The reported prevalence of occult hepatitis B infection (OBI) varies widely: from < 1% to as high as 89.5% in HIV patients. Among patients with chronic hepatitis, the prevalence—again—ranges widely, from 0% to 52% but is highest in patients with chronic hepatitis C (CHC).

The clinical impact of OBI on patients with CHC has been extensively investigated, say researchers from the Institute of Liver and Biliary Sciences in New Delhi, India, but the available data are conflicting. In fact, when they conducted their study to assess the prevalence of OBI and evaluate its impact on clinical outcomes and response to antiviral therapy in CHC, the findings were “largely inconclusive.”

The study included 80 patients, of whom 32 (40%) had seropositive OBI. Hepatitis C virus genotype information was available for 59 patients, revealing that genotype 3 was most common.

However, analysis of clinical, biochemical, histopathologic and treatment response based on seropositivity and semiquantitative estimate of anti-HBc did not yield statistically significant results. Plasma samples of 14 were reactive for anti-HBc, 12 for anti-HBs, and 6 for both antibodies. Hepatitis B virus DNA (34 IU/mL) was detected in the plasma sample of only 1 patient by quantitative polymerase chain reaction.  Therefore, the researchers say, the prevalence of OBI was 1.25%.

Anti-HBc total antibody levels did not influence clinical outcomes and response to directly acting antiviral therapy. Nor did genotype make a significant difference: 90.7% of genotype 3 patients and 92.8% of genotype 1 patients attained sustained virologic response.

More prospective studies should be conducted, the researchers urge, to further explore “this seemingly enigmatic issue.” 

Source:
Bhatia M, Gupta E, Choudhary MC, Jindal A, Sarin SK. J Lab Physicians. 2018;10(3):304-308.
doi:  10.4103/JLP.JLP_12_18.

The reported prevalence of occult hepatitis B infection (OBI) varies widely: from < 1% to as high as 89.5% in HIV patients. Among patients with chronic hepatitis, the prevalence—again—ranges widely, from 0% to 52% but is highest in patients with chronic hepatitis C (CHC).

The clinical impact of OBI on patients with CHC has been extensively investigated, say researchers from the Institute of Liver and Biliary Sciences in New Delhi, India, but the available data are conflicting. In fact, when they conducted their study to assess the prevalence of OBI and evaluate its impact on clinical outcomes and response to antiviral therapy in CHC, the findings were “largely inconclusive.”

The study included 80 patients, of whom 32 (40%) had seropositive OBI. Hepatitis C virus genotype information was available for 59 patients, revealing that genotype 3 was most common.

However, analysis of clinical, biochemical, histopathologic and treatment response based on seropositivity and semiquantitative estimate of anti-HBc did not yield statistically significant results. Plasma samples of 14 were reactive for anti-HBc, 12 for anti-HBs, and 6 for both antibodies. Hepatitis B virus DNA (34 IU/mL) was detected in the plasma sample of only 1 patient by quantitative polymerase chain reaction.  Therefore, the researchers say, the prevalence of OBI was 1.25%.

Anti-HBc total antibody levels did not influence clinical outcomes and response to directly acting antiviral therapy. Nor did genotype make a significant difference: 90.7% of genotype 3 patients and 92.8% of genotype 1 patients attained sustained virologic response.

More prospective studies should be conducted, the researchers urge, to further explore “this seemingly enigmatic issue.” 

Source:
Bhatia M, Gupta E, Choudhary MC, Jindal A, Sarin SK. J Lab Physicians. 2018;10(3):304-308.
doi:  10.4103/JLP.JLP_12_18.

The reported prevalence of occult hepatitis B infection (OBI) varies widely: from < 1% to as high as 89.5% in HIV patients. Among patients with chronic hepatitis, the prevalence—again—ranges widely, from 0% to 52% but is highest in patients with chronic hepatitis C (CHC).

The clinical impact of OBI on patients with CHC has been extensively investigated, say researchers from the Institute of Liver and Biliary Sciences in New Delhi, India, but the available data are conflicting. In fact, when they conducted their study to assess the prevalence of OBI and evaluate its impact on clinical outcomes and response to antiviral therapy in CHC, the findings were “largely inconclusive.”

The study included 80 patients, of whom 32 (40%) had seropositive OBI. Hepatitis C virus genotype information was available for 59 patients, revealing that genotype 3 was most common.

However, analysis of clinical, biochemical, histopathologic and treatment response based on seropositivity and semiquantitative estimate of anti-HBc did not yield statistically significant results. Plasma samples of 14 were reactive for anti-HBc, 12 for anti-HBs, and 6 for both antibodies. Hepatitis B virus DNA (34 IU/mL) was detected in the plasma sample of only 1 patient by quantitative polymerase chain reaction.  Therefore, the researchers say, the prevalence of OBI was 1.25%.

Anti-HBc total antibody levels did not influence clinical outcomes and response to directly acting antiviral therapy. Nor did genotype make a significant difference: 90.7% of genotype 3 patients and 92.8% of genotype 1 patients attained sustained virologic response.

More prospective studies should be conducted, the researchers urge, to further explore “this seemingly enigmatic issue.” 

Source:
Bhatia M, Gupta E, Choudhary MC, Jindal A, Sarin SK. J Lab Physicians. 2018;10(3):304-308.
doi:  10.4103/JLP.JLP_12_18.

of North Carolina

New research could aid the development of immunotherapies tailored to patients with acute myeloid leukemia (AML) who are undergoing stem cell transplant (SCT).

Researchers found they could use genetic sequencing and computer software to identify minor histocompatibility antigens (mHAs) known to occur in AML.

The team used this method to predict novel graft-versus-leukemia (GVL) mHAs and demonstrated that one of these mHAs could be a “potentially useful” therapeutic target.

Ben Vincent, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, and his colleagues reported these findings in Blood Advances.

In their retrospective study, the researchers tested whether their software could predict antigenic targets in 101 SCT donor-recipient pairs.

The researchers found they could correctly identify 14 of 18 mHAs known to occur in AML, but they were also able to predict 102 new GVL mHAs.

The researchers then confirmed one of these GVL mHAs, called UNC-GRK4-V, as a potential target for immunotherapy. The team observed immune responses to UNC-GRK4-V in four of nine AML patients who had undergone SCT.

Looking ahead, the researchers want to optimize their software to predict the most common AML-associated mHAs present in the U.S. population and confirm these predicted antigens as valid immunotherapy targets.

The team believes they could potentially use their predictions to engineer donor immune cells to specifically target the cancer cell antigens while preventing graft-versus-host disease.

“We’ve developed a software package that predicts leukemia-specific immune targets in any leukemia patient undergoing a stem cell transplant based on DNA and RNA sequencing and demonstrated that these data can lead to actual targets expressed on leukemia cells,” Dr. Vincent said.

“The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse.”

The current research was supported by a National Cancer Institute grant, an ASCO Young Investigator Award, the North Carolina University Cancer Research Fund, and the Scott Neil Schwirck Fellowship.

of North Carolina

New research could aid the development of immunotherapies tailored to patients with acute myeloid leukemia (AML) who are undergoing stem cell transplant (SCT).

Researchers found they could use genetic sequencing and computer software to identify minor histocompatibility antigens (mHAs) known to occur in AML.

The team used this method to predict novel graft-versus-leukemia (GVL) mHAs and demonstrated that one of these mHAs could be a “potentially useful” therapeutic target.

Ben Vincent, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, and his colleagues reported these findings in Blood Advances.

In their retrospective study, the researchers tested whether their software could predict antigenic targets in 101 SCT donor-recipient pairs.

The researchers found they could correctly identify 14 of 18 mHAs known to occur in AML, but they were also able to predict 102 new GVL mHAs.

The researchers then confirmed one of these GVL mHAs, called UNC-GRK4-V, as a potential target for immunotherapy. The team observed immune responses to UNC-GRK4-V in four of nine AML patients who had undergone SCT.

Looking ahead, the researchers want to optimize their software to predict the most common AML-associated mHAs present in the U.S. population and confirm these predicted antigens as valid immunotherapy targets.

The team believes they could potentially use their predictions to engineer donor immune cells to specifically target the cancer cell antigens while preventing graft-versus-host disease.

“We’ve developed a software package that predicts leukemia-specific immune targets in any leukemia patient undergoing a stem cell transplant based on DNA and RNA sequencing and demonstrated that these data can lead to actual targets expressed on leukemia cells,” Dr. Vincent said.

“The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse.”

The current research was supported by a National Cancer Institute grant, an ASCO Young Investigator Award, the North Carolina University Cancer Research Fund, and the Scott Neil Schwirck Fellowship.

of North Carolina

New research could aid the development of immunotherapies tailored to patients with acute myeloid leukemia (AML) who are undergoing stem cell transplant (SCT).

Researchers found they could use genetic sequencing and computer software to identify minor histocompatibility antigens (mHAs) known to occur in AML.

The team used this method to predict novel graft-versus-leukemia (GVL) mHAs and demonstrated that one of these mHAs could be a “potentially useful” therapeutic target.

Ben Vincent, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, and his colleagues reported these findings in Blood Advances.

In their retrospective study, the researchers tested whether their software could predict antigenic targets in 101 SCT donor-recipient pairs.

The researchers found they could correctly identify 14 of 18 mHAs known to occur in AML, but they were also able to predict 102 new GVL mHAs.

The researchers then confirmed one of these GVL mHAs, called UNC-GRK4-V, as a potential target for immunotherapy. The team observed immune responses to UNC-GRK4-V in four of nine AML patients who had undergone SCT.

Looking ahead, the researchers want to optimize their software to predict the most common AML-associated mHAs present in the U.S. population and confirm these predicted antigens as valid immunotherapy targets.

The team believes they could potentially use their predictions to engineer donor immune cells to specifically target the cancer cell antigens while preventing graft-versus-host disease.

“We’ve developed a software package that predicts leukemia-specific immune targets in any leukemia patient undergoing a stem cell transplant based on DNA and RNA sequencing and demonstrated that these data can lead to actual targets expressed on leukemia cells,” Dr. Vincent said.

“The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse.”

The current research was supported by a National Cancer Institute grant, an ASCO Young Investigator Award, the North Carolina University Cancer Research Fund, and the Scott Neil Schwirck Fellowship.

ANSWER

The radiograph shows an obvious metallic foreign body that appears to be lodged within the first and second lumbar disc space. This is likely the tip of the knife, which presumably broke off when the patient was stabbed. 

The patient was promptly transferred to a trauma center with neurosurgery coverage. Subsequent CT showed that the blade had penetrated the spinal canal, but remarkably, the patient remained neurologically intact. He underwent successful removal without any neurologic compromise.

This case highlights several points for clinicians: First, provider-to-provider sign-out of patients should be complete and detailed. Second, obtaining a thorough history is essential. And third, you should maintain a low threshold for obtaining radiographs of wounds, to rule out a foreign body.

ANSWER

The radiograph shows an obvious metallic foreign body that appears to be lodged within the first and second lumbar disc space. This is likely the tip of the knife, which presumably broke off when the patient was stabbed. 

The patient was promptly transferred to a trauma center with neurosurgery coverage. Subsequent CT showed that the blade had penetrated the spinal canal, but remarkably, the patient remained neurologically intact. He underwent successful removal without any neurologic compromise.

This case highlights several points for clinicians: First, provider-to-provider sign-out of patients should be complete and detailed. Second, obtaining a thorough history is essential. And third, you should maintain a low threshold for obtaining radiographs of wounds, to rule out a foreign body.

ANSWER

The radiograph shows an obvious metallic foreign body that appears to be lodged within the first and second lumbar disc space. This is likely the tip of the knife, which presumably broke off when the patient was stabbed. 

The patient was promptly transferred to a trauma center with neurosurgery coverage. Subsequent CT showed that the blade had penetrated the spinal canal, but remarkably, the patient remained neurologically intact. He underwent successful removal without any neurologic compromise.

This case highlights several points for clinicians: First, provider-to-provider sign-out of patients should be complete and detailed. Second, obtaining a thorough history is essential. And third, you should maintain a low threshold for obtaining radiographs of wounds, to rule out a foreign body.

LAKE TAHOE, CALIF. – Dermatologists prescribe more antibiotics than any other physician group, a statistic that George G. Zhanel, PhD, would like to see go by the wayside.

After all, the World Health Organization projects that the number of annual deaths in North America attributable to antibiotic resistance will reach 317,000 by the year 2050.

“It doesn’t really matter where you are in the world – we’re going to have a lot of deaths due to infections caused by antibiotic-resistant organisms,” Dr. Zhanel, a microbiologist at the College of Medicine, University of Manitoba, Winnipeg, Canada, said at the annual meeting of the Society for Pediatric Dermatology. “Many of us are very concerned about this. Countries have put together an optimal action plan. What are we going to do about this? The plans are quite similar from country to country. They talk about surveillance, finding where these pathogens are. They talk about infection control such as washing your hands in the clinic so you’re not moving antibiotic-resistant organisms around. They talk about diagnostic and treatment guidelines, new antibiotic therapies, probiotics, and vaccination strategies. My own group is doing research on all of these areas, but today I’m going to focus on antibiotic stewardship: Using antibiotics wisely, trying to optimize efficacy while trying to minimize the development of resistant organisms.”

Dr. Zhanel, who is also director of the Canadian Antimicrobial Resistance Alliance (CARA) at the College of Medicine, University of Manitoba, described dermatologists as “big players” when it comes to antibiotic use. According to a 2016 report from the Scientific Panel on Antibiotic Use in Dermatology, dermatologists order 8.2 million oral antibiotic prescriptions each year, which is more common than any other physician group based on the prescribing rate per clinician (J Clin Aesthet Dermatol. 2016;9[4]:18-24). In addition, the prescribed duration of antibiotic therapy is often markedly longer with therapies treated by dermatologists, especially acne and rosacea. One study of general practitioners in the United Kingdom found that the mean duration of oral antibiotic use for treating acne was 175 days (J Am Acad Dermatol 2016;75:1142-50). “For some patients it went on much longer,” said Dr. Zhanel, who was not affiliated with the study.

“You are important players when it comes to antibiotics. How you use them and if you use them wisely impacts not only your patients, but the world.”

The correlation between antibiotic use and resistance is widely established, he continued. “We have known for 30 to 40 years that if you treat patients with tetracyclines, the Staphylococcus epidermidis that we all have on our skin develop tetracycline resistance,” he said. “The tetracycline resistance genes from S. epidermidis can then transfer to putative pathogens such as Staphylococcus aureus, and potentially [methicillin-resistant S. aureus]. That’s why we need to try to minimize oral tetracycline exposure on the normal microbiome.” In addition, tetracycline use can help create multidrug resistant organisms.

Next, Dr. Zhanel discussed potential solutions to antimicrobial usage/resistance in dermatology. According to recent guidelines on the care for the management of acne vulgaris, systemic antibiotic use should be limited to the shortest possible duration, typically 90 days (J Am Acad Dermatol. 2016;74[5]:945-73). A common treatment for moderate to-severe acne is to combine a topical retinoid with an oral or topical antimicrobial (J Am Acad Dermatol. 2009;60(5 suppl):S1-S50). If the addition of an oral antibiotic is required, limit its use to 3 or 4 months and co-prescribe with a product that contains benzoyl peroxide (BPO), or use as a washout. “Ideally, that’s your exit strategy,” he said. “Once you finish the oral antibiotic, in about 3 months if possible, continue with the topical retinoids plus BPO to maintain that particular remission.”

Why add benzoyl peroxide to topical retinoids for maintenance therapy? “Benzoyl peroxide and topical retinoids affect multiple targets in your acne strategy, and when you use them together they are powerful,” Dr. Zhanel said. He advises dermatologists not to prescribe oral or topical clindamycin unless they have to, because that drug is one of the main drivers of Clostridium difficile infection.

Dr. Zhanel’s stewardship tips for topical antibiotics involve not using topical tetracyclines/clindamycin/macrolides, in favor of using a topical antimicrobial such as BPO. “We think that benzoyl peroxide is less likely to drive resistance than are the traditional topical antibiotics like tetracyclines and clindamycin,” he said. “Use topical retinoids and benzoyl peroxide, if possible.”

Subtherapeutic oral doses of tetracyclines such as doxycycline 40 mg modified release “look very powerful for treating rosacea and do not affect the normal microbiome or select for resistance,” he said. In the meantime, Dr. Zhanel and other researchers are working to develop narrow spectrum tetracyclines with less impact on the GI flora, such as sarecycline. “So there is the potential for more eco-friendly tetracyclines,” he said.

Going forward, many questions remain about optimal antibiotic stewardship in dermatology, Dr. Zhanel said. For example, if you combine a topical antibiotic with benzoyl peroxide, are you less likely to get resistance to that topical antibiotic? “I think the answer is yes, but the literature isn’t very strong on that,” he said. “Also, is benzoyl peroxide plus a topical retinoid better than benzoyl peroxide plus a topical antibiotic in terms of resistance? I think the answer is yes, but again there is very little data on this.”

Dr. Zhanel disclosed having numerous financial ties to the pharmaceutical industry.

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – Dermatologists prescribe more antibiotics than any other physician group, a statistic that George G. Zhanel, PhD, would like to see go by the wayside.

After all, the World Health Organization projects that the number of annual deaths in North America attributable to antibiotic resistance will reach 317,000 by the year 2050.

“It doesn’t really matter where you are in the world – we’re going to have a lot of deaths due to infections caused by antibiotic-resistant organisms,” Dr. Zhanel, a microbiologist at the College of Medicine, University of Manitoba, Winnipeg, Canada, said at the annual meeting of the Society for Pediatric Dermatology. “Many of us are very concerned about this. Countries have put together an optimal action plan. What are we going to do about this? The plans are quite similar from country to country. They talk about surveillance, finding where these pathogens are. They talk about infection control such as washing your hands in the clinic so you’re not moving antibiotic-resistant organisms around. They talk about diagnostic and treatment guidelines, new antibiotic therapies, probiotics, and vaccination strategies. My own group is doing research on all of these areas, but today I’m going to focus on antibiotic stewardship: Using antibiotics wisely, trying to optimize efficacy while trying to minimize the development of resistant organisms.”

Dr. Zhanel, who is also director of the Canadian Antimicrobial Resistance Alliance (CARA) at the College of Medicine, University of Manitoba, described dermatologists as “big players” when it comes to antibiotic use. According to a 2016 report from the Scientific Panel on Antibiotic Use in Dermatology, dermatologists order 8.2 million oral antibiotic prescriptions each year, which is more common than any other physician group based on the prescribing rate per clinician (J Clin Aesthet Dermatol. 2016;9[4]:18-24). In addition, the prescribed duration of antibiotic therapy is often markedly longer with therapies treated by dermatologists, especially acne and rosacea. One study of general practitioners in the United Kingdom found that the mean duration of oral antibiotic use for treating acne was 175 days (J Am Acad Dermatol 2016;75:1142-50). “For some patients it went on much longer,” said Dr. Zhanel, who was not affiliated with the study.

“You are important players when it comes to antibiotics. How you use them and if you use them wisely impacts not only your patients, but the world.”

The correlation between antibiotic use and resistance is widely established, he continued. “We have known for 30 to 40 years that if you treat patients with tetracyclines, the Staphylococcus epidermidis that we all have on our skin develop tetracycline resistance,” he said. “The tetracycline resistance genes from S. epidermidis can then transfer to putative pathogens such as Staphylococcus aureus, and potentially [methicillin-resistant S. aureus]. That’s why we need to try to minimize oral tetracycline exposure on the normal microbiome.” In addition, tetracycline use can help create multidrug resistant organisms.

Next, Dr. Zhanel discussed potential solutions to antimicrobial usage/resistance in dermatology. According to recent guidelines on the care for the management of acne vulgaris, systemic antibiotic use should be limited to the shortest possible duration, typically 90 days (J Am Acad Dermatol. 2016;74[5]:945-73). A common treatment for moderate to-severe acne is to combine a topical retinoid with an oral or topical antimicrobial (J Am Acad Dermatol. 2009;60(5 suppl):S1-S50). If the addition of an oral antibiotic is required, limit its use to 3 or 4 months and co-prescribe with a product that contains benzoyl peroxide (BPO), or use as a washout. “Ideally, that’s your exit strategy,” he said. “Once you finish the oral antibiotic, in about 3 months if possible, continue with the topical retinoids plus BPO to maintain that particular remission.”

Why add benzoyl peroxide to topical retinoids for maintenance therapy? “Benzoyl peroxide and topical retinoids affect multiple targets in your acne strategy, and when you use them together they are powerful,” Dr. Zhanel said. He advises dermatologists not to prescribe oral or topical clindamycin unless they have to, because that drug is one of the main drivers of Clostridium difficile infection.

Dr. Zhanel’s stewardship tips for topical antibiotics involve not using topical tetracyclines/clindamycin/macrolides, in favor of using a topical antimicrobial such as BPO. “We think that benzoyl peroxide is less likely to drive resistance than are the traditional topical antibiotics like tetracyclines and clindamycin,” he said. “Use topical retinoids and benzoyl peroxide, if possible.”

Subtherapeutic oral doses of tetracyclines such as doxycycline 40 mg modified release “look very powerful for treating rosacea and do not affect the normal microbiome or select for resistance,” he said. In the meantime, Dr. Zhanel and other researchers are working to develop narrow spectrum tetracyclines with less impact on the GI flora, such as sarecycline. “So there is the potential for more eco-friendly tetracyclines,” he said.

Going forward, many questions remain about optimal antibiotic stewardship in dermatology, Dr. Zhanel said. For example, if you combine a topical antibiotic with benzoyl peroxide, are you less likely to get resistance to that topical antibiotic? “I think the answer is yes, but the literature isn’t very strong on that,” he said. “Also, is benzoyl peroxide plus a topical retinoid better than benzoyl peroxide plus a topical antibiotic in terms of resistance? I think the answer is yes, but again there is very little data on this.”

Dr. Zhanel disclosed having numerous financial ties to the pharmaceutical industry.

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – Dermatologists prescribe more antibiotics than any other physician group, a statistic that George G. Zhanel, PhD, would like to see go by the wayside.

After all, the World Health Organization projects that the number of annual deaths in North America attributable to antibiotic resistance will reach 317,000 by the year 2050.

“It doesn’t really matter where you are in the world – we’re going to have a lot of deaths due to infections caused by antibiotic-resistant organisms,” Dr. Zhanel, a microbiologist at the College of Medicine, University of Manitoba, Winnipeg, Canada, said at the annual meeting of the Society for Pediatric Dermatology. “Many of us are very concerned about this. Countries have put together an optimal action plan. What are we going to do about this? The plans are quite similar from country to country. They talk about surveillance, finding where these pathogens are. They talk about infection control such as washing your hands in the clinic so you’re not moving antibiotic-resistant organisms around. They talk about diagnostic and treatment guidelines, new antibiotic therapies, probiotics, and vaccination strategies. My own group is doing research on all of these areas, but today I’m going to focus on antibiotic stewardship: Using antibiotics wisely, trying to optimize efficacy while trying to minimize the development of resistant organisms.”

Dr. Zhanel, who is also director of the Canadian Antimicrobial Resistance Alliance (CARA) at the College of Medicine, University of Manitoba, described dermatologists as “big players” when it comes to antibiotic use. According to a 2016 report from the Scientific Panel on Antibiotic Use in Dermatology, dermatologists order 8.2 million oral antibiotic prescriptions each year, which is more common than any other physician group based on the prescribing rate per clinician (J Clin Aesthet Dermatol. 2016;9[4]:18-24). In addition, the prescribed duration of antibiotic therapy is often markedly longer with therapies treated by dermatologists, especially acne and rosacea. One study of general practitioners in the United Kingdom found that the mean duration of oral antibiotic use for treating acne was 175 days (J Am Acad Dermatol 2016;75:1142-50). “For some patients it went on much longer,” said Dr. Zhanel, who was not affiliated with the study.

“You are important players when it comes to antibiotics. How you use them and if you use them wisely impacts not only your patients, but the world.”

The correlation between antibiotic use and resistance is widely established, he continued. “We have known for 30 to 40 years that if you treat patients with tetracyclines, the Staphylococcus epidermidis that we all have on our skin develop tetracycline resistance,” he said. “The tetracycline resistance genes from S. epidermidis can then transfer to putative pathogens such as Staphylococcus aureus, and potentially [methicillin-resistant S. aureus]. That’s why we need to try to minimize oral tetracycline exposure on the normal microbiome.” In addition, tetracycline use can help create multidrug resistant organisms.

Next, Dr. Zhanel discussed potential solutions to antimicrobial usage/resistance in dermatology. According to recent guidelines on the care for the management of acne vulgaris, systemic antibiotic use should be limited to the shortest possible duration, typically 90 days (J Am Acad Dermatol. 2016;74[5]:945-73). A common treatment for moderate to-severe acne is to combine a topical retinoid with an oral or topical antimicrobial (J Am Acad Dermatol. 2009;60(5 suppl):S1-S50). If the addition of an oral antibiotic is required, limit its use to 3 or 4 months and co-prescribe with a product that contains benzoyl peroxide (BPO), or use as a washout. “Ideally, that’s your exit strategy,” he said. “Once you finish the oral antibiotic, in about 3 months if possible, continue with the topical retinoids plus BPO to maintain that particular remission.”

Why add benzoyl peroxide to topical retinoids for maintenance therapy? “Benzoyl peroxide and topical retinoids affect multiple targets in your acne strategy, and when you use them together they are powerful,” Dr. Zhanel said. He advises dermatologists not to prescribe oral or topical clindamycin unless they have to, because that drug is one of the main drivers of Clostridium difficile infection.

Dr. Zhanel’s stewardship tips for topical antibiotics involve not using topical tetracyclines/clindamycin/macrolides, in favor of using a topical antimicrobial such as BPO. “We think that benzoyl peroxide is less likely to drive resistance than are the traditional topical antibiotics like tetracyclines and clindamycin,” he said. “Use topical retinoids and benzoyl peroxide, if possible.”

Subtherapeutic oral doses of tetracyclines such as doxycycline 40 mg modified release “look very powerful for treating rosacea and do not affect the normal microbiome or select for resistance,” he said. In the meantime, Dr. Zhanel and other researchers are working to develop narrow spectrum tetracyclines with less impact on the GI flora, such as sarecycline. “So there is the potential for more eco-friendly tetracyclines,” he said.

Going forward, many questions remain about optimal antibiotic stewardship in dermatology, Dr. Zhanel said. For example, if you combine a topical antibiotic with benzoyl peroxide, are you less likely to get resistance to that topical antibiotic? “I think the answer is yes, but the literature isn’t very strong on that,” he said. “Also, is benzoyl peroxide plus a topical retinoid better than benzoyl peroxide plus a topical antibiotic in terms of resistance? I think the answer is yes, but again there is very little data on this.”

Dr. Zhanel disclosed having numerous financial ties to the pharmaceutical industry.

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – Mosaicism makes everything in genetics more challenging, but it also enables researchers to understand how genes and cell pathways work in cancer and during human development, Leslie G. Biesecker, MD said at the annual meeting of the Society for Pediatric Dermatology.

Dr. Biesecker, senior investigator and head of the clinical genomics section of the National Human Genome Research Institute’s Medical Genomics and Metabolic Genetics Branch, discussed mosaicism and a number of overgrowth syndromes that he and his associates have been studying that have clinical relevance for pediatric dermatologists. He noted that mosaicism can affect any tissue, anywhere, in any pattern. “If an affected cell cannot survive gametogenesis, fertilization, or survive early development, this generates Happle-type mosaicism,” explained Dr. Biesecker, who is trained in pediatrics and in clinical and molecular genetics.

“This is characterized by patchy manifestations, and no parent-to-child transmission or recurrence. You must always be careful here, though, because Mother Nature does what she wants to. Mosaic mutations can happen more than once, but it’s a very unlikely outcome. Happle-type mosaicism is also characterized by discordant monozygotic twins,” he noted.

The prototype for Happle-type mosaicism is Proteus syndrome, formerly known as Elephant Man disease, which is caused by a mutation in the AKT1 gene. Patients with Proteus syndrome undergo severe, relentless overgrowth, and about 25% of them die during childhood. “If you see one of these patients, you have a serious clinical problem on your hands,” he said. “There is enormous individual variability, but it is ultra rare.”

Dermatologic lesions that are characteristic of Proteus syndrome include cerebriform connective tissue nevus, which typically presents on the hands and feet. “A wide range of vascular malformations have also been associated with this, even patients with arteriovenous malformations,” Dr. Biesecker said. “They are a serious problem.” Linear verrucous epidermal nevus is another characteristic lesion of Proteus syndrome. It can present in a number of ways and in various body sites. “The natural history of these lesions is important,” he commented. “Over time, are they stable, or do they spread and expand over time? These lesions do not ever spontaneously regress. This does enable molecular diagnosis, but don’t bother sampling their blood, because it will be negative. You have to have a biopsy sample.”

Overgrowth syndromes that do not meet criteria for Proteus syndrome fall into a category known as PIK3CA-related overgrowth spectrum, which Dr. Biesecker characterized as “a bunch of clinical designations all caused by the same underlying somatic mutation in a gene called PIK3CA. There is an enormous variability in these patients, ranging from those who have profound overgrowth, including malformations, truncal overgrowth, and vascular malformations, and digital overgrowth in all sorts of patterns. We designate this as PIK3CA-related overgrowth spectrum (PROS), because we can’t clinically separate these things from one another.”

These conditions include what used to be called CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal/spinal anomalies), facial infiltrating lipomatosis, and megalencephaly-capillary malformation syndrome. PROS is about 100 times more common than Proteus syndrome. “There are no rational boundaries to distinguish these entities,” Dr. Biesecker said. “They are rationalized under a combined clinical-molecular PROS framework, meaning that the molecular diagnosis is absolutely key to correctly diagnosing these patients.”

In this way, mosaicism challenges the traditional concept of diagnosing overgrowth disorders. “What we thought were separate disorders are in fact many manifestations of a single disorder,” he continued. “When I was doing my genetics training, we were taught that it would turn out that there was one gene for every disease, and one disease for every gene. That is completely wrong; it’s much more complicated than that. Mosaicism is also important for us as biologists, because it gives us a window into biology we otherwise would not see. Without a mosaicism, Proteus syndrome cannot exist biologically. So if I want to understand that gene product, I have to study patients who are mosaics. Mosaicism can happen in any tissue, whether it’s visible or not.”

Dr. Biesecker, who has been elected to serve as president of the American Society of Human Genetics for 2019, noted that most of the gene mutations that cause overgrowth disorders are the same ones implicated in cancer. “It makes sense, because cancer is a disorder of uncontrolled proliferation and differentiation,” he said. “These overgrowth disorders are similar but less severe manifestations of the same problem. It turns out that these mosaic patients are single gene model systems of cancer biology.” Therefore, when a drug company develops an anti-cancer drug, he continued, it also can be useful for PROS or Proteus syndrome. It’s much easier to inhibit a protein that’s overactive than it is to replace the activity of a gene that has lost its function.

But in PROS and Proteus, “we have very different treatment objectives than oncologists do,” he said. “Our goal is to reduce the signaling caused by these mutations; we do not want to kill the cells. Some of my patients with these disorders have pretty close to 50% of cells in their body carrying these mutations. If I were thinking like an oncologist, the oncologist wants to kill cancer cells; that’s their objective. If I were to kill all of the mutant cells in my patients, I’m certain that would kill them.”

One promising development is the investigational oral agent ARQ 092, which is an inhibitor of AKT1. Dr. Biesecker and his colleagues at the NIH have been working to figure out what dosing should be used in humans based on mouse data, lab data, and data from cancer patients. They started with about one-twelvth the dose that oncologists use. After treating the first patient with overgrowth syndrome, on day 15 that person’s AKT1 level dropped to about 20% of normal, while on day 75 it moved to around 60% of normal. “We are right in that zone where we want to drive the activity of that protein to about half of what it should be,” Dr. Biesecker said. He and his colleagues also have observed regression of lesions in a patient with cerebriform connective tissue nevus who was treated with ARQ 092. “We’ve never seen this before.”

Dr. Biesecker disclosed that he is a member of the Illumina medical ethics board. He has received royalties from Genentech and in-kind research support from ArQule and Pfizer.

dbrunk@mdedge.com

 

LAKE TAHOE, CALIF. – Mosaicism makes everything in genetics more challenging, but it also enables researchers to understand how genes and cell pathways work in cancer and during human development, Leslie G. Biesecker, MD said at the annual meeting of the Society for Pediatric Dermatology.

Dr. Biesecker, senior investigator and head of the clinical genomics section of the National Human Genome Research Institute’s Medical Genomics and Metabolic Genetics Branch, discussed mosaicism and a number of overgrowth syndromes that he and his associates have been studying that have clinical relevance for pediatric dermatologists. He noted that mosaicism can affect any tissue, anywhere, in any pattern. “If an affected cell cannot survive gametogenesis, fertilization, or survive early development, this generates Happle-type mosaicism,” explained Dr. Biesecker, who is trained in pediatrics and in clinical and molecular genetics.

“This is characterized by patchy manifestations, and no parent-to-child transmission or recurrence. You must always be careful here, though, because Mother Nature does what she wants to. Mosaic mutations can happen more than once, but it’s a very unlikely outcome. Happle-type mosaicism is also characterized by discordant monozygotic twins,” he noted.

The prototype for Happle-type mosaicism is Proteus syndrome, formerly known as Elephant Man disease, which is caused by a mutation in the AKT1 gene. Patients with Proteus syndrome undergo severe, relentless overgrowth, and about 25% of them die during childhood. “If you see one of these patients, you have a serious clinical problem on your hands,” he said. “There is enormous individual variability, but it is ultra rare.”

Dermatologic lesions that are characteristic of Proteus syndrome include cerebriform connective tissue nevus, which typically presents on the hands and feet. “A wide range of vascular malformations have also been associated with this, even patients with arteriovenous malformations,” Dr. Biesecker said. “They are a serious problem.” Linear verrucous epidermal nevus is another characteristic lesion of Proteus syndrome. It can present in a number of ways and in various body sites. “The natural history of these lesions is important,” he commented. “Over time, are they stable, or do they spread and expand over time? These lesions do not ever spontaneously regress. This does enable molecular diagnosis, but don’t bother sampling their blood, because it will be negative. You have to have a biopsy sample.”

Overgrowth syndromes that do not meet criteria for Proteus syndrome fall into a category known as PIK3CA-related overgrowth spectrum, which Dr. Biesecker characterized as “a bunch of clinical designations all caused by the same underlying somatic mutation in a gene called PIK3CA. There is an enormous variability in these patients, ranging from those who have profound overgrowth, including malformations, truncal overgrowth, and vascular malformations, and digital overgrowth in all sorts of patterns. We designate this as PIK3CA-related overgrowth spectrum (PROS), because we can’t clinically separate these things from one another.”

These conditions include what used to be called CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal/spinal anomalies), facial infiltrating lipomatosis, and megalencephaly-capillary malformation syndrome. PROS is about 100 times more common than Proteus syndrome. “There are no rational boundaries to distinguish these entities,” Dr. Biesecker said. “They are rationalized under a combined clinical-molecular PROS framework, meaning that the molecular diagnosis is absolutely key to correctly diagnosing these patients.”

In this way, mosaicism challenges the traditional concept of diagnosing overgrowth disorders. “What we thought were separate disorders are in fact many manifestations of a single disorder,” he continued. “When I was doing my genetics training, we were taught that it would turn out that there was one gene for every disease, and one disease for every gene. That is completely wrong; it’s much more complicated than that. Mosaicism is also important for us as biologists, because it gives us a window into biology we otherwise would not see. Without a mosaicism, Proteus syndrome cannot exist biologically. So if I want to understand that gene product, I have to study patients who are mosaics. Mosaicism can happen in any tissue, whether it’s visible or not.”

Dr. Biesecker, who has been elected to serve as president of the American Society of Human Genetics for 2019, noted that most of the gene mutations that cause overgrowth disorders are the same ones implicated in cancer. “It makes sense, because cancer is a disorder of uncontrolled proliferation and differentiation,” he said. “These overgrowth disorders are similar but less severe manifestations of the same problem. It turns out that these mosaic patients are single gene model systems of cancer biology.” Therefore, when a drug company develops an anti-cancer drug, he continued, it also can be useful for PROS or Proteus syndrome. It’s much easier to inhibit a protein that’s overactive than it is to replace the activity of a gene that has lost its function.

But in PROS and Proteus, “we have very different treatment objectives than oncologists do,” he said. “Our goal is to reduce the signaling caused by these mutations; we do not want to kill the cells. Some of my patients with these disorders have pretty close to 50% of cells in their body carrying these mutations. If I were thinking like an oncologist, the oncologist wants to kill cancer cells; that’s their objective. If I were to kill all of the mutant cells in my patients, I’m certain that would kill them.”

One promising development is the investigational oral agent ARQ 092, which is an inhibitor of AKT1. Dr. Biesecker and his colleagues at the NIH have been working to figure out what dosing should be used in humans based on mouse data, lab data, and data from cancer patients. They started with about one-twelvth the dose that oncologists use. After treating the first patient with overgrowth syndrome, on day 15 that person’s AKT1 level dropped to about 20% of normal, while on day 75 it moved to around 60% of normal. “We are right in that zone where we want to drive the activity of that protein to about half of what it should be,” Dr. Biesecker said. He and his colleagues also have observed regression of lesions in a patient with cerebriform connective tissue nevus who was treated with ARQ 092. “We’ve never seen this before.”

Dr. Biesecker disclosed that he is a member of the Illumina medical ethics board. He has received royalties from Genentech and in-kind research support from ArQule and Pfizer.

dbrunk@mdedge.com

 

LAKE TAHOE, CALIF. – Mosaicism makes everything in genetics more challenging, but it also enables researchers to understand how genes and cell pathways work in cancer and during human development, Leslie G. Biesecker, MD said at the annual meeting of the Society for Pediatric Dermatology.

Dr. Biesecker, senior investigator and head of the clinical genomics section of the National Human Genome Research Institute’s Medical Genomics and Metabolic Genetics Branch, discussed mosaicism and a number of overgrowth syndromes that he and his associates have been studying that have clinical relevance for pediatric dermatologists. He noted that mosaicism can affect any tissue, anywhere, in any pattern. “If an affected cell cannot survive gametogenesis, fertilization, or survive early development, this generates Happle-type mosaicism,” explained Dr. Biesecker, who is trained in pediatrics and in clinical and molecular genetics.

“This is characterized by patchy manifestations, and no parent-to-child transmission or recurrence. You must always be careful here, though, because Mother Nature does what she wants to. Mosaic mutations can happen more than once, but it’s a very unlikely outcome. Happle-type mosaicism is also characterized by discordant monozygotic twins,” he noted.

The prototype for Happle-type mosaicism is Proteus syndrome, formerly known as Elephant Man disease, which is caused by a mutation in the AKT1 gene. Patients with Proteus syndrome undergo severe, relentless overgrowth, and about 25% of them die during childhood. “If you see one of these patients, you have a serious clinical problem on your hands,” he said. “There is enormous individual variability, but it is ultra rare.”

Dermatologic lesions that are characteristic of Proteus syndrome include cerebriform connective tissue nevus, which typically presents on the hands and feet. “A wide range of vascular malformations have also been associated with this, even patients with arteriovenous malformations,” Dr. Biesecker said. “They are a serious problem.” Linear verrucous epidermal nevus is another characteristic lesion of Proteus syndrome. It can present in a number of ways and in various body sites. “The natural history of these lesions is important,” he commented. “Over time, are they stable, or do they spread and expand over time? These lesions do not ever spontaneously regress. This does enable molecular diagnosis, but don’t bother sampling their blood, because it will be negative. You have to have a biopsy sample.”

Overgrowth syndromes that do not meet criteria for Proteus syndrome fall into a category known as PIK3CA-related overgrowth spectrum, which Dr. Biesecker characterized as “a bunch of clinical designations all caused by the same underlying somatic mutation in a gene called PIK3CA. There is an enormous variability in these patients, ranging from those who have profound overgrowth, including malformations, truncal overgrowth, and vascular malformations, and digital overgrowth in all sorts of patterns. We designate this as PIK3CA-related overgrowth spectrum (PROS), because we can’t clinically separate these things from one another.”

These conditions include what used to be called CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal/spinal anomalies), facial infiltrating lipomatosis, and megalencephaly-capillary malformation syndrome. PROS is about 100 times more common than Proteus syndrome. “There are no rational boundaries to distinguish these entities,” Dr. Biesecker said. “They are rationalized under a combined clinical-molecular PROS framework, meaning that the molecular diagnosis is absolutely key to correctly diagnosing these patients.”

In this way, mosaicism challenges the traditional concept of diagnosing overgrowth disorders. “What we thought were separate disorders are in fact many manifestations of a single disorder,” he continued. “When I was doing my genetics training, we were taught that it would turn out that there was one gene for every disease, and one disease for every gene. That is completely wrong; it’s much more complicated than that. Mosaicism is also important for us as biologists, because it gives us a window into biology we otherwise would not see. Without a mosaicism, Proteus syndrome cannot exist biologically. So if I want to understand that gene product, I have to study patients who are mosaics. Mosaicism can happen in any tissue, whether it’s visible or not.”

Dr. Biesecker, who has been elected to serve as president of the American Society of Human Genetics for 2019, noted that most of the gene mutations that cause overgrowth disorders are the same ones implicated in cancer. “It makes sense, because cancer is a disorder of uncontrolled proliferation and differentiation,” he said. “These overgrowth disorders are similar but less severe manifestations of the same problem. It turns out that these mosaic patients are single gene model systems of cancer biology.” Therefore, when a drug company develops an anti-cancer drug, he continued, it also can be useful for PROS or Proteus syndrome. It’s much easier to inhibit a protein that’s overactive than it is to replace the activity of a gene that has lost its function.

But in PROS and Proteus, “we have very different treatment objectives than oncologists do,” he said. “Our goal is to reduce the signaling caused by these mutations; we do not want to kill the cells. Some of my patients with these disorders have pretty close to 50% of cells in their body carrying these mutations. If I were thinking like an oncologist, the oncologist wants to kill cancer cells; that’s their objective. If I were to kill all of the mutant cells in my patients, I’m certain that would kill them.”

One promising development is the investigational oral agent ARQ 092, which is an inhibitor of AKT1. Dr. Biesecker and his colleagues at the NIH have been working to figure out what dosing should be used in humans based on mouse data, lab data, and data from cancer patients. They started with about one-twelvth the dose that oncologists use. After treating the first patient with overgrowth syndrome, on day 15 that person’s AKT1 level dropped to about 20% of normal, while on day 75 it moved to around 60% of normal. “We are right in that zone where we want to drive the activity of that protein to about half of what it should be,” Dr. Biesecker said. He and his colleagues also have observed regression of lesions in a patient with cerebriform connective tissue nevus who was treated with ARQ 092. “We’ve never seen this before.”

Dr. Biesecker disclosed that he is a member of the Illumina medical ethics board. He has received royalties from Genentech and in-kind research support from ArQule and Pfizer.

dbrunk@mdedge.com

 

LAKE TAHOE, CALIF. – After Brett King, MD, PhD, and his wife and collaborator, Brittany G. Craiglow, MD, published an index case of oral tofacitinib reversing alopecia universalis in a 25-year-old male patient back in 2014 (J Invest Dermatol. 2014;134:2988-90), they received hundreds of e-mails and phone calls from clinicians and patients.

“We also received quite a bit of media attention from around the world,” Dr. King recalled at the annual meeting of the Society for Pediatric Dermatology.

After all, alopecia areata and its variants affect 1%-2% of the population and have a marked impact on health-related quality of life, with high rates of concomitant generalized anxiety disorder and major depressive disorder. “The health-related quality of life is similar to that of atopic dermatitis and psoriasis, and there are no reliably effective therapies, especially for severe disease,” he said. “If treating atopic dermatitis and psoriasis with systemic agents is appropriate, then certainly treating alopecia areata is, too.”

Currently available Janus kinase (JAK) inhibitors include tofacitinib (Xeljanz), ruxolitinib (Jakafi), and baricitinib (Olumiant). “These medicines are not [Food and Drug Administration] approved for alopecia areata, though tofacitinib was recently approved for psoriatic arthritis, and so we have formal entry of this medicine into dermatology for the first time,” said Dr. King, who is a dermatologist at Yale University, New Haven, Conn.

Potential adverse effects of JAKs include nasopharyngitis, headache, diarrhea, elevated cholesterol, uncommonly herpes zoster, cytopenias, transaminitis, and rarely non-melanoma skin cancer, solid organ malignancy and lymphoma, and GI perforation. Tofacitinib has an FDA black box warning regarding serious infections and malignancies, and baricitinib has these plus an additional warning about thrombosis.

In an open label, two-center trial that followed the index patient report, Dr. King and his associates enrolled 66 patients aged 19-35 years who had greater than 50% scalp hair loss for at least 6 months to receive tofacitinib 5 mg twice daily for 3 months (JCI Insight. 2016; 1[15]:e89776). A primary outcome of interest was regrowth of hair as measured by the percent change in Severity of Alopecia Tool (SALT) score. A SALT score of 100 indicates baldness, while a score of zero indicates no hair loss. Following 3 months of treatment, 32% of patients had a greater than 50% change in their SALT score, 32% had a change in the range of 5%-50%, while 36% had a change that was less than 5%.

“One of the interesting findings was that long duration of current episode of complete scalp hair loss was a negative predictor of treatment response, especially for those who have had hair loss greater than 10 years,” Dr. King said. Adverse events were “pretty bland,” with the most common being upper respiratory infection (17%), headache (8%), abdominal pain (8%), and acne (8%). Weight gain occurred in 1.5% of patients.

Next, Dr. King and colleagues reviewed the records of 90 patients aged 18 years or older who were treated with tofacitinib for at least 4 months (J Am Acad Dermatol. 2017;76[1]:22-8). Patients had greater than 40% scalp hair loss, and the tofacitinib dose was up to 10 mg per day at the discretion of the physician. “About 43% of patients were treated with tofacitinib 5 mg” twice daily, Dr. King said. “Other patients had higher doses or the addition of prednisone for three doses to see if that would help.”

After treatment, 20% of patients had a greater than 90% change in their SALT score (complete scalp hair regrowth), while 38.4% had a change that ranged from 51%-90%. At the same time, 18% had a change in their SALT score that ranged from 6%-50%, while 23% had a change that was 5% or less. As observed in the earlier trial, researchers saw a negative correlation between duration of current episode of hair loss and latest percent change in SALT score.

“We believe that you have to catch people before they get to more than 10 years of complete scalp hair loss,” Dr. King said. “This is important for the pediatric age group. I just saw somebody who’s 13, and they’ve been bald for 8 years. You might make the argument that this person deserves treatment, at least for a period of time long enough to regrow their hair in order to reset the clock.”

The most common adverse events were acne and weight gain.

In a separate analysis, Dr. King, Dr. Craiglow, and Lucy Y. Liu, evaluated the use of tofacitinib for at least 2 months in 13 alopecia areata patients aged 12-17 years (J Am Acad Dermatol. 2017;76[1]:29-32). They limited the analysis to those who had greater than 20% scalp hair loss, alopecia totalis, or alopecia universalis that was stable or worsening for 6 months or longer. Of the 13 patients, 9 (69%) were responders. Of the four non-responders, one had a very long duration of baldness. The percent change in SALT score was 93% overall, including 100% in the responder group over a median of 5 months and just 1% in the non-responder group over a median of 4 months. “This does not work every time,” Dr. King said.

While some preliminary studies of topical JAK inhibitors for alopecia areata show promise, it remains unclear if this approach will translate in a clinically meaningful way, he said. Clinical trials are currently under way.

Dr. King disclosed that he has received honoraria or consulting fees from Aclaris Therapeutics, Celgene, Concert Pharmaceuticals, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, and Dermavant Sciences. He has also received funding support from The Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – After Brett King, MD, PhD, and his wife and collaborator, Brittany G. Craiglow, MD, published an index case of oral tofacitinib reversing alopecia universalis in a 25-year-old male patient back in 2014 (J Invest Dermatol. 2014;134:2988-90), they received hundreds of e-mails and phone calls from clinicians and patients.

“We also received quite a bit of media attention from around the world,” Dr. King recalled at the annual meeting of the Society for Pediatric Dermatology.

After all, alopecia areata and its variants affect 1%-2% of the population and have a marked impact on health-related quality of life, with high rates of concomitant generalized anxiety disorder and major depressive disorder. “The health-related quality of life is similar to that of atopic dermatitis and psoriasis, and there are no reliably effective therapies, especially for severe disease,” he said. “If treating atopic dermatitis and psoriasis with systemic agents is appropriate, then certainly treating alopecia areata is, too.”

Currently available Janus kinase (JAK) inhibitors include tofacitinib (Xeljanz), ruxolitinib (Jakafi), and baricitinib (Olumiant). “These medicines are not [Food and Drug Administration] approved for alopecia areata, though tofacitinib was recently approved for psoriatic arthritis, and so we have formal entry of this medicine into dermatology for the first time,” said Dr. King, who is a dermatologist at Yale University, New Haven, Conn.

Potential adverse effects of JAKs include nasopharyngitis, headache, diarrhea, elevated cholesterol, uncommonly herpes zoster, cytopenias, transaminitis, and rarely non-melanoma skin cancer, solid organ malignancy and lymphoma, and GI perforation. Tofacitinib has an FDA black box warning regarding serious infections and malignancies, and baricitinib has these plus an additional warning about thrombosis.

In an open label, two-center trial that followed the index patient report, Dr. King and his associates enrolled 66 patients aged 19-35 years who had greater than 50% scalp hair loss for at least 6 months to receive tofacitinib 5 mg twice daily for 3 months (JCI Insight. 2016; 1[15]:e89776). A primary outcome of interest was regrowth of hair as measured by the percent change in Severity of Alopecia Tool (SALT) score. A SALT score of 100 indicates baldness, while a score of zero indicates no hair loss. Following 3 months of treatment, 32% of patients had a greater than 50% change in their SALT score, 32% had a change in the range of 5%-50%, while 36% had a change that was less than 5%.

“One of the interesting findings was that long duration of current episode of complete scalp hair loss was a negative predictor of treatment response, especially for those who have had hair loss greater than 10 years,” Dr. King said. Adverse events were “pretty bland,” with the most common being upper respiratory infection (17%), headache (8%), abdominal pain (8%), and acne (8%). Weight gain occurred in 1.5% of patients.

Next, Dr. King and colleagues reviewed the records of 90 patients aged 18 years or older who were treated with tofacitinib for at least 4 months (J Am Acad Dermatol. 2017;76[1]:22-8). Patients had greater than 40% scalp hair loss, and the tofacitinib dose was up to 10 mg per day at the discretion of the physician. “About 43% of patients were treated with tofacitinib 5 mg” twice daily, Dr. King said. “Other patients had higher doses or the addition of prednisone for three doses to see if that would help.”

After treatment, 20% of patients had a greater than 90% change in their SALT score (complete scalp hair regrowth), while 38.4% had a change that ranged from 51%-90%. At the same time, 18% had a change in their SALT score that ranged from 6%-50%, while 23% had a change that was 5% or less. As observed in the earlier trial, researchers saw a negative correlation between duration of current episode of hair loss and latest percent change in SALT score.

“We believe that you have to catch people before they get to more than 10 years of complete scalp hair loss,” Dr. King said. “This is important for the pediatric age group. I just saw somebody who’s 13, and they’ve been bald for 8 years. You might make the argument that this person deserves treatment, at least for a period of time long enough to regrow their hair in order to reset the clock.”

The most common adverse events were acne and weight gain.

In a separate analysis, Dr. King, Dr. Craiglow, and Lucy Y. Liu, evaluated the use of tofacitinib for at least 2 months in 13 alopecia areata patients aged 12-17 years (J Am Acad Dermatol. 2017;76[1]:29-32). They limited the analysis to those who had greater than 20% scalp hair loss, alopecia totalis, or alopecia universalis that was stable or worsening for 6 months or longer. Of the 13 patients, 9 (69%) were responders. Of the four non-responders, one had a very long duration of baldness. The percent change in SALT score was 93% overall, including 100% in the responder group over a median of 5 months and just 1% in the non-responder group over a median of 4 months. “This does not work every time,” Dr. King said.

While some preliminary studies of topical JAK inhibitors for alopecia areata show promise, it remains unclear if this approach will translate in a clinically meaningful way, he said. Clinical trials are currently under way.

Dr. King disclosed that he has received honoraria or consulting fees from Aclaris Therapeutics, Celgene, Concert Pharmaceuticals, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, and Dermavant Sciences. He has also received funding support from The Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – After Brett King, MD, PhD, and his wife and collaborator, Brittany G. Craiglow, MD, published an index case of oral tofacitinib reversing alopecia universalis in a 25-year-old male patient back in 2014 (J Invest Dermatol. 2014;134:2988-90), they received hundreds of e-mails and phone calls from clinicians and patients.

“We also received quite a bit of media attention from around the world,” Dr. King recalled at the annual meeting of the Society for Pediatric Dermatology.

After all, alopecia areata and its variants affect 1%-2% of the population and have a marked impact on health-related quality of life, with high rates of concomitant generalized anxiety disorder and major depressive disorder. “The health-related quality of life is similar to that of atopic dermatitis and psoriasis, and there are no reliably effective therapies, especially for severe disease,” he said. “If treating atopic dermatitis and psoriasis with systemic agents is appropriate, then certainly treating alopecia areata is, too.”

Currently available Janus kinase (JAK) inhibitors include tofacitinib (Xeljanz), ruxolitinib (Jakafi), and baricitinib (Olumiant). “These medicines are not [Food and Drug Administration] approved for alopecia areata, though tofacitinib was recently approved for psoriatic arthritis, and so we have formal entry of this medicine into dermatology for the first time,” said Dr. King, who is a dermatologist at Yale University, New Haven, Conn.

Potential adverse effects of JAKs include nasopharyngitis, headache, diarrhea, elevated cholesterol, uncommonly herpes zoster, cytopenias, transaminitis, and rarely non-melanoma skin cancer, solid organ malignancy and lymphoma, and GI perforation. Tofacitinib has an FDA black box warning regarding serious infections and malignancies, and baricitinib has these plus an additional warning about thrombosis.

In an open label, two-center trial that followed the index patient report, Dr. King and his associates enrolled 66 patients aged 19-35 years who had greater than 50% scalp hair loss for at least 6 months to receive tofacitinib 5 mg twice daily for 3 months (JCI Insight. 2016; 1[15]:e89776). A primary outcome of interest was regrowth of hair as measured by the percent change in Severity of Alopecia Tool (SALT) score. A SALT score of 100 indicates baldness, while a score of zero indicates no hair loss. Following 3 months of treatment, 32% of patients had a greater than 50% change in their SALT score, 32% had a change in the range of 5%-50%, while 36% had a change that was less than 5%.

“One of the interesting findings was that long duration of current episode of complete scalp hair loss was a negative predictor of treatment response, especially for those who have had hair loss greater than 10 years,” Dr. King said. Adverse events were “pretty bland,” with the most common being upper respiratory infection (17%), headache (8%), abdominal pain (8%), and acne (8%). Weight gain occurred in 1.5% of patients.

Next, Dr. King and colleagues reviewed the records of 90 patients aged 18 years or older who were treated with tofacitinib for at least 4 months (J Am Acad Dermatol. 2017;76[1]:22-8). Patients had greater than 40% scalp hair loss, and the tofacitinib dose was up to 10 mg per day at the discretion of the physician. “About 43% of patients were treated with tofacitinib 5 mg” twice daily, Dr. King said. “Other patients had higher doses or the addition of prednisone for three doses to see if that would help.”

After treatment, 20% of patients had a greater than 90% change in their SALT score (complete scalp hair regrowth), while 38.4% had a change that ranged from 51%-90%. At the same time, 18% had a change in their SALT score that ranged from 6%-50%, while 23% had a change that was 5% or less. As observed in the earlier trial, researchers saw a negative correlation between duration of current episode of hair loss and latest percent change in SALT score.

“We believe that you have to catch people before they get to more than 10 years of complete scalp hair loss,” Dr. King said. “This is important for the pediatric age group. I just saw somebody who’s 13, and they’ve been bald for 8 years. You might make the argument that this person deserves treatment, at least for a period of time long enough to regrow their hair in order to reset the clock.”

The most common adverse events were acne and weight gain.

In a separate analysis, Dr. King, Dr. Craiglow, and Lucy Y. Liu, evaluated the use of tofacitinib for at least 2 months in 13 alopecia areata patients aged 12-17 years (J Am Acad Dermatol. 2017;76[1]:29-32). They limited the analysis to those who had greater than 20% scalp hair loss, alopecia totalis, or alopecia universalis that was stable or worsening for 6 months or longer. Of the 13 patients, 9 (69%) were responders. Of the four non-responders, one had a very long duration of baldness. The percent change in SALT score was 93% overall, including 100% in the responder group over a median of 5 months and just 1% in the non-responder group over a median of 4 months. “This does not work every time,” Dr. King said.

While some preliminary studies of topical JAK inhibitors for alopecia areata show promise, it remains unclear if this approach will translate in a clinically meaningful way, he said. Clinical trials are currently under way.

Dr. King disclosed that he has received honoraria or consulting fees from Aclaris Therapeutics, Celgene, Concert Pharmaceuticals, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, and Dermavant Sciences. He has also received funding support from The Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – Strong associations exist between intestinal dysbiosis and a wide variety of gut and systemic diseases, according to Mark A. Underwood, MD.

Doug Brunk/MDedge News

“Antibiotic exposure changes the composition of the intestinal microbiota,” he said at the annual meeting of the Society for Pediatric Dermatology. “That clearly causes both antibiotic-associated diarrhea and Clostridium difficile colitis. The bigger question is, is it possible that intestinal dysbiosis is related to a whole bunch of other systemic diseases? In other words, does an insult during a critical window of development cause changes in the intestinal microbiota that can lead to systemic diseases in the brain, the lung, the liver, or the immune system?”

According Dr. Underwood, a pediatrician who is chief of the division of neonatology at the University of California, Davis, the prevalence of dysbiosis is increasing worldwide, particularly in developed countries, where Bifidobacteria are decreasing and Enterobacteriaceae are increasing. “Those changes are associated with gut permeability and alterations in both local and systemic inflammation, and the risk for a number of diseases, including atopic dermatitis,” he said. Key reasons for the increasing prevalence of dysbiosis, he continued, include the use of antibiotics, cesarean section delivery, formula feeding, changes in hygiene that alter the intestinal biota, the high-fat, high-sugar Western diet, and a loss of vertical and horizontal transmission over generations.

In an effort to evaluate the association between early childhood antibiotic use with allergic diseases in later childhood, Japanese researchers followed 1,200 infants to the age of 5 years (Ann Allergy Asthma Immunol. 2017;119:54-8). They found that antibiotic exposure within the first 2 years of life was associated with an increased risk of asthma (adjusted odds ratio 1.72), allergic rhinitis (adjusted OR 1.65), and atopic dermatitis (adjusted OR 1.40). In a more recent, smaller prospective study, 436 Dutch infants were followed to 1 year of age (Pediatr Allergy Immunol. 2018;29[2]:151-8). The researchers found that antibiotic exposure within the first week of life was associated with allergic sensitization (adjusted OR 3.26), colic (adjusted OR 1.66), and wheezing (adjusted OR 1.56).

In a study of 44 term infants with a family history of allergy, changes in the fecal microbiota, especially colonization with Ruminococcus gnavus, preceded the onset of allergic symptoms (Gastroenterol. 2018;154[1]:154-67). The same researchers observed similar findings in an animal model.

One potential mechanism by which intestinal dysbiosis causes systemic disease is stimulation of toll-like receptor 4 (TLR4), “which is a receptor on a variety of mucosal cells that senses the presence of a microbial pathogen-associated patterns, particularly those of Gram-negative Enterobacteriaceae,” Dr. Underwood explained. Other potential mechanisms include increased intestinal permeability, an increase in the pH and decreases in short-chain fatty acids within the gut lumen, and a loss of intraluminal hypoxia. “Think of the colon as an anaerobic chamber,” he said. “The colon lumen should be very low in oxygen. It should be dominated by obligate anaerobes.”

Efforts to prevent or treat dysbiosis-related diseases include the use of probiotics and fecal transplantation. A recent Cochrane review of 8,672 patients found “moderate certainty evidence” that probiotics are effective for preventing C. difficile-associated diarrhea. The analysis included 31 randomized, controlled trials of adults who were treated either with a probiotic or with a placebo. When pooled, the risk ratio was 0.40, which represented a significant protection. In addition, a summary of 7 randomized controlled trials and 30 case series suggests that fecal microbial transplantation is superior to vancomycin for adults with recurrent C. difficile colitis (relative risk 0.23) (Aliment Pharmacol Ther. 2017;46[5]:470-93).

To date, the effect of giving probiotics to pregnant women who have a family history of allergy is less clear. One pooled analysis of such studies put the overall risk ratio at 0.74 (Mil Med. 2014;179[6]:580-92). “While I think the jury’s still out on how to best prevent atopic dermatitis in these families, it looks like there is some potential benefit in treating these moms during pregnancy with probiotics and treating the infant during the first few months of life,” Dr. Underwood said. The most effective were mixtures including one or more Lactobacillus species or L. rhamnosus, mixtures including one or more Bifidobacterium species, or B. lactis by itself. The use of probiotics also has been found to prevent necrotizing enterocolitis, sepsis, and death in premature infants (Semin Pediatr Surg. 2018;27[1]:39-46).

Dr. Underwood disclosed that he has received honoraria from Abbott and that he was a member of the scientific review board for Avexegen. He also chaired the data safety and monitoring board for Infant Bacterial Therapeutics and has received support from Evolve BioSystems to perform a clinical trial.

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – Strong associations exist between intestinal dysbiosis and a wide variety of gut and systemic diseases, according to Mark A. Underwood, MD.

Doug Brunk/MDedge News

“Antibiotic exposure changes the composition of the intestinal microbiota,” he said at the annual meeting of the Society for Pediatric Dermatology. “That clearly causes both antibiotic-associated diarrhea and Clostridium difficile colitis. The bigger question is, is it possible that intestinal dysbiosis is related to a whole bunch of other systemic diseases? In other words, does an insult during a critical window of development cause changes in the intestinal microbiota that can lead to systemic diseases in the brain, the lung, the liver, or the immune system?”

According Dr. Underwood, a pediatrician who is chief of the division of neonatology at the University of California, Davis, the prevalence of dysbiosis is increasing worldwide, particularly in developed countries, where Bifidobacteria are decreasing and Enterobacteriaceae are increasing. “Those changes are associated with gut permeability and alterations in both local and systemic inflammation, and the risk for a number of diseases, including atopic dermatitis,” he said. Key reasons for the increasing prevalence of dysbiosis, he continued, include the use of antibiotics, cesarean section delivery, formula feeding, changes in hygiene that alter the intestinal biota, the high-fat, high-sugar Western diet, and a loss of vertical and horizontal transmission over generations.

In an effort to evaluate the association between early childhood antibiotic use with allergic diseases in later childhood, Japanese researchers followed 1,200 infants to the age of 5 years (Ann Allergy Asthma Immunol. 2017;119:54-8). They found that antibiotic exposure within the first 2 years of life was associated with an increased risk of asthma (adjusted odds ratio 1.72), allergic rhinitis (adjusted OR 1.65), and atopic dermatitis (adjusted OR 1.40). In a more recent, smaller prospective study, 436 Dutch infants were followed to 1 year of age (Pediatr Allergy Immunol. 2018;29[2]:151-8). The researchers found that antibiotic exposure within the first week of life was associated with allergic sensitization (adjusted OR 3.26), colic (adjusted OR 1.66), and wheezing (adjusted OR 1.56).

In a study of 44 term infants with a family history of allergy, changes in the fecal microbiota, especially colonization with Ruminococcus gnavus, preceded the onset of allergic symptoms (Gastroenterol. 2018;154[1]:154-67). The same researchers observed similar findings in an animal model.

One potential mechanism by which intestinal dysbiosis causes systemic disease is stimulation of toll-like receptor 4 (TLR4), “which is a receptor on a variety of mucosal cells that senses the presence of a microbial pathogen-associated patterns, particularly those of Gram-negative Enterobacteriaceae,” Dr. Underwood explained. Other potential mechanisms include increased intestinal permeability, an increase in the pH and decreases in short-chain fatty acids within the gut lumen, and a loss of intraluminal hypoxia. “Think of the colon as an anaerobic chamber,” he said. “The colon lumen should be very low in oxygen. It should be dominated by obligate anaerobes.”

Efforts to prevent or treat dysbiosis-related diseases include the use of probiotics and fecal transplantation. A recent Cochrane review of 8,672 patients found “moderate certainty evidence” that probiotics are effective for preventing C. difficile-associated diarrhea. The analysis included 31 randomized, controlled trials of adults who were treated either with a probiotic or with a placebo. When pooled, the risk ratio was 0.40, which represented a significant protection. In addition, a summary of 7 randomized controlled trials and 30 case series suggests that fecal microbial transplantation is superior to vancomycin for adults with recurrent C. difficile colitis (relative risk 0.23) (Aliment Pharmacol Ther. 2017;46[5]:470-93).

To date, the effect of giving probiotics to pregnant women who have a family history of allergy is less clear. One pooled analysis of such studies put the overall risk ratio at 0.74 (Mil Med. 2014;179[6]:580-92). “While I think the jury’s still out on how to best prevent atopic dermatitis in these families, it looks like there is some potential benefit in treating these moms during pregnancy with probiotics and treating the infant during the first few months of life,” Dr. Underwood said. The most effective were mixtures including one or more Lactobacillus species or L. rhamnosus, mixtures including one or more Bifidobacterium species, or B. lactis by itself. The use of probiotics also has been found to prevent necrotizing enterocolitis, sepsis, and death in premature infants (Semin Pediatr Surg. 2018;27[1]:39-46).

Dr. Underwood disclosed that he has received honoraria from Abbott and that he was a member of the scientific review board for Avexegen. He also chaired the data safety and monitoring board for Infant Bacterial Therapeutics and has received support from Evolve BioSystems to perform a clinical trial.

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – Strong associations exist between intestinal dysbiosis and a wide variety of gut and systemic diseases, according to Mark A. Underwood, MD.

Doug Brunk/MDedge News

“Antibiotic exposure changes the composition of the intestinal microbiota,” he said at the annual meeting of the Society for Pediatric Dermatology. “That clearly causes both antibiotic-associated diarrhea and Clostridium difficile colitis. The bigger question is, is it possible that intestinal dysbiosis is related to a whole bunch of other systemic diseases? In other words, does an insult during a critical window of development cause changes in the intestinal microbiota that can lead to systemic diseases in the brain, the lung, the liver, or the immune system?”

According Dr. Underwood, a pediatrician who is chief of the division of neonatology at the University of California, Davis, the prevalence of dysbiosis is increasing worldwide, particularly in developed countries, where Bifidobacteria are decreasing and Enterobacteriaceae are increasing. “Those changes are associated with gut permeability and alterations in both local and systemic inflammation, and the risk for a number of diseases, including atopic dermatitis,” he said. Key reasons for the increasing prevalence of dysbiosis, he continued, include the use of antibiotics, cesarean section delivery, formula feeding, changes in hygiene that alter the intestinal biota, the high-fat, high-sugar Western diet, and a loss of vertical and horizontal transmission over generations.

In an effort to evaluate the association between early childhood antibiotic use with allergic diseases in later childhood, Japanese researchers followed 1,200 infants to the age of 5 years (Ann Allergy Asthma Immunol. 2017;119:54-8). They found that antibiotic exposure within the first 2 years of life was associated with an increased risk of asthma (adjusted odds ratio 1.72), allergic rhinitis (adjusted OR 1.65), and atopic dermatitis (adjusted OR 1.40). In a more recent, smaller prospective study, 436 Dutch infants were followed to 1 year of age (Pediatr Allergy Immunol. 2018;29[2]:151-8). The researchers found that antibiotic exposure within the first week of life was associated with allergic sensitization (adjusted OR 3.26), colic (adjusted OR 1.66), and wheezing (adjusted OR 1.56).

In a study of 44 term infants with a family history of allergy, changes in the fecal microbiota, especially colonization with Ruminococcus gnavus, preceded the onset of allergic symptoms (Gastroenterol. 2018;154[1]:154-67). The same researchers observed similar findings in an animal model.

One potential mechanism by which intestinal dysbiosis causes systemic disease is stimulation of toll-like receptor 4 (TLR4), “which is a receptor on a variety of mucosal cells that senses the presence of a microbial pathogen-associated patterns, particularly those of Gram-negative Enterobacteriaceae,” Dr. Underwood explained. Other potential mechanisms include increased intestinal permeability, an increase in the pH and decreases in short-chain fatty acids within the gut lumen, and a loss of intraluminal hypoxia. “Think of the colon as an anaerobic chamber,” he said. “The colon lumen should be very low in oxygen. It should be dominated by obligate anaerobes.”

Efforts to prevent or treat dysbiosis-related diseases include the use of probiotics and fecal transplantation. A recent Cochrane review of 8,672 patients found “moderate certainty evidence” that probiotics are effective for preventing C. difficile-associated diarrhea. The analysis included 31 randomized, controlled trials of adults who were treated either with a probiotic or with a placebo. When pooled, the risk ratio was 0.40, which represented a significant protection. In addition, a summary of 7 randomized controlled trials and 30 case series suggests that fecal microbial transplantation is superior to vancomycin for adults with recurrent C. difficile colitis (relative risk 0.23) (Aliment Pharmacol Ther. 2017;46[5]:470-93).

To date, the effect of giving probiotics to pregnant women who have a family history of allergy is less clear. One pooled analysis of such studies put the overall risk ratio at 0.74 (Mil Med. 2014;179[6]:580-92). “While I think the jury’s still out on how to best prevent atopic dermatitis in these families, it looks like there is some potential benefit in treating these moms during pregnancy with probiotics and treating the infant during the first few months of life,” Dr. Underwood said. The most effective were mixtures including one or more Lactobacillus species or L. rhamnosus, mixtures including one or more Bifidobacterium species, or B. lactis by itself. The use of probiotics also has been found to prevent necrotizing enterocolitis, sepsis, and death in premature infants (Semin Pediatr Surg. 2018;27[1]:39-46).

Dr. Underwood disclosed that he has received honoraria from Abbott and that he was a member of the scientific review board for Avexegen. He also chaired the data safety and monitoring board for Infant Bacterial Therapeutics and has received support from Evolve BioSystems to perform a clinical trial.

dbrunk@mdedge.com

CHICAGO – Though research shows that nail fungus occurs in just 0.3% of pediatric patients in the United States, that’s not what Sheila Friedlander, MD, is seeing in her southern California practice, where it’s not uncommon to see children whose nails, toe nails in particular, have fungal involvement.

fotokostic/iStock/Getty Images

“I know I started out telling you fungus isn’t that common in children … but you do need to think about it,” said Dr. Friedlander during a nail-focused session at the annual summer meeting of the American Academy of Dermatology. Dr. Friedlander, professor of dermatology and pediatrics at the University of California San Diego and Rady Children’s Hospital, said that she suspects that more participation in organized sports at a young age may be contributing to the increase, with occlusive sports footwear replacing bare feet or sandals for more hours of the day, presenting more opportunities for toenail trauma in sports such as soccer.

When making the clinical call about a nail problem, bear in mind that the younger the child, the less likely a nail problem is fungal, Dr. Friedlander noted. “Little children are much less likely than older children to have nail fungus. Pediatric nails are thinner, and they are faster growing, with better blood supply to the matrix.”

And if frank onychomadesis is observed, think about the time of year, and ask about recent fevers and rashes, because coxsackievirus may be the culprit. “Be not afraid, and look everywhere if the nail is confusing to you,” she said. In all ages, the diagnosis is primarily clinical, “but I culture them, I ‘PAS’ [periodic acid-Schiff stain] them, too. If you do both, you’ll increase your yield,” Dr. Friedlander said, adding, “the beauty of PAS is you can use it to give your families an answer very soon.”

Once you’ve established that fungus is to blame for a nail problem, there’s a conundrum: There are no Food and Drug Administration-approved therapies, either topical or systemic, for pediatric onychomycosis, Dr. Friedlander said. She, along with coauthors and first author Aditya Gupta, MD, of Mediprobe Research, London, Ontario, Canada, recently published an article reviewing the safety and efficacy of antifungal agents in this age group (Pediatr Dermatol. 2018 Jun 26. doi: 10.1111/pde.13561).

Reviewing information available in the United States and Canada, Dr. Friedlander and her coauthors came up with three topical and four oral options for children, along with recommendations for dosage and duration.

In response to an audience question about the use of topical antifungal treatment for nail involvement, Dr. Friedlander responded, “I think topicals would be great for kids, but it’s for kids where there is no nail matrix involvement. Also, cost is a problem. Nobody will cover it. But some families are willing to do this to avoid systemic therapy,” and if the family budget can accommodate a topical choice, it’s a logical option, she said, noting that partial reimbursement via a coupon system is available from some pharmaceutical companies.

Where appropriate, ciclopirox 8%, efinaconazole 10%, and tavaborole 5% can each be considered. Dr. Friedlander cited one study she coauthored, which reported that 70% of pediatric participants with nonmatrix onychomycosis saw effective treatment, with a 71% mycological cure rate (P = .03), after 32 weeks of treatment with ciclopirox lacquer versus vehicle (Pediatr Dermatol. 2013 May-Jun;30[3]:316-22).

Systemic therapies – which, when studied, have been given at tinea capitis doses – could include griseofulvin, terbinafine, itraconazole, and fluconazole.

In terms of oral options, Dr. Friedlander said, griseofulvin has some practical limitations. While prolonged treatment is required in any case, terbinafine may produce results in about 3 months, whereas griseofulvin may require up to 9 months of therapy. “I always try to use terbinafine … griseofulvin takes a year and a day,” she said.

She also shared some tips to improve pediatric adherence with oral antifungals: “You can tell parents to crush terbinafine tablets and mix in peanut butter or applesauce to improve adherence. Griseofulvin can be flavored by the pharmacy, but volumes are big with griseofulvin, so it’s a challenge to get kids to take it all,” she said.

Dr. Friedlander reported that she had no relevant financial disclosures.

koakes@mdedge.com



 

CHICAGO – Though research shows that nail fungus occurs in just 0.3% of pediatric patients in the United States, that’s not what Sheila Friedlander, MD, is seeing in her southern California practice, where it’s not uncommon to see children whose nails, toe nails in particular, have fungal involvement.

fotokostic/iStock/Getty Images

“I know I started out telling you fungus isn’t that common in children … but you do need to think about it,” said Dr. Friedlander during a nail-focused session at the annual summer meeting of the American Academy of Dermatology. Dr. Friedlander, professor of dermatology and pediatrics at the University of California San Diego and Rady Children’s Hospital, said that she suspects that more participation in organized sports at a young age may be contributing to the increase, with occlusive sports footwear replacing bare feet or sandals for more hours of the day, presenting more opportunities for toenail trauma in sports such as soccer.

When making the clinical call about a nail problem, bear in mind that the younger the child, the less likely a nail problem is fungal, Dr. Friedlander noted. “Little children are much less likely than older children to have nail fungus. Pediatric nails are thinner, and they are faster growing, with better blood supply to the matrix.”

And if frank onychomadesis is observed, think about the time of year, and ask about recent fevers and rashes, because coxsackievirus may be the culprit. “Be not afraid, and look everywhere if the nail is confusing to you,” she said. In all ages, the diagnosis is primarily clinical, “but I culture them, I ‘PAS’ [periodic acid-Schiff stain] them, too. If you do both, you’ll increase your yield,” Dr. Friedlander said, adding, “the beauty of PAS is you can use it to give your families an answer very soon.”

Once you’ve established that fungus is to blame for a nail problem, there’s a conundrum: There are no Food and Drug Administration-approved therapies, either topical or systemic, for pediatric onychomycosis, Dr. Friedlander said. She, along with coauthors and first author Aditya Gupta, MD, of Mediprobe Research, London, Ontario, Canada, recently published an article reviewing the safety and efficacy of antifungal agents in this age group (Pediatr Dermatol. 2018 Jun 26. doi: 10.1111/pde.13561).

Reviewing information available in the United States and Canada, Dr. Friedlander and her coauthors came up with three topical and four oral options for children, along with recommendations for dosage and duration.

In response to an audience question about the use of topical antifungal treatment for nail involvement, Dr. Friedlander responded, “I think topicals would be great for kids, but it’s for kids where there is no nail matrix involvement. Also, cost is a problem. Nobody will cover it. But some families are willing to do this to avoid systemic therapy,” and if the family budget can accommodate a topical choice, it’s a logical option, she said, noting that partial reimbursement via a coupon system is available from some pharmaceutical companies.

Where appropriate, ciclopirox 8%, efinaconazole 10%, and tavaborole 5% can each be considered. Dr. Friedlander cited one study she coauthored, which reported that 70% of pediatric participants with nonmatrix onychomycosis saw effective treatment, with a 71% mycological cure rate (P = .03), after 32 weeks of treatment with ciclopirox lacquer versus vehicle (Pediatr Dermatol. 2013 May-Jun;30[3]:316-22).

Systemic therapies – which, when studied, have been given at tinea capitis doses – could include griseofulvin, terbinafine, itraconazole, and fluconazole.

In terms of oral options, Dr. Friedlander said, griseofulvin has some practical limitations. While prolonged treatment is required in any case, terbinafine may produce results in about 3 months, whereas griseofulvin may require up to 9 months of therapy. “I always try to use terbinafine … griseofulvin takes a year and a day,” she said.

She also shared some tips to improve pediatric adherence with oral antifungals: “You can tell parents to crush terbinafine tablets and mix in peanut butter or applesauce to improve adherence. Griseofulvin can be flavored by the pharmacy, but volumes are big with griseofulvin, so it’s a challenge to get kids to take it all,” she said.

Dr. Friedlander reported that she had no relevant financial disclosures.

koakes@mdedge.com



 

CHICAGO – Though research shows that nail fungus occurs in just 0.3% of pediatric patients in the United States, that’s not what Sheila Friedlander, MD, is seeing in her southern California practice, where it’s not uncommon to see children whose nails, toe nails in particular, have fungal involvement.

fotokostic/iStock/Getty Images

“I know I started out telling you fungus isn’t that common in children … but you do need to think about it,” said Dr. Friedlander during a nail-focused session at the annual summer meeting of the American Academy of Dermatology. Dr. Friedlander, professor of dermatology and pediatrics at the University of California San Diego and Rady Children’s Hospital, said that she suspects that more participation in organized sports at a young age may be contributing to the increase, with occlusive sports footwear replacing bare feet or sandals for more hours of the day, presenting more opportunities for toenail trauma in sports such as soccer.

When making the clinical call about a nail problem, bear in mind that the younger the child, the less likely a nail problem is fungal, Dr. Friedlander noted. “Little children are much less likely than older children to have nail fungus. Pediatric nails are thinner, and they are faster growing, with better blood supply to the matrix.”

And if frank onychomadesis is observed, think about the time of year, and ask about recent fevers and rashes, because coxsackievirus may be the culprit. “Be not afraid, and look everywhere if the nail is confusing to you,” she said. In all ages, the diagnosis is primarily clinical, “but I culture them, I ‘PAS’ [periodic acid-Schiff stain] them, too. If you do both, you’ll increase your yield,” Dr. Friedlander said, adding, “the beauty of PAS is you can use it to give your families an answer very soon.”

Once you’ve established that fungus is to blame for a nail problem, there’s a conundrum: There are no Food and Drug Administration-approved therapies, either topical or systemic, for pediatric onychomycosis, Dr. Friedlander said. She, along with coauthors and first author Aditya Gupta, MD, of Mediprobe Research, London, Ontario, Canada, recently published an article reviewing the safety and efficacy of antifungal agents in this age group (Pediatr Dermatol. 2018 Jun 26. doi: 10.1111/pde.13561).

Reviewing information available in the United States and Canada, Dr. Friedlander and her coauthors came up with three topical and four oral options for children, along with recommendations for dosage and duration.

In response to an audience question about the use of topical antifungal treatment for nail involvement, Dr. Friedlander responded, “I think topicals would be great for kids, but it’s for kids where there is no nail matrix involvement. Also, cost is a problem. Nobody will cover it. But some families are willing to do this to avoid systemic therapy,” and if the family budget can accommodate a topical choice, it’s a logical option, she said, noting that partial reimbursement via a coupon system is available from some pharmaceutical companies.

Where appropriate, ciclopirox 8%, efinaconazole 10%, and tavaborole 5% can each be considered. Dr. Friedlander cited one study she coauthored, which reported that 70% of pediatric participants with nonmatrix onychomycosis saw effective treatment, with a 71% mycological cure rate (P = .03), after 32 weeks of treatment with ciclopirox lacquer versus vehicle (Pediatr Dermatol. 2013 May-Jun;30[3]:316-22).

Systemic therapies – which, when studied, have been given at tinea capitis doses – could include griseofulvin, terbinafine, itraconazole, and fluconazole.

In terms of oral options, Dr. Friedlander said, griseofulvin has some practical limitations. While prolonged treatment is required in any case, terbinafine may produce results in about 3 months, whereas griseofulvin may require up to 9 months of therapy. “I always try to use terbinafine … griseofulvin takes a year and a day,” she said.

She also shared some tips to improve pediatric adherence with oral antifungals: “You can tell parents to crush terbinafine tablets and mix in peanut butter or applesauce to improve adherence. Griseofulvin can be flavored by the pharmacy, but volumes are big with griseofulvin, so it’s a challenge to get kids to take it all,” she said.

Dr. Friedlander reported that she had no relevant financial disclosures.

koakes@mdedge.com



 

Photo by Rhoda Baer

Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.

The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.

The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.

For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.

However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.

Recommendations

The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.

Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.

Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.

However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.

Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.

Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.

Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.

Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.

Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.

The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.

The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.

Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.

Photo by Rhoda Baer

Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.

The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.

The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.

For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.

However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.

Recommendations

The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.

Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.

Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.

However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.

Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.

Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.

Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.

Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.

Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.

The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.

The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.

Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.

Photo by Rhoda Baer

Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.

The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.

The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.

For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.

However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.

Recommendations

The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.

Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.

Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.

However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.

Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.

Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.

Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.

Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.

Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.

The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.

The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.

Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.

Most clinicians do not think about receptor occupancy when they prescribe a medication. Most simply assume that if they use a low dose of a medication, they will get a small effect, and if they use a higher dose, they will get a larger effect. However, this is frequently not accurate. Clinicians need to understand the relationship between receptor occupancy and drug response.

In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor.^1-3 Similarly, despite significant variability in antidepressant response,⁴ blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants,^5,6 or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline⁷—is necessary for these medications to be effective.

It is reasonable to think of the drug response of such agents as following a “threshold” model (Figure 1). This model makes 2 predictions. The first prediction is that a low dose of the drug might result in <50% receptor occupancy, but is not associated with a smaller response; it is simply ineffective. The second prediction is that a very high dose of the drug (eg, one that may exceed 90% receptor occupancy) does not result in any additional benefit, but may cause additional adverse consequences.⁸

Alternatively, agonist medications, such as benzodiazepines or opiates, have their efficacy in a continuous dose-dependent fashion (Figure 2). Titrating these medications for clinical response is necessary, and minimal effective doses are highly individual. Agonist medications will not be addressed further in this article.

In this article, the term “response” is used to denote the average (population) symptom change in a study population. This term is not used as clinicians often use it to mean that their specific patient’s illness has improved, or that the patient has gone into remission. Furthermore, the information described in this article does not optimize clinical outcome, but instead is intended to help clinicians optimize the use of their pharmacologic tools.

Minimal effective dose

Medications that have a threshold for activity will display that clinically in a minimal effective dose (Table 1^3,9 and Table 2⁵). The minimal effective dose of medications that act by blocking a neurotransmitter receptor is usually the dose that achieves 65% to 80% receptor occupancy in typical individuals (Table 2⁵). The minimal effective doses for antipsychotics are listed in Table 1.^3,9 These doses are known to occupy approximately 65% to 70% of postsynaptic D2 receptors in living humans as confirmed by positron emission tomography (PET) scans.¹⁰ Similar minimal effective doses can be determined for serotonin-reuptake inhibiting (SRI) antidepressants (Table 2⁵). In placebo-controlled trials, doses that were smaller than the minimal effective dose did not provide any benefit.

There are important caveats to this. First is the use of partial agonists. Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations.¹¹ Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%.^12-14 Since aripiprazole has an intrinsic activity of approximately 30% (ie, when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor¹⁵), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls.¹⁶ Clinically, this still appears as the minimal effective dose achieving maximal response^17-19 without significant parkinsonism despite >90% receptor occupancy.¹²

Continue to: The second caveat is...

The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.²⁰ It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.^21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by cloza­pine²³ compared with other second-generation antipsychotics such as risperidone and olanzapine,^24,25 although this point remains debatable.²⁶ Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study²⁷). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.

Minimal effective dose achieves maximal response

An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.^18,28,29

For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.²⁸ Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.³⁰ When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.²⁹ This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.¹⁸

Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.³¹ Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.^32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.³⁴

Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.³ This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.³⁵ Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).³⁶ For both quetiapine and lurasidone, higher doses are generally required to control psychosis.^29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.⁹

Continue to: Clinical implications

 

 

Clinical implications

The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.

Related Resource

• Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon

Most clinicians do not think about receptor occupancy when they prescribe a medication. Most simply assume that if they use a low dose of a medication, they will get a small effect, and if they use a higher dose, they will get a larger effect. However, this is frequently not accurate. Clinicians need to understand the relationship between receptor occupancy and drug response.

In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor.^1-3 Similarly, despite significant variability in antidepressant response,⁴ blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants,^5,6 or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline⁷—is necessary for these medications to be effective.

It is reasonable to think of the drug response of such agents as following a “threshold” model (Figure 1). This model makes 2 predictions. The first prediction is that a low dose of the drug might result in <50% receptor occupancy, but is not associated with a smaller response; it is simply ineffective. The second prediction is that a very high dose of the drug (eg, one that may exceed 90% receptor occupancy) does not result in any additional benefit, but may cause additional adverse consequences.⁸

Alternatively, agonist medications, such as benzodiazepines or opiates, have their efficacy in a continuous dose-dependent fashion (Figure 2). Titrating these medications for clinical response is necessary, and minimal effective doses are highly individual. Agonist medications will not be addressed further in this article.

In this article, the term “response” is used to denote the average (population) symptom change in a study population. This term is not used as clinicians often use it to mean that their specific patient’s illness has improved, or that the patient has gone into remission. Furthermore, the information described in this article does not optimize clinical outcome, but instead is intended to help clinicians optimize the use of their pharmacologic tools.

Minimal effective dose

Medications that have a threshold for activity will display that clinically in a minimal effective dose (Table 1^3,9 and Table 2⁵). The minimal effective dose of medications that act by blocking a neurotransmitter receptor is usually the dose that achieves 65% to 80% receptor occupancy in typical individuals (Table 2⁵). The minimal effective doses for antipsychotics are listed in Table 1.^3,9 These doses are known to occupy approximately 65% to 70% of postsynaptic D2 receptors in living humans as confirmed by positron emission tomography (PET) scans.¹⁰ Similar minimal effective doses can be determined for serotonin-reuptake inhibiting (SRI) antidepressants (Table 2⁵). In placebo-controlled trials, doses that were smaller than the minimal effective dose did not provide any benefit.

There are important caveats to this. First is the use of partial agonists. Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations.¹¹ Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%.^12-14 Since aripiprazole has an intrinsic activity of approximately 30% (ie, when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor¹⁵), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls.¹⁶ Clinically, this still appears as the minimal effective dose achieving maximal response^17-19 without significant parkinsonism despite >90% receptor occupancy.¹²

Continue to: The second caveat is...

The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.²⁰ It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.^21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by cloza­pine²³ compared with other second-generation antipsychotics such as risperidone and olanzapine,^24,25 although this point remains debatable.²⁶ Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study²⁷). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.

Minimal effective dose achieves maximal response

An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.^18,28,29

For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.²⁸ Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.³⁰ When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.²⁹ This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.¹⁸

Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.³¹ Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.^32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.³⁴

Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.³ This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.³⁵ Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).³⁶ For both quetiapine and lurasidone, higher doses are generally required to control psychosis.^29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.⁹

Continue to: Clinical implications

 

 

Clinical implications

The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.

Related Resource

• Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon

Most clinicians do not think about receptor occupancy when they prescribe a medication. Most simply assume that if they use a low dose of a medication, they will get a small effect, and if they use a higher dose, they will get a larger effect. However, this is frequently not accurate. Clinicians need to understand the relationship between receptor occupancy and drug response.

In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor.^1-3 Similarly, despite significant variability in antidepressant response,⁴ blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants,^5,6 or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline⁷—is necessary for these medications to be effective.

It is reasonable to think of the drug response of such agents as following a “threshold” model (Figure 1). This model makes 2 predictions. The first prediction is that a low dose of the drug might result in <50% receptor occupancy, but is not associated with a smaller response; it is simply ineffective. The second prediction is that a very high dose of the drug (eg, one that may exceed 90% receptor occupancy) does not result in any additional benefit, but may cause additional adverse consequences.⁸

Alternatively, agonist medications, such as benzodiazepines or opiates, have their efficacy in a continuous dose-dependent fashion (Figure 2). Titrating these medications for clinical response is necessary, and minimal effective doses are highly individual. Agonist medications will not be addressed further in this article.

In this article, the term “response” is used to denote the average (population) symptom change in a study population. This term is not used as clinicians often use it to mean that their specific patient’s illness has improved, or that the patient has gone into remission. Furthermore, the information described in this article does not optimize clinical outcome, but instead is intended to help clinicians optimize the use of their pharmacologic tools.

Minimal effective dose

Medications that have a threshold for activity will display that clinically in a minimal effective dose (Table 1^3,9 and Table 2⁵). The minimal effective dose of medications that act by blocking a neurotransmitter receptor is usually the dose that achieves 65% to 80% receptor occupancy in typical individuals (Table 2⁵). The minimal effective doses for antipsychotics are listed in Table 1.^3,9 These doses are known to occupy approximately 65% to 70% of postsynaptic D2 receptors in living humans as confirmed by positron emission tomography (PET) scans.¹⁰ Similar minimal effective doses can be determined for serotonin-reuptake inhibiting (SRI) antidepressants (Table 2⁵). In placebo-controlled trials, doses that were smaller than the minimal effective dose did not provide any benefit.

There are important caveats to this. First is the use of partial agonists. Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example, aripiprazole will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations.¹¹ Unlike antagonist antipsychotics, which require only 65% to 70% D2 receptor occupancy to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%.^12-14 Since aripiprazole has an intrinsic activity of approximately 30% (ie, when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor¹⁵), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls.¹⁶ Clinically, this still appears as the minimal effective dose achieving maximal response^17-19 without significant parkinsonism despite >90% receptor occupancy.¹²

Continue to: The second caveat is...

The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.²⁰ It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.^21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by cloza­pine²³ compared with other second-generation antipsychotics such as risperidone and olanzapine,^24,25 although this point remains debatable.²⁶ Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study²⁷). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.

Minimal effective dose achieves maximal response

An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.^18,28,29

For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.²⁸ Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.³⁰ When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.²⁹ This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.¹⁸

Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.³¹ Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.^32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.³⁴

Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.³ This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.³⁵ Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).³⁶ For both quetiapine and lurasidone, higher doses are generally required to control psychosis.^29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.⁹

Continue to: Clinical implications

 

 

Clinical implications

The implications for clinicians are relatively clear. Knowing the minimal effective doses for depression, psychosis, or mania informs the target dose. If improvement is seen at lower doses, the clinician needs to assess the profile of symptoms that improved, potential drug–drug interactions, or potential irregularities in the patient’s metabolic pathways. Clinicians need to increase doses above the minimally effective dose carefully, and expend additional effort in analyzing changes in their patient’s symptoms and adverse effects; this analysis should be performed with skepticism and willingness to reduce a dosage if no additional benefit is seen. Attention to these receptor-symptom interactions will improve response and reduce adverse consequences in the majority of patients.

Related Resource

• Lako IM, van den Heuvel ER, Knegtering H, et al. Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. J Clin Psychopharmacol. 2013;33(5):675-681.

Drug Brand Names

Aripiprazole • Abilify
Asenapine • Saphris
Citalopram • Celexa
Clozapine • Clozaril
Fluoxetine • Prozac
Haloperidol • Haldol
Iloperidone • Fanapt
Lurasidone • Latuda
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Paroxetine • Paxil
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Venlafaxine • Effexor
Ziprasidone • Geodon