapies directed at HIF-2a may be on the horizon for the prevention and treatment of reflux esophagitis, she added.

Neither Dr. Souza nor her colleagues had any relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

CHICAGO – A new model of gastroesophageal reflux disease (GERD) paints it as a disease caused by inflammatory molecules, rather than a reaction to an acid-inflicted wound.

And rather than esophagitis due to GERD being a top-down process, from surface epithelium to submucosa, multiple lines of evidence now suggest it is a bottom-up phenomenon sparked by activation of a hypoxia-inducible factor that occurs when esophageal epithelium is exposed to acidic bile salts, Rhonda Souza, MD, said at the meeting sponsored by the American Gastroenterological Association.

Michele G. Sullivan/Frontline Medical News

“We’re proposing that reflux is a cytokine-mediated injury,” said Dr. Souza of the University of Texas Southwestern Medical Center, Dallas, and the Dallas VA Medical Center. “The reflux of acid and bile doesn’t destroy the epithelial cells directly, but induces them to produce proinflammatory cytokines. These cytokines attract lymphocytes first, which induce the basal cell proliferation characteristic of GERD. Ultimately, it’s these inflammatory cells that mediate the epithelial injury – not the direct caustic effects of gastric acid.”

Dr. Souza and her colleagues, including Dr. Stuart Spechler and Dr. Kerry Dunbar, also of UT Southwestern and the Dallas VA Medical Center, have been building this case for several years, beginning with a surgical rat model of GERD. Their histologic findings in this model have been recapitulated in human cell lines and, most recently, in a clinical trial of 12 patients (JAMA. 2016. doi:10.1001/jama.2016.5657).

The rat model, published in 2009 (Gastroenterology. 2009. doi:10.1053/j.gastro.2009.07.055) provided one of the first very early looks at the pathogenesis of acute GERD.

Rats underwent esophagoduodenostomy, a procedure that left the stomach in place so that both gastric and duodenal contents could reflux into the esophagus, thus ensuring immediate esophageal exposure to acid and bile acids. But the investigators were puzzled as to why it took weeks to see changes in the esophageal surface. “The epithelial mucosa stayed intact for far longer than it should have – up to 3 weeks – if acid simply caused a caustic injury as the mechanism of cell death and replacement,” Dr. Souza said.

What she did see, however, was a rapid migration of T cells into the submucosa. “By postoperative week 3, we observed profound basal cell and papillary hyperplasia, but the surface cells were still intact, so this hyperplasia was not due to the death of surface cells.”

The team proceeded to an in vitro model using esophageal squamous cell lines established from endoscopic biopsies obtained from GERD patients. When the squamous cells were exposed in culture to acidic bile salts, the cells ramped up their production of several proinflammatory cytokines, including interleukin-8 and interleukin-1b. The production of proinflammatory cytokines released into the surrounding media were potent recruitment signals for lymphocytes.

The researchers saw this same signaling response in their rat model. “We saw a dramatic increase in IL-8 by postoperative week 2. It was in the intracellular spaces between cells at the epithelial surface and in the cell cytoplasm, and we also saw it in the submucosa and in the lamina propria.”

Acute reflux esophagitis has been almost impossible to observe in humans, Dr. Souza said, because most patients don’t seek medical attention until they’ve had months or years of acid reflux symptoms. By then, the injury response to gastroesophageal reflux has become chronic and well established.

The human study, published in May, confirmed the findings in the rat model. It comprised 12 patients with severe GERD who had been on twice-daily proton pump inhibitor (PPI) therapy for at least 1 month. Successful PPI treatment heals reflux esophagitis rapidly, and healing was endoscopically confirmed at baseline in all these patients. Then, however, they gave up their medication so that the damage would begin again. Dr. Souza and her colleagues could travel back in time, clinically speaking, and track the histopatholgic changes as they occurred. Within 2 weeks, esophagitis had reappeared in every patient: Three had the least-severe LA (Los Angeles) grade A, four had LA grade B, and five had LA grade C esophagitis, with extensive mucosal breaks.

“We know from older studies that within 6 months of going off of PPIs, most patients with reflux esophagitis develop it again, but we weren’t sure we would get this response within 2 weeks. It was surprising that not only did everyone get it, but that a few were so severe,” Dr. Souza said.

Biopsies at weeks 1 and 2 showed the same kind of inflammatory signaling seen in the rats. Again, the responding cells were almost exclusively lymphocytes; neutrophils and eosinophils were very rare or absent in all specimens. The team also observed basal cell and papillary hyperplasia and areas of spongiosis, even though the surface cells were still intact.

The lymphocyte-predominant response is the key to this new pathogenic theory, Dr. Souza wrote in her JAMA paper.

“If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily.”

She also suggested that PPIs may be healing esophagitis not simply by preventing acid reflux, but by exerting anti-inflammatory properties.

“Cytokines like IL-8 may also have proliferative effects which might have contributed to esophageal basal cell and papillary hyperplasia observed in the absence of surface erosions. In esophageal epithelial cells in culture, PPIs inhibit secretion of IL-8 through acid-independent mechanisms. This observation raises the interesting possibility that anti-inflammatory PPI effects, independent of their effects on acid inhibition, might contribute to GERD healing by PPIs.”

Dr. Souza said she continues to investigate, focusing now on how the initial insult of acidic bile salts on esophageal epithelium stimulates this inflammatory response. The key may be in a small protein called hypoxia-inducible factor-2 alpha (HIF-2a), one of a family of transcription factors that enable cells to respond to hypoxic stress.

Under normal oxygen conditions, HIF proteins are low, their levels regulated by an enzyme called prolyl hydroxylase. This enzyme is inactivated under hypoxic conditions, or in the presence of reactive oxygen species. HIF factors then rise and, among other functions, stimulate a strong inflammatory response. Inflamed tissues like those seen in esophagitis are frequently hypoxic, Dr. Souza said, and this state could be activating HIFs.

She examined HIF levels in her 12-patient cohort. These results were presented earlier this year at the Digestive Disease Weekmeeting in San Diego.

“At weeks 1 and 2, we found large associations between HIF-2a and increases in a number of proinflammatory cytokines including IL-8 and intercellular adhesion molecule–1,” a protein that facilitates leukocyte migration. Preliminary studies of HIF-2a inhibition in esophageal squamous cells in culture exposed to acidic bile salts show promising results as a potential therapeutic strategy to reduce proinflammatory cytokine expression. It is conceivable that anti-inflammatory therapies directed at HIF-2a may be on the horizon for the prevention and treatment of reflux esophagitis, she added.

Neither Dr. Souza nor her colleagues had any relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

CHICAGO – A new model of gastroesophageal reflux disease (GERD) paints it as a disease caused by inflammatory molecules, rather than a reaction to an acid-inflicted wound.

And rather than esophagitis due to GERD being a top-down process, from surface epithelium to submucosa, multiple lines of evidence now suggest it is a bottom-up phenomenon sparked by activation of a hypoxia-inducible factor that occurs when esophageal epithelium is exposed to acidic bile salts, Rhonda Souza, MD, said at the meeting sponsored by the American Gastroenterological Association.

Michele G. Sullivan/Frontline Medical News

“We’re proposing that reflux is a cytokine-mediated injury,” said Dr. Souza of the University of Texas Southwestern Medical Center, Dallas, and the Dallas VA Medical Center. “The reflux of acid and bile doesn’t destroy the epithelial cells directly, but induces them to produce proinflammatory cytokines. These cytokines attract lymphocytes first, which induce the basal cell proliferation characteristic of GERD. Ultimately, it’s these inflammatory cells that mediate the epithelial injury – not the direct caustic effects of gastric acid.”

Dr. Souza and her colleagues, including Dr. Stuart Spechler and Dr. Kerry Dunbar, also of UT Southwestern and the Dallas VA Medical Center, have been building this case for several years, beginning with a surgical rat model of GERD. Their histologic findings in this model have been recapitulated in human cell lines and, most recently, in a clinical trial of 12 patients (JAMA. 2016. doi:10.1001/jama.2016.5657).

The rat model, published in 2009 (Gastroenterology. 2009. doi:10.1053/j.gastro.2009.07.055) provided one of the first very early looks at the pathogenesis of acute GERD.

Rats underwent esophagoduodenostomy, a procedure that left the stomach in place so that both gastric and duodenal contents could reflux into the esophagus, thus ensuring immediate esophageal exposure to acid and bile acids. But the investigators were puzzled as to why it took weeks to see changes in the esophageal surface. “The epithelial mucosa stayed intact for far longer than it should have – up to 3 weeks – if acid simply caused a caustic injury as the mechanism of cell death and replacement,” Dr. Souza said.

What she did see, however, was a rapid migration of T cells into the submucosa. “By postoperative week 3, we observed profound basal cell and papillary hyperplasia, but the surface cells were still intact, so this hyperplasia was not due to the death of surface cells.”

The team proceeded to an in vitro model using esophageal squamous cell lines established from endoscopic biopsies obtained from GERD patients. When the squamous cells were exposed in culture to acidic bile salts, the cells ramped up their production of several proinflammatory cytokines, including interleukin-8 and interleukin-1b. The production of proinflammatory cytokines released into the surrounding media were potent recruitment signals for lymphocytes.

The researchers saw this same signaling response in their rat model. “We saw a dramatic increase in IL-8 by postoperative week 2. It was in the intracellular spaces between cells at the epithelial surface and in the cell cytoplasm, and we also saw it in the submucosa and in the lamina propria.”

Acute reflux esophagitis has been almost impossible to observe in humans, Dr. Souza said, because most patients don’t seek medical attention until they’ve had months or years of acid reflux symptoms. By then, the injury response to gastroesophageal reflux has become chronic and well established.

The human study, published in May, confirmed the findings in the rat model. It comprised 12 patients with severe GERD who had been on twice-daily proton pump inhibitor (PPI) therapy for at least 1 month. Successful PPI treatment heals reflux esophagitis rapidly, and healing was endoscopically confirmed at baseline in all these patients. Then, however, they gave up their medication so that the damage would begin again. Dr. Souza and her colleagues could travel back in time, clinically speaking, and track the histopatholgic changes as they occurred. Within 2 weeks, esophagitis had reappeared in every patient: Three had the least-severe LA (Los Angeles) grade A, four had LA grade B, and five had LA grade C esophagitis, with extensive mucosal breaks.

“We know from older studies that within 6 months of going off of PPIs, most patients with reflux esophagitis develop it again, but we weren’t sure we would get this response within 2 weeks. It was surprising that not only did everyone get it, but that a few were so severe,” Dr. Souza said.

Biopsies at weeks 1 and 2 showed the same kind of inflammatory signaling seen in the rats. Again, the responding cells were almost exclusively lymphocytes; neutrophils and eosinophils were very rare or absent in all specimens. The team also observed basal cell and papillary hyperplasia and areas of spongiosis, even though the surface cells were still intact.

The lymphocyte-predominant response is the key to this new pathogenic theory, Dr. Souza wrote in her JAMA paper.

“If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily.”

She also suggested that PPIs may be healing esophagitis not simply by preventing acid reflux, but by exerting anti-inflammatory properties.

“Cytokines like IL-8 may also have proliferative effects which might have contributed to esophageal basal cell and papillary hyperplasia observed in the absence of surface erosions. In esophageal epithelial cells in culture, PPIs inhibit secretion of IL-8 through acid-independent mechanisms. This observation raises the interesting possibility that anti-inflammatory PPI effects, independent of their effects on acid inhibition, might contribute to GERD healing by PPIs.”

Dr. Souza said she continues to investigate, focusing now on how the initial insult of acidic bile salts on esophageal epithelium stimulates this inflammatory response. The key may be in a small protein called hypoxia-inducible factor-2 alpha (HIF-2a), one of a family of transcription factors that enable cells to respond to hypoxic stress.

Under normal oxygen conditions, HIF proteins are low, their levels regulated by an enzyme called prolyl hydroxylase. This enzyme is inactivated under hypoxic conditions, or in the presence of reactive oxygen species. HIF factors then rise and, among other functions, stimulate a strong inflammatory response. Inflamed tissues like those seen in esophagitis are frequently hypoxic, Dr. Souza said, and this state could be activating HIFs.

She examined HIF levels in her 12-patient cohort. These results were presented earlier this year at the Digestive Disease Weekmeeting in San Diego.

“At weeks 1 and 2, we found large associations between HIF-2a and increases in a number of proinflammatory cytokines including IL-8 and intercellular adhesion molecule–1,” a protein that facilitates leukocyte migration. Preliminary studies of HIF-2a inhibition in esophageal squamous cells in culture exposed to acidic bile salts show promising results as a potential therapeutic strategy to reduce proinflammatory cytokine expression. It is conceivable that anti-inflammatory therapies directed at HIF-2a may be on the horizon for the prevention and treatment of reflux esophagitis, she added.

Neither Dr. Souza nor her colleagues had any relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson