Key clinical point: Galcanezumab is safe and effective in the prophylactic treatment of adult migraine.

Major finding: Compared with placebo, galcanezumab at doses of 120, 150, 240, and 300 mg significantly reduced monthly migraine days (mean difference [MD], −1.79, −1.20, −1.85, and –0.62, respectively). Reduction in migraine-specific medication days was statistically significant for galcanezumab doses of 120 and 240 mg vs. placebo. Total adverse events did not differ significantly between galcanezumab and placebo.

Study details: Meta-analysis of 5 studies evaluated the safety and efficacy of galcanezumab in the prophylactic treatment of adult migraine. 

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Citation: Zhao X et al. J Neurol. 2020 Jan 31. doi: 10.1007/s00415-020-09707-5. 

Key clinical point: Galcanezumab is safe and effective in the prophylactic treatment of adult migraine.

Major finding: Compared with placebo, galcanezumab at doses of 120, 150, 240, and 300 mg significantly reduced monthly migraine days (mean difference [MD], −1.79, −1.20, −1.85, and –0.62, respectively). Reduction in migraine-specific medication days was statistically significant for galcanezumab doses of 120 and 240 mg vs. placebo. Total adverse events did not differ significantly between galcanezumab and placebo.

Study details: Meta-analysis of 5 studies evaluated the safety and efficacy of galcanezumab in the prophylactic treatment of adult migraine. 

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Citation: Zhao X et al. J Neurol. 2020 Jan 31. doi: 10.1007/s00415-020-09707-5. 

Key clinical point: Galcanezumab is safe and effective in the prophylactic treatment of adult migraine.

Major finding: Compared with placebo, galcanezumab at doses of 120, 150, 240, and 300 mg significantly reduced monthly migraine days (mean difference [MD], −1.79, −1.20, −1.85, and –0.62, respectively). Reduction in migraine-specific medication days was statistically significant for galcanezumab doses of 120 and 240 mg vs. placebo. Total adverse events did not differ significantly between galcanezumab and placebo.

Study details: Meta-analysis of 5 studies evaluated the safety and efficacy of galcanezumab in the prophylactic treatment of adult migraine. 

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Citation: Zhao X et al. J Neurol. 2020 Jan 31. doi: 10.1007/s00415-020-09707-5. 

Amid the growing SARS-CoV-2 pandemic, currently in its expansive growth phase in the United States, the American Gastroenterological Association (AGA), the American Association for the Study of Liver Diseases (AASLD), the American College of Gastroenterology (ACG), and the American Society for Gastrointestinal Endoscopy (ASGE) have jointly released “COVID-19 Clinical Insights for Our Community of Gastroenterologists and Gastroenterology Care Providers,” which can be found on the websites of the various societies.

“The purpose of this communication is to jointly provide you with up to date COVID-19 information in order to maintain the highest level of health and safety for our patients, staff, community, and ourselves,” according to the AGA website announcement.

In particular, the societies point out that there is recent evidence suggesting the potential for coronavirus transmission through droplets and perhaps fecal shedding, which pose potential risks in particular during endoscopy and colonoscopy procedures to other patients, endoscopy personnel, and practitioners.

Relevant clinical factors related to COVID-19 are discussed, including the fact that asymptomatic spread can occur during the prodromal phase (the mean incubation period is approximately 5 days, with a range of 0-14 days), with viral shedding greatest when symptoms begin.

Between 20% and 30% of patients with COVID-19 infection show abnormal liver enzymes. In addition, COVID-19 patients show drops in their leukocyte counts, and elevated white blood cell counts is a poor prognostic sign, according to the release.

The Centers for Disease Control and Prevention lists vulnerable populations at the greatest risk for more serious outcomes; these include the elderly and those with severe chronic health conditions, such as heart disease, lung disease, diabetes, decompensated cirrhosis, HIV with low CD4 counts, and immunosuppression (including liver and other solid organ transplant recipients), are at higher risk of developing more serious illness. In addition pregnancy may provide added risk.
 

Specific advice for the gastroenterology profession

The joint statement urges that practitioners strongly consider rescheduling elective nonurgent endoscopic procedures, although some nonurgent procedures are higher priority and may need to be performed, including cancer evaluations, prosthetic removals, and evaluation of significant symptoms. “Of note, the Surgeon General on 3/14/20 advised hospitals to postpone all elective surgeries,” the document states.

Patient concerns

In all cases, patients should be prescreened for high-risk exposure or symptoms. This includes asking about history of fever or respiratory symptoms, family members or close contacts with similar symptoms, any contact with a confirmed case of COVID-19, and recent travel to a high-risk area. “Avoid bringing patients (or their escorts) into the medical facility who are over age 65 or have one of the CDC recognized risks listed above,” the societies advise.

Check body temperature of the patient upon arrival at endoscopy unit or clinic, and keep all patients at an appropriate distance from each other (6 feet is recommended) throughout the entire time in the endoscopy unit.

“For COVID-19 positive patients, or those awaiting test results, isolation precautions should be taken with procedures performed in negative pressure rooms,” according to the statement.

In addition, use telemedicine where possible in elective cases, and consider phone follow-up after any procedures at 7 and 14 days to ask about new diagnosis of COVID-19 or development of its symptoms, .

Those patients who are on immunosuppressive drugs for inflammatory bowel disease and autoimmune hepatitis should continue taking their medications because the risk of disease flare outweighs the chance of contracting coronavirus, according to the document. In addition, these patients should be advised to follow CDC guidelines for at-risk groups by avoiding crowds and limiting travel.
 

Protection of practitioners

Key factors in ensuring practitioner safety and maintaining practice functionality are discussed by the joint document. In particular, appropriate personal protective equipment (PPE) should be worn by all members of the endoscopy team: gloves, mask, eye shield/goggles, face shields, and gown, but practitioners should also be aware of how to put on and take off PPE appropriately.

“Conservation of PPE is critical. Only essential personnel should be present in cases. Consider extended use or reuse of surgical masks and eye protection in accordance with hospital policies,” the document recommends.

“It is important to address our collective staff needs and institute policies that protect our workforce.” To that end, the document recommends that centers should strategically assign available personnel in order to minimize concomitant exposure of those with similar or unique skill sets. This includes the use of nonphysician practitioners and fellows that cannot participate in cases for screening and triaging patients, or performing virtual visits.

Coming at a time of pandemic, when gastrointestinal symptoms have been recognized as a more common symptom of COVID-19 than previously expected and liver damage has been noted as a potential repercussion of SARS-CoV-2 infection, these clinical insights provide a template for gastroenterologists and related professionals for dealing with their patients and keeping themselves safe under dramatically changed circumstances.

The partnered organizations, AASLD, ACG, AGA, and ASGE, are committed to providing updated COVID-19 information as appropriate. However: “Given the evolving and fluid nature of the situation, institutions, hospitals and clinics have also been formulating their own local guidelines, so we urge you to follow the evolving CDC recommendations and your local requirements,” according to the AGA website announcement.

In addition to the joint communication, the society websites each offer additional COVID-19 information. The AGA practice updates on the COVID-19 webpage provides information about announcements, such as the cancellation of Digestive Disease Week^® in May, a location for AGA members to discuss their COVID-19 experiences and share advice, and links to the CDC COVID-19 updates.
 

mlesney@mdedge.com

SOURCE: American Gastroenterological Association et al. March 2020, COVID-19 Clinical Insights for Our Community of Gastroenterologists and Gastroenterology Care Providers.

Amid the growing SARS-CoV-2 pandemic, currently in its expansive growth phase in the United States, the American Gastroenterological Association (AGA), the American Association for the Study of Liver Diseases (AASLD), the American College of Gastroenterology (ACG), and the American Society for Gastrointestinal Endoscopy (ASGE) have jointly released “COVID-19 Clinical Insights for Our Community of Gastroenterologists and Gastroenterology Care Providers,” which can be found on the websites of the various societies.

“The purpose of this communication is to jointly provide you with up to date COVID-19 information in order to maintain the highest level of health and safety for our patients, staff, community, and ourselves,” according to the AGA website announcement.

In particular, the societies point out that there is recent evidence suggesting the potential for coronavirus transmission through droplets and perhaps fecal shedding, which pose potential risks in particular during endoscopy and colonoscopy procedures to other patients, endoscopy personnel, and practitioners.

Relevant clinical factors related to COVID-19 are discussed, including the fact that asymptomatic spread can occur during the prodromal phase (the mean incubation period is approximately 5 days, with a range of 0-14 days), with viral shedding greatest when symptoms begin.

Between 20% and 30% of patients with COVID-19 infection show abnormal liver enzymes. In addition, COVID-19 patients show drops in their leukocyte counts, and elevated white blood cell counts is a poor prognostic sign, according to the release.

The Centers for Disease Control and Prevention lists vulnerable populations at the greatest risk for more serious outcomes; these include the elderly and those with severe chronic health conditions, such as heart disease, lung disease, diabetes, decompensated cirrhosis, HIV with low CD4 counts, and immunosuppression (including liver and other solid organ transplant recipients), are at higher risk of developing more serious illness. In addition pregnancy may provide added risk.
 

Specific advice for the gastroenterology profession

The joint statement urges that practitioners strongly consider rescheduling elective nonurgent endoscopic procedures, although some nonurgent procedures are higher priority and may need to be performed, including cancer evaluations, prosthetic removals, and evaluation of significant symptoms. “Of note, the Surgeon General on 3/14/20 advised hospitals to postpone all elective surgeries,” the document states.

Patient concerns

In all cases, patients should be prescreened for high-risk exposure or symptoms. This includes asking about history of fever or respiratory symptoms, family members or close contacts with similar symptoms, any contact with a confirmed case of COVID-19, and recent travel to a high-risk area. “Avoid bringing patients (or their escorts) into the medical facility who are over age 65 or have one of the CDC recognized risks listed above,” the societies advise.

Check body temperature of the patient upon arrival at endoscopy unit or clinic, and keep all patients at an appropriate distance from each other (6 feet is recommended) throughout the entire time in the endoscopy unit.

“For COVID-19 positive patients, or those awaiting test results, isolation precautions should be taken with procedures performed in negative pressure rooms,” according to the statement.

In addition, use telemedicine where possible in elective cases, and consider phone follow-up after any procedures at 7 and 14 days to ask about new diagnosis of COVID-19 or development of its symptoms, .

Those patients who are on immunosuppressive drugs for inflammatory bowel disease and autoimmune hepatitis should continue taking their medications because the risk of disease flare outweighs the chance of contracting coronavirus, according to the document. In addition, these patients should be advised to follow CDC guidelines for at-risk groups by avoiding crowds and limiting travel.
 

Protection of practitioners

Key factors in ensuring practitioner safety and maintaining practice functionality are discussed by the joint document. In particular, appropriate personal protective equipment (PPE) should be worn by all members of the endoscopy team: gloves, mask, eye shield/goggles, face shields, and gown, but practitioners should also be aware of how to put on and take off PPE appropriately.

“Conservation of PPE is critical. Only essential personnel should be present in cases. Consider extended use or reuse of surgical masks and eye protection in accordance with hospital policies,” the document recommends.

“It is important to address our collective staff needs and institute policies that protect our workforce.” To that end, the document recommends that centers should strategically assign available personnel in order to minimize concomitant exposure of those with similar or unique skill sets. This includes the use of nonphysician practitioners and fellows that cannot participate in cases for screening and triaging patients, or performing virtual visits.

Coming at a time of pandemic, when gastrointestinal symptoms have been recognized as a more common symptom of COVID-19 than previously expected and liver damage has been noted as a potential repercussion of SARS-CoV-2 infection, these clinical insights provide a template for gastroenterologists and related professionals for dealing with their patients and keeping themselves safe under dramatically changed circumstances.

The partnered organizations, AASLD, ACG, AGA, and ASGE, are committed to providing updated COVID-19 information as appropriate. However: “Given the evolving and fluid nature of the situation, institutions, hospitals and clinics have also been formulating their own local guidelines, so we urge you to follow the evolving CDC recommendations and your local requirements,” according to the AGA website announcement.

In addition to the joint communication, the society websites each offer additional COVID-19 information. The AGA practice updates on the COVID-19 webpage provides information about announcements, such as the cancellation of Digestive Disease Week^® in May, a location for AGA members to discuss their COVID-19 experiences and share advice, and links to the CDC COVID-19 updates.
 

mlesney@mdedge.com

SOURCE: American Gastroenterological Association et al. March 2020, COVID-19 Clinical Insights for Our Community of Gastroenterologists and Gastroenterology Care Providers.

Amid the growing SARS-CoV-2 pandemic, currently in its expansive growth phase in the United States, the American Gastroenterological Association (AGA), the American Association for the Study of Liver Diseases (AASLD), the American College of Gastroenterology (ACG), and the American Society for Gastrointestinal Endoscopy (ASGE) have jointly released “COVID-19 Clinical Insights for Our Community of Gastroenterologists and Gastroenterology Care Providers,” which can be found on the websites of the various societies.

“The purpose of this communication is to jointly provide you with up to date COVID-19 information in order to maintain the highest level of health and safety for our patients, staff, community, and ourselves,” according to the AGA website announcement.

In particular, the societies point out that there is recent evidence suggesting the potential for coronavirus transmission through droplets and perhaps fecal shedding, which pose potential risks in particular during endoscopy and colonoscopy procedures to other patients, endoscopy personnel, and practitioners.

Relevant clinical factors related to COVID-19 are discussed, including the fact that asymptomatic spread can occur during the prodromal phase (the mean incubation period is approximately 5 days, with a range of 0-14 days), with viral shedding greatest when symptoms begin.

Between 20% and 30% of patients with COVID-19 infection show abnormal liver enzymes. In addition, COVID-19 patients show drops in their leukocyte counts, and elevated white blood cell counts is a poor prognostic sign, according to the release.

The Centers for Disease Control and Prevention lists vulnerable populations at the greatest risk for more serious outcomes; these include the elderly and those with severe chronic health conditions, such as heart disease, lung disease, diabetes, decompensated cirrhosis, HIV with low CD4 counts, and immunosuppression (including liver and other solid organ transplant recipients), are at higher risk of developing more serious illness. In addition pregnancy may provide added risk.
 

Specific advice for the gastroenterology profession

The joint statement urges that practitioners strongly consider rescheduling elective nonurgent endoscopic procedures, although some nonurgent procedures are higher priority and may need to be performed, including cancer evaluations, prosthetic removals, and evaluation of significant symptoms. “Of note, the Surgeon General on 3/14/20 advised hospitals to postpone all elective surgeries,” the document states.

Patient concerns

In all cases, patients should be prescreened for high-risk exposure or symptoms. This includes asking about history of fever or respiratory symptoms, family members or close contacts with similar symptoms, any contact with a confirmed case of COVID-19, and recent travel to a high-risk area. “Avoid bringing patients (or their escorts) into the medical facility who are over age 65 or have one of the CDC recognized risks listed above,” the societies advise.

Check body temperature of the patient upon arrival at endoscopy unit or clinic, and keep all patients at an appropriate distance from each other (6 feet is recommended) throughout the entire time in the endoscopy unit.

“For COVID-19 positive patients, or those awaiting test results, isolation precautions should be taken with procedures performed in negative pressure rooms,” according to the statement.

In addition, use telemedicine where possible in elective cases, and consider phone follow-up after any procedures at 7 and 14 days to ask about new diagnosis of COVID-19 or development of its symptoms, .

Those patients who are on immunosuppressive drugs for inflammatory bowel disease and autoimmune hepatitis should continue taking their medications because the risk of disease flare outweighs the chance of contracting coronavirus, according to the document. In addition, these patients should be advised to follow CDC guidelines for at-risk groups by avoiding crowds and limiting travel.
 

Protection of practitioners

Key factors in ensuring practitioner safety and maintaining practice functionality are discussed by the joint document. In particular, appropriate personal protective equipment (PPE) should be worn by all members of the endoscopy team: gloves, mask, eye shield/goggles, face shields, and gown, but practitioners should also be aware of how to put on and take off PPE appropriately.

“Conservation of PPE is critical. Only essential personnel should be present in cases. Consider extended use or reuse of surgical masks and eye protection in accordance with hospital policies,” the document recommends.

“It is important to address our collective staff needs and institute policies that protect our workforce.” To that end, the document recommends that centers should strategically assign available personnel in order to minimize concomitant exposure of those with similar or unique skill sets. This includes the use of nonphysician practitioners and fellows that cannot participate in cases for screening and triaging patients, or performing virtual visits.

Coming at a time of pandemic, when gastrointestinal symptoms have been recognized as a more common symptom of COVID-19 than previously expected and liver damage has been noted as a potential repercussion of SARS-CoV-2 infection, these clinical insights provide a template for gastroenterologists and related professionals for dealing with their patients and keeping themselves safe under dramatically changed circumstances.

The partnered organizations, AASLD, ACG, AGA, and ASGE, are committed to providing updated COVID-19 information as appropriate. However: “Given the evolving and fluid nature of the situation, institutions, hospitals and clinics have also been formulating their own local guidelines, so we urge you to follow the evolving CDC recommendations and your local requirements,” according to the AGA website announcement.

In addition to the joint communication, the society websites each offer additional COVID-19 information. The AGA practice updates on the COVID-19 webpage provides information about announcements, such as the cancellation of Digestive Disease Week^® in May, a location for AGA members to discuss their COVID-19 experiences and share advice, and links to the CDC COVID-19 updates.
 

mlesney@mdedge.com

SOURCE: American Gastroenterological Association et al. March 2020, COVID-19 Clinical Insights for Our Community of Gastroenterologists and Gastroenterology Care Providers.

Key clinical point: Intravenous (IV) eptinezumab could be a safe and effective preventive therapy for adult patients with episodic migraine.

Main finding: Eptinezumab 100 and 300 mg significantly reduced monthly migraine days across weeks 1-12 compared with the placebo (difference from placebo for 100 and 300 mg: –0.69; P = .0182 and –1.11; P = .0001, respectively). Safety and tolerability of eptinezumab across doses were acceptable compared with placebo, with no dose-related trend in the nature, frequency, or severity of treatment-related adverse events.

Study details: In phase 3, multicenter, double-blind, parallel-group study, 888 patients were randomly assigned to IV eptinezumab (30, 100, and 300 mg) or placebo administered every 12 weeks. 

Disclosures: The study was funded by H. Lundbeck A/S, Copenhagen, Denmark. Some of the authors were full-time employees of or contracted to Lundbeck Seattle BioPharmaceuticals, Inc. (previously known as Alder BioPharmaceuticals, Inc.), a subsidiary H. Lundbeck A/S. Some also were stockholders of Lundbeck Seattle BioPharmaceuticals, Inc.

Citation: Ashina M et al. Cephalalgia. 2020 Feb 19. doi: 10.1177/0333102420905132.

Key clinical point: Intravenous (IV) eptinezumab could be a safe and effective preventive therapy for adult patients with episodic migraine.

Main finding: Eptinezumab 100 and 300 mg significantly reduced monthly migraine days across weeks 1-12 compared with the placebo (difference from placebo for 100 and 300 mg: –0.69; P = .0182 and –1.11; P = .0001, respectively). Safety and tolerability of eptinezumab across doses were acceptable compared with placebo, with no dose-related trend in the nature, frequency, or severity of treatment-related adverse events.

Study details: In phase 3, multicenter, double-blind, parallel-group study, 888 patients were randomly assigned to IV eptinezumab (30, 100, and 300 mg) or placebo administered every 12 weeks. 

Disclosures: The study was funded by H. Lundbeck A/S, Copenhagen, Denmark. Some of the authors were full-time employees of or contracted to Lundbeck Seattle BioPharmaceuticals, Inc. (previously known as Alder BioPharmaceuticals, Inc.), a subsidiary H. Lundbeck A/S. Some also were stockholders of Lundbeck Seattle BioPharmaceuticals, Inc.

Citation: Ashina M et al. Cephalalgia. 2020 Feb 19. doi: 10.1177/0333102420905132.

Key clinical point: Intravenous (IV) eptinezumab could be a safe and effective preventive therapy for adult patients with episodic migraine.

Main finding: Eptinezumab 100 and 300 mg significantly reduced monthly migraine days across weeks 1-12 compared with the placebo (difference from placebo for 100 and 300 mg: –0.69; P = .0182 and –1.11; P = .0001, respectively). Safety and tolerability of eptinezumab across doses were acceptable compared with placebo, with no dose-related trend in the nature, frequency, or severity of treatment-related adverse events.

Study details: In phase 3, multicenter, double-blind, parallel-group study, 888 patients were randomly assigned to IV eptinezumab (30, 100, and 300 mg) or placebo administered every 12 weeks. 

Disclosures: The study was funded by H. Lundbeck A/S, Copenhagen, Denmark. Some of the authors were full-time employees of or contracted to Lundbeck Seattle BioPharmaceuticals, Inc. (previously known as Alder BioPharmaceuticals, Inc.), a subsidiary H. Lundbeck A/S. Some also were stockholders of Lundbeck Seattle BioPharmaceuticals, Inc.

Citation: Ashina M et al. Cephalalgia. 2020 Feb 19. doi: 10.1177/0333102420905132.

Key clinical point: Migraineurs with aura are more likely to show a higher anger response, but not impulsivity, compared with migraineurs without aura and healthy control individuals.

Main finding: Scores of anger symptoms were significantly higher migraineurs with aura than those without aura and control individuals (P less than .001); however, there was no significant difference in total Barratt impulsiveness scale-11 score, attentional impulsiveness, motor impulsiveness, and nonplanning impulsiveness between the 3 groups (P greater than .05).

Study details: The prospective cross-sectional study included 55 patients aged 18-55 years with episodic migraine (31 with aura and 24 without aura) and 40 healthy control individuals.

Disclosures: The authors declared no conflict of interest.

Citation: Tanik N et al. Neurol Res. 2020 Feb 5. doi: 10.1080/01616412.2020.1723974.

Key clinical point: Migraineurs with aura are more likely to show a higher anger response, but not impulsivity, compared with migraineurs without aura and healthy control individuals.

Main finding: Scores of anger symptoms were significantly higher migraineurs with aura than those without aura and control individuals (P less than .001); however, there was no significant difference in total Barratt impulsiveness scale-11 score, attentional impulsiveness, motor impulsiveness, and nonplanning impulsiveness between the 3 groups (P greater than .05).

Study details: The prospective cross-sectional study included 55 patients aged 18-55 years with episodic migraine (31 with aura and 24 without aura) and 40 healthy control individuals.

Disclosures: The authors declared no conflict of interest.

Citation: Tanik N et al. Neurol Res. 2020 Feb 5. doi: 10.1080/01616412.2020.1723974.

Key clinical point: Migraineurs with aura are more likely to show a higher anger response, but not impulsivity, compared with migraineurs without aura and healthy control individuals.

Main finding: Scores of anger symptoms were significantly higher migraineurs with aura than those without aura and control individuals (P less than .001); however, there was no significant difference in total Barratt impulsiveness scale-11 score, attentional impulsiveness, motor impulsiveness, and nonplanning impulsiveness between the 3 groups (P greater than .05).

Study details: The prospective cross-sectional study included 55 patients aged 18-55 years with episodic migraine (31 with aura and 24 without aura) and 40 healthy control individuals.

Disclosures: The authors declared no conflict of interest.

Citation: Tanik N et al. Neurol Res. 2020 Feb 5. doi: 10.1080/01616412.2020.1723974.

Key clinical point: Plasma glucose level increases during spontaneous migraine attacks, and the increase is independent of the presence of aura symptoms and pain intensity.

Main finding: Plasma glucose levels were higher in the ictal phase than in the interictal phase of migraine (mean, 98.83 vs. 88.63 mg/dL; P = .0014) after adjusting for diurnal variation. The attack-related elevation in plasma glucose level was not influenced by pain intensity or the presence of aura symptoms.

Study details: In this study, plasma glucose levels were measured during and outside of spontaneous attacks of migraine in 31 patients (13 with aura and 18 without aura).

Disclosures: The study was funded by the Lundbeck Foundation, the Novo Nordisk Foundation, the University of Copenhagen, the Research Foundation of the Capital Region of Denmark, and the Danish Council for Independent Research-Medical Sciences. Faisal Mohammad Amin and Anders Hougaard reported receiving personal fees and/or honoraria from multiple pharmaceutical companies. Messoud Ashina reported consultancy/advisory for multiple pharmaceutical companies. Other authors declared no disclosures. 

Citation: Zhang DG et al. Headache. 2020 Feb 7. doi: 10.1111/head.13760.

Key clinical point: Plasma glucose level increases during spontaneous migraine attacks, and the increase is independent of the presence of aura symptoms and pain intensity.

Main finding: Plasma glucose levels were higher in the ictal phase than in the interictal phase of migraine (mean, 98.83 vs. 88.63 mg/dL; P = .0014) after adjusting for diurnal variation. The attack-related elevation in plasma glucose level was not influenced by pain intensity or the presence of aura symptoms.

Study details: In this study, plasma glucose levels were measured during and outside of spontaneous attacks of migraine in 31 patients (13 with aura and 18 without aura).

Disclosures: The study was funded by the Lundbeck Foundation, the Novo Nordisk Foundation, the University of Copenhagen, the Research Foundation of the Capital Region of Denmark, and the Danish Council for Independent Research-Medical Sciences. Faisal Mohammad Amin and Anders Hougaard reported receiving personal fees and/or honoraria from multiple pharmaceutical companies. Messoud Ashina reported consultancy/advisory for multiple pharmaceutical companies. Other authors declared no disclosures. 

Citation: Zhang DG et al. Headache. 2020 Feb 7. doi: 10.1111/head.13760.

Key clinical point: Plasma glucose level increases during spontaneous migraine attacks, and the increase is independent of the presence of aura symptoms and pain intensity.

Main finding: Plasma glucose levels were higher in the ictal phase than in the interictal phase of migraine (mean, 98.83 vs. 88.63 mg/dL; P = .0014) after adjusting for diurnal variation. The attack-related elevation in plasma glucose level was not influenced by pain intensity or the presence of aura symptoms.

Study details: In this study, plasma glucose levels were measured during and outside of spontaneous attacks of migraine in 31 patients (13 with aura and 18 without aura).

Disclosures: The study was funded by the Lundbeck Foundation, the Novo Nordisk Foundation, the University of Copenhagen, the Research Foundation of the Capital Region of Denmark, and the Danish Council for Independent Research-Medical Sciences. Faisal Mohammad Amin and Anders Hougaard reported receiving personal fees and/or honoraria from multiple pharmaceutical companies. Messoud Ashina reported consultancy/advisory for multiple pharmaceutical companies. Other authors declared no disclosures. 

Citation: Zhang DG et al. Headache. 2020 Feb 7. doi: 10.1111/head.13760.

Key clinical point: Quarterly treatment with OnabotulinumtoxinA (BoNT-A) up to 4 years can provide long-lasting prevention of chronic migraine in real-life settings.

Main finding: From baseline to 48 months, there was a significant reduction in the mean number of monthly headache days and hours, consumption of analgesics, and latency time (P less than .001 for all). With repeated BoNT-A treatment, a progressive shift toward lower degrees of disability was seen at each subsequent timepoint (P less than .001 for trend). Six patients experienced transitory neck pain. 

Study details: The data come from a retrospective real-life study of patients with chronic migraine who received quarterly treatment with BoNT-A up to 16 cycles (n = 109).

Disclosures: The authors declared no conflict of interest.

Citation: Santoro A et al. Neurol Sci. 2020 Feb 12. doi: 10.1007/s10072-020-04283-y.

Key clinical point: Quarterly treatment with OnabotulinumtoxinA (BoNT-A) up to 4 years can provide long-lasting prevention of chronic migraine in real-life settings.

Main finding: From baseline to 48 months, there was a significant reduction in the mean number of monthly headache days and hours, consumption of analgesics, and latency time (P less than .001 for all). With repeated BoNT-A treatment, a progressive shift toward lower degrees of disability was seen at each subsequent timepoint (P less than .001 for trend). Six patients experienced transitory neck pain. 

Study details: The data come from a retrospective real-life study of patients with chronic migraine who received quarterly treatment with BoNT-A up to 16 cycles (n = 109).

Disclosures: The authors declared no conflict of interest.

Citation: Santoro A et al. Neurol Sci. 2020 Feb 12. doi: 10.1007/s10072-020-04283-y.

Key clinical point: Quarterly treatment with OnabotulinumtoxinA (BoNT-A) up to 4 years can provide long-lasting prevention of chronic migraine in real-life settings.

Main finding: From baseline to 48 months, there was a significant reduction in the mean number of monthly headache days and hours, consumption of analgesics, and latency time (P less than .001 for all). With repeated BoNT-A treatment, a progressive shift toward lower degrees of disability was seen at each subsequent timepoint (P less than .001 for trend). Six patients experienced transitory neck pain. 

Study details: The data come from a retrospective real-life study of patients with chronic migraine who received quarterly treatment with BoNT-A up to 16 cycles (n = 109).

Disclosures: The authors declared no conflict of interest.

Citation: Santoro A et al. Neurol Sci. 2020 Feb 12. doi: 10.1007/s10072-020-04283-y.

Key clinical point: Rimegepant 75 mg demonstrates favorable efficacy and safety for the treatment of acute migraine compared with the placebo.

Main finding: Rimegepant 75 mg resulted in a significant freedom from pain (20.6% vs. 12.5%; relative risk [RR], 1.70; P less than .001), pain relief (58.6% vs. 44.6%; RR, 1.34; P less than .001), and freedom from the most bothersome symptoms (36.0% vs. 25.1%; RR, 1.44; P less than .001) at 2 hours after dosing compared with the placebo. There was no significant increase in adverse events compared with the placebo.

Study details: A meta-analysis of 4 randomized controlled trials including 3,827 patients with acute migraine.

Disclosures: This study was supported by the Suzhou Health Talents Training Project. The authors declared no conflict of interest.

Citation: Gao B et al. Front Pharmacol. 2020 Jan 24. doi: 10.3389/fphar.2019.01577.

Key clinical point: Rimegepant 75 mg demonstrates favorable efficacy and safety for the treatment of acute migraine compared with the placebo.

Main finding: Rimegepant 75 mg resulted in a significant freedom from pain (20.6% vs. 12.5%; relative risk [RR], 1.70; P less than .001), pain relief (58.6% vs. 44.6%; RR, 1.34; P less than .001), and freedom from the most bothersome symptoms (36.0% vs. 25.1%; RR, 1.44; P less than .001) at 2 hours after dosing compared with the placebo. There was no significant increase in adverse events compared with the placebo.

Study details: A meta-analysis of 4 randomized controlled trials including 3,827 patients with acute migraine.

Disclosures: This study was supported by the Suzhou Health Talents Training Project. The authors declared no conflict of interest.

Citation: Gao B et al. Front Pharmacol. 2020 Jan 24. doi: 10.3389/fphar.2019.01577.

Key clinical point: Rimegepant 75 mg demonstrates favorable efficacy and safety for the treatment of acute migraine compared with the placebo.

Main finding: Rimegepant 75 mg resulted in a significant freedom from pain (20.6% vs. 12.5%; relative risk [RR], 1.70; P less than .001), pain relief (58.6% vs. 44.6%; RR, 1.34; P less than .001), and freedom from the most bothersome symptoms (36.0% vs. 25.1%; RR, 1.44; P less than .001) at 2 hours after dosing compared with the placebo. There was no significant increase in adverse events compared with the placebo.

Study details: A meta-analysis of 4 randomized controlled trials including 3,827 patients with acute migraine.

Disclosures: This study was supported by the Suzhou Health Talents Training Project. The authors declared no conflict of interest.

Citation: Gao B et al. Front Pharmacol. 2020 Jan 24. doi: 10.3389/fphar.2019.01577.

CASE Pregnant woman with symptoms of genital infection

A 23-year-old primigravid woman at 15 weeks and 2 days’ gestation reported having a 2-week history of increased urinary frequency and vaginal discharge. She said she experienced similar symptoms 6 weeks previously that resolved within a week. The patient has had 3 sexual partners in the past year. Her current partner was experiencing a yellow urethral discharge and dysuria. On the patient’s speculum examination, the clinician noted a yellow-green discharge emanating from the cervix as well as cervical motion tenderness.

What is the most likely diagnosis, and how would you treat this patient?
 

The culprit was chlamydia

Chlamydia trachomatis is an obligate intracellular bacterium that does not stain with Gram staining. A rigid cell wall encloses its intracellular component. C trachomatis infection begins when the chlamydial elementary body enters a susceptible host cell.

Once ingested, the organism’s surface antigens (major outer membrane protein and lipopolysaccharide antigens) provide intracellular sanctuary for the bacterium by inhibiting phagolysosomal fusion. Subsequently, the elementary body morphs into a reticular body, which replicates through adenosine triphosphate (ATP)–dependent binary fission. After approximately 48 hours of replication, the organism again morphs into an elementary body and is released to infect additional cells and acquire new ATP stores for further replication.

Chlamydia can be transmitted horizontally during oral, vaginal, or anal intercourse or vertically to the infant during vaginal delivery.

The US’s most common notifiable disease

According to the Centers for Disease Control and Prevention (CDC), the incidence of chlamydia infection in the United States increased considerably in recent years: from 976,455 cases in 2005 to 1,758,668 cases in 2018.¹ In 2018, rates of chlamydia infection in women were nearly double the rates in men, with an incidence of 688.2 versus 377.5 per 100,000 cases, and a prevalence of 1,150,672 versus 612,020.¹

Young adults have a higher frequency of chlamydia infection than any other age group. From 2017 to 2018, reported cases in women aged 15–19 years increased by 1.3%, to 3,306.8 per 100,000; in women aged 20–24 years, cases increased by 0.8%, to 4,064.6 per 100,000. In young men in the same age ranges, reported cases increased by 3.7%, to 959.0 cases per 100,000, and by 3.3%, to 1,784.5 per 100,000 cases, respectively.¹

Both the incidence and prevalence of chlamydia infection are higher in African Americans than in whites, while Asians have the lowest rates.¹ The prevalence of infection also is increased with incarceration, lower socioeconomic status, and residence in the southern United States.

The prevalence of chlamydia infection in pregnant women is approximately 2% to 3%, but it may be as high as 30% in high-risk populations, such as women who are unmarried, have multiple sex partners, are coinfected with another sexually transmitted disease (STD), have partners with nongonococcal urethritis, have mucopurulent discharge, have acute urethral syndrome, and have late or no prenatal care.² Since chlamydia infection often is asymptomatic and some infections resolve spontaneously, the true prevalence of infection probably is underreported.

Continue to: Chlamydia infection can cause serious clinical manifestations...

Chlamydia infection can cause serious clinical manifestations

The 15 serotypes of C trachomatis are grouped into 3 categories according to clinical manifestations:

• Serotypes A, B, Ba, and C cause endemic trachoma, characterized by bilateral irritation of the eyelids that progresses to eyelid thickening and scarring, eventually leading to corneal abrasion and blindness.
• Serotypes D–K manifest as conjunctivitis and pneumonia in newborns, proctitis in men (especially in men who have sex with men), and genitourinary infections in women. Reactive arthritis and inclusion conjunctivitis also can occur with D–K serotypes.
• Serotypes L1–L3 cause lymphogranuloma venereum.

About 70% of women with chlamydia infection are asymptomatic. Those who have symptoms often present with endocervicitis or acute urethral syndrome (acute urethritis). Manifestations of these 2 conditions include a frothy yellow-green vaginal and/or urethral discharge, dysuria, and frequency. Women who engage in rectal intercourse also may notice a purulent discharge from the anus. Untreated, C trachomatis organisms may ascend the reproductive tract, causing both endometritis and pelvic inflammatory disease (PID).

While a single episode of PID increases tubal infertility risk by 10%, a second episode increases the risk by 40%.³ Over time, recurrent and/or chronic PID causes scarring and adhesion formation, which may result in chronic pelvic pain. In addition, chronic infection is the single most important risk factor for ectopic pregnancy. Finally, chlamydia infection is a risk factor for Fitz-Hugh-Cutis syndrome (perihepatitis). In this condition, organisms ascend from the site of pelvic infection along the pericolic gutter to ultimately infect the liver capsule.

Specific complications in pregnancy

Chlamydia infection in pregnant women is associated with preterm delivery and preterm premature rupture of membranes. Infants born to mothers with untreated chlamydia infection are at risk for pneumonia, conjunctivitis, and even perinatal death.² Acquisition of infection occurs at the time of delivery rather than in the antepartum period.

The significant morbidity associated with chlamydia infection underscores the importance of regular screening, especially in pregnant women. The current United States Preventive Service Task Force guidelines recommend annual screening of all sexually active women who are 24 years of age or younger, as well as of older, high-risk women.

The CDC recommends routine screening of all pregnant women for chlamydia at the first prenatal visit. Repeat screening is recommended in the third trimester for all pregnant women younger than 25 years, those at increased risk, and those infected within the past 3 to 6 months or during the first trimester. Those who test positive should be retested 3 weeks after completion of treatment.¹

Chlamydia screening strategies

Historically, a chlamydia diagnosis was made by isolating the organisms in tissue culture. In the 1990s, however, that extremely time-consuming and resource-intensive procedure was replaced by nucleic acid amplification testing (NAAT).

NAAT methodology. NAAT is the gold standard for diagnosing C trachomatis infection; this methodology utilizes various assays, including polymerase chain reaction, ligase chain reaction, and transcription-mediated amplification.

Continue to: Compared with previous culture and antigen detection techniques...

Compared with previous culture and antigen detection techniques, NAAT’s advantages include excellent sensitivity and specificity (>90% and ≥99%, respectively), enabling detection of a low inoculum of organisms in a sample obtained by noninvasive methods, such as first-void urine collection or vaginal swab.^2,4,5 Furthermore, NAAT does not impose any specific storage regulations on collected specimens, is cost effective, and can jointly test for Neisseria gonorrhoeae, which commonly co-infects with C trachomatis.⁶

Screening in pregnancy. In 2012, Blatt and colleagues examined testing patterns in nearly 1.3 million obstetric patients and found that only 59% (761,315) of women were tested for chlamydia at least once in pregnancy.⁷ Only 1 in 3 women were tested during the first prenatal visit, as CDC guidelines recommend. Testing rates declined with increasing age. Of women screened, 3.5% tested positive for chlamydia.⁷ Of these, 3 of 4 were retested at least once, with almost 20% having at least 1 subsequent positive result.⁷

Of note, in a study of women who reported receptive anal intercourse (n = 2,818), 292 women tested positive for chlamydia; 10.4% tested positive in genital-only sites, 58.6% in genital and rectal sites, and 20.5% at the rectal site only.⁸

It is alarming that only 59% of pregnant women are screened for chlamydia given the significant perinatal complications associated with this infection. Barriers to screening pregnant women may include clinician discomfort in discussing STDs and patient refusal of screening. Furthermore, clinicians should routinely ask women about receptive anal sex. Women who report this risk factor should be tested for chlamydia in both the endocervix and rectum.

Retesting and follow-up. After the initial diagnosis of chlamydia, a test of cure 3 weeks after treatment is an important aspect of care. Thus, identifying and overcoming barriers to retesting is important. Clinicians should educate patients about the importance of follow-up. Also consider incorporating the use of home-based, self-obtained vaginal swabs for retesting. Results from 2 randomized trials showed that eliminating a patient’s transportation barriers and providing a home-based alternative to a follow-up visit significantly increased rescreening rates by 33% in STD clinic patients and by 59.2% in family planning clinic patients.⁹

Reinfection risk. The rate of venereal chlamydia transmission in heterosexual partners is 70%. Since sexually active chlamydia-positive patients are at risk for reinfection by their partner after treatment completion, clinicians should refer the sex partners for evaluation. If the sex partners are reluctant to have testing, it is reasonable to provide empiric antibiotic treatment to decrease the risk of re-infection in the patient.⁷ Before doing so, however, make certain that state law permits this practice, and be sure to document the prescribed treatment in the patient’s record.

Continue to: Treatment options...

Treatment options

Prompt treatment of C trachomatis infection is essential to decrease the risk of disease sequelae. Nonpregnant adults can be treated with oral doxycycline 100 mg twice daily for 7 days.

In a head-to-head study performed in a controlled environment that ensured treatment adherence, 97% efficacy was achieved with one oral dose of azithromycin (1 g) compared with 100% efficacy with doxycycline.¹⁰ However, in the real-world setting, imperfect adherence to the multi-day doxycycline regimen is associated with treatment failures. Thus, a single dose of azithromycin is preferable for patients with questionable compliance.¹¹

In obstetric patients, azithromycin and amoxicillin are preferred as first-line agents for treatment of C trachomatis due to their improved safety profile in this demographic. Amoxicillin 500 mg orally 3 times daily for 7 days has 95% efficacy.²

Women allergic to these agents may be treated with an alternative regimen of erythromycin base, 500 mg orally 4 times daily for 7 days, or erythromycin ethylsuccinate, 800 mg orally 4 times daily for 7 days. Erythromycin should be reserved for second-line therapy because of its lower efficacy (64%) and frequent gastrointestinal adverse effects.² Doxycycline is contraindicated in pregnancy because of possible teratogenic effects on the teeth and bone of the fetus.

CASE Pregnant woman with symptoms of genital infection

A 23-year-old primigravid woman at 15 weeks and 2 days’ gestation reported having a 2-week history of increased urinary frequency and vaginal discharge. She said she experienced similar symptoms 6 weeks previously that resolved within a week. The patient has had 3 sexual partners in the past year. Her current partner was experiencing a yellow urethral discharge and dysuria. On the patient’s speculum examination, the clinician noted a yellow-green discharge emanating from the cervix as well as cervical motion tenderness.

What is the most likely diagnosis, and how would you treat this patient?
 

The culprit was chlamydia

Chlamydia trachomatis is an obligate intracellular bacterium that does not stain with Gram staining. A rigid cell wall encloses its intracellular component. C trachomatis infection begins when the chlamydial elementary body enters a susceptible host cell.

Once ingested, the organism’s surface antigens (major outer membrane protein and lipopolysaccharide antigens) provide intracellular sanctuary for the bacterium by inhibiting phagolysosomal fusion. Subsequently, the elementary body morphs into a reticular body, which replicates through adenosine triphosphate (ATP)–dependent binary fission. After approximately 48 hours of replication, the organism again morphs into an elementary body and is released to infect additional cells and acquire new ATP stores for further replication.

Chlamydia can be transmitted horizontally during oral, vaginal, or anal intercourse or vertically to the infant during vaginal delivery.

The US’s most common notifiable disease

According to the Centers for Disease Control and Prevention (CDC), the incidence of chlamydia infection in the United States increased considerably in recent years: from 976,455 cases in 2005 to 1,758,668 cases in 2018.¹ In 2018, rates of chlamydia infection in women were nearly double the rates in men, with an incidence of 688.2 versus 377.5 per 100,000 cases, and a prevalence of 1,150,672 versus 612,020.¹

Young adults have a higher frequency of chlamydia infection than any other age group. From 2017 to 2018, reported cases in women aged 15–19 years increased by 1.3%, to 3,306.8 per 100,000; in women aged 20–24 years, cases increased by 0.8%, to 4,064.6 per 100,000. In young men in the same age ranges, reported cases increased by 3.7%, to 959.0 cases per 100,000, and by 3.3%, to 1,784.5 per 100,000 cases, respectively.¹

Both the incidence and prevalence of chlamydia infection are higher in African Americans than in whites, while Asians have the lowest rates.¹ The prevalence of infection also is increased with incarceration, lower socioeconomic status, and residence in the southern United States.

The prevalence of chlamydia infection in pregnant women is approximately 2% to 3%, but it may be as high as 30% in high-risk populations, such as women who are unmarried, have multiple sex partners, are coinfected with another sexually transmitted disease (STD), have partners with nongonococcal urethritis, have mucopurulent discharge, have acute urethral syndrome, and have late or no prenatal care.² Since chlamydia infection often is asymptomatic and some infections resolve spontaneously, the true prevalence of infection probably is underreported.

Continue to: Chlamydia infection can cause serious clinical manifestations...

Chlamydia infection can cause serious clinical manifestations

The 15 serotypes of C trachomatis are grouped into 3 categories according to clinical manifestations:

• Serotypes A, B, Ba, and C cause endemic trachoma, characterized by bilateral irritation of the eyelids that progresses to eyelid thickening and scarring, eventually leading to corneal abrasion and blindness.
• Serotypes D–K manifest as conjunctivitis and pneumonia in newborns, proctitis in men (especially in men who have sex with men), and genitourinary infections in women. Reactive arthritis and inclusion conjunctivitis also can occur with D–K serotypes.
• Serotypes L1–L3 cause lymphogranuloma venereum.

About 70% of women with chlamydia infection are asymptomatic. Those who have symptoms often present with endocervicitis or acute urethral syndrome (acute urethritis). Manifestations of these 2 conditions include a frothy yellow-green vaginal and/or urethral discharge, dysuria, and frequency. Women who engage in rectal intercourse also may notice a purulent discharge from the anus. Untreated, C trachomatis organisms may ascend the reproductive tract, causing both endometritis and pelvic inflammatory disease (PID).

While a single episode of PID increases tubal infertility risk by 10%, a second episode increases the risk by 40%.³ Over time, recurrent and/or chronic PID causes scarring and adhesion formation, which may result in chronic pelvic pain. In addition, chronic infection is the single most important risk factor for ectopic pregnancy. Finally, chlamydia infection is a risk factor for Fitz-Hugh-Cutis syndrome (perihepatitis). In this condition, organisms ascend from the site of pelvic infection along the pericolic gutter to ultimately infect the liver capsule.

Specific complications in pregnancy

Chlamydia infection in pregnant women is associated with preterm delivery and preterm premature rupture of membranes. Infants born to mothers with untreated chlamydia infection are at risk for pneumonia, conjunctivitis, and even perinatal death.² Acquisition of infection occurs at the time of delivery rather than in the antepartum period.

The significant morbidity associated with chlamydia infection underscores the importance of regular screening, especially in pregnant women. The current United States Preventive Service Task Force guidelines recommend annual screening of all sexually active women who are 24 years of age or younger, as well as of older, high-risk women.

The CDC recommends routine screening of all pregnant women for chlamydia at the first prenatal visit. Repeat screening is recommended in the third trimester for all pregnant women younger than 25 years, those at increased risk, and those infected within the past 3 to 6 months or during the first trimester. Those who test positive should be retested 3 weeks after completion of treatment.¹

Chlamydia screening strategies

Historically, a chlamydia diagnosis was made by isolating the organisms in tissue culture. In the 1990s, however, that extremely time-consuming and resource-intensive procedure was replaced by nucleic acid amplification testing (NAAT).

NAAT methodology. NAAT is the gold standard for diagnosing C trachomatis infection; this methodology utilizes various assays, including polymerase chain reaction, ligase chain reaction, and transcription-mediated amplification.

Continue to: Compared with previous culture and antigen detection techniques...

Compared with previous culture and antigen detection techniques, NAAT’s advantages include excellent sensitivity and specificity (>90% and ≥99%, respectively), enabling detection of a low inoculum of organisms in a sample obtained by noninvasive methods, such as first-void urine collection or vaginal swab.^2,4,5 Furthermore, NAAT does not impose any specific storage regulations on collected specimens, is cost effective, and can jointly test for Neisseria gonorrhoeae, which commonly co-infects with C trachomatis.⁶

Screening in pregnancy. In 2012, Blatt and colleagues examined testing patterns in nearly 1.3 million obstetric patients and found that only 59% (761,315) of women were tested for chlamydia at least once in pregnancy.⁷ Only 1 in 3 women were tested during the first prenatal visit, as CDC guidelines recommend. Testing rates declined with increasing age. Of women screened, 3.5% tested positive for chlamydia.⁷ Of these, 3 of 4 were retested at least once, with almost 20% having at least 1 subsequent positive result.⁷

Of note, in a study of women who reported receptive anal intercourse (n = 2,818), 292 women tested positive for chlamydia; 10.4% tested positive in genital-only sites, 58.6% in genital and rectal sites, and 20.5% at the rectal site only.⁸

It is alarming that only 59% of pregnant women are screened for chlamydia given the significant perinatal complications associated with this infection. Barriers to screening pregnant women may include clinician discomfort in discussing STDs and patient refusal of screening. Furthermore, clinicians should routinely ask women about receptive anal sex. Women who report this risk factor should be tested for chlamydia in both the endocervix and rectum.

Retesting and follow-up. After the initial diagnosis of chlamydia, a test of cure 3 weeks after treatment is an important aspect of care. Thus, identifying and overcoming barriers to retesting is important. Clinicians should educate patients about the importance of follow-up. Also consider incorporating the use of home-based, self-obtained vaginal swabs for retesting. Results from 2 randomized trials showed that eliminating a patient’s transportation barriers and providing a home-based alternative to a follow-up visit significantly increased rescreening rates by 33% in STD clinic patients and by 59.2% in family planning clinic patients.⁹

Reinfection risk. The rate of venereal chlamydia transmission in heterosexual partners is 70%. Since sexually active chlamydia-positive patients are at risk for reinfection by their partner after treatment completion, clinicians should refer the sex partners for evaluation. If the sex partners are reluctant to have testing, it is reasonable to provide empiric antibiotic treatment to decrease the risk of re-infection in the patient.⁷ Before doing so, however, make certain that state law permits this practice, and be sure to document the prescribed treatment in the patient’s record.

Continue to: Treatment options...

Treatment options

Prompt treatment of C trachomatis infection is essential to decrease the risk of disease sequelae. Nonpregnant adults can be treated with oral doxycycline 100 mg twice daily for 7 days.

In a head-to-head study performed in a controlled environment that ensured treatment adherence, 97% efficacy was achieved with one oral dose of azithromycin (1 g) compared with 100% efficacy with doxycycline.¹⁰ However, in the real-world setting, imperfect adherence to the multi-day doxycycline regimen is associated with treatment failures. Thus, a single dose of azithromycin is preferable for patients with questionable compliance.¹¹

In obstetric patients, azithromycin and amoxicillin are preferred as first-line agents for treatment of C trachomatis due to their improved safety profile in this demographic. Amoxicillin 500 mg orally 3 times daily for 7 days has 95% efficacy.²

Women allergic to these agents may be treated with an alternative regimen of erythromycin base, 500 mg orally 4 times daily for 7 days, or erythromycin ethylsuccinate, 800 mg orally 4 times daily for 7 days. Erythromycin should be reserved for second-line therapy because of its lower efficacy (64%) and frequent gastrointestinal adverse effects.² Doxycycline is contraindicated in pregnancy because of possible teratogenic effects on the teeth and bone of the fetus.

CASE Pregnant woman with symptoms of genital infection

A 23-year-old primigravid woman at 15 weeks and 2 days’ gestation reported having a 2-week history of increased urinary frequency and vaginal discharge. She said she experienced similar symptoms 6 weeks previously that resolved within a week. The patient has had 3 sexual partners in the past year. Her current partner was experiencing a yellow urethral discharge and dysuria. On the patient’s speculum examination, the clinician noted a yellow-green discharge emanating from the cervix as well as cervical motion tenderness.

What is the most likely diagnosis, and how would you treat this patient?
 

The culprit was chlamydia

Chlamydia trachomatis is an obligate intracellular bacterium that does not stain with Gram staining. A rigid cell wall encloses its intracellular component. C trachomatis infection begins when the chlamydial elementary body enters a susceptible host cell.

Once ingested, the organism’s surface antigens (major outer membrane protein and lipopolysaccharide antigens) provide intracellular sanctuary for the bacterium by inhibiting phagolysosomal fusion. Subsequently, the elementary body morphs into a reticular body, which replicates through adenosine triphosphate (ATP)–dependent binary fission. After approximately 48 hours of replication, the organism again morphs into an elementary body and is released to infect additional cells and acquire new ATP stores for further replication.

Chlamydia can be transmitted horizontally during oral, vaginal, or anal intercourse or vertically to the infant during vaginal delivery.

The US’s most common notifiable disease

According to the Centers for Disease Control and Prevention (CDC), the incidence of chlamydia infection in the United States increased considerably in recent years: from 976,455 cases in 2005 to 1,758,668 cases in 2018.¹ In 2018, rates of chlamydia infection in women were nearly double the rates in men, with an incidence of 688.2 versus 377.5 per 100,000 cases, and a prevalence of 1,150,672 versus 612,020.¹

Young adults have a higher frequency of chlamydia infection than any other age group. From 2017 to 2018, reported cases in women aged 15–19 years increased by 1.3%, to 3,306.8 per 100,000; in women aged 20–24 years, cases increased by 0.8%, to 4,064.6 per 100,000. In young men in the same age ranges, reported cases increased by 3.7%, to 959.0 cases per 100,000, and by 3.3%, to 1,784.5 per 100,000 cases, respectively.¹

Both the incidence and prevalence of chlamydia infection are higher in African Americans than in whites, while Asians have the lowest rates.¹ The prevalence of infection also is increased with incarceration, lower socioeconomic status, and residence in the southern United States.

The prevalence of chlamydia infection in pregnant women is approximately 2% to 3%, but it may be as high as 30% in high-risk populations, such as women who are unmarried, have multiple sex partners, are coinfected with another sexually transmitted disease (STD), have partners with nongonococcal urethritis, have mucopurulent discharge, have acute urethral syndrome, and have late or no prenatal care.² Since chlamydia infection often is asymptomatic and some infections resolve spontaneously, the true prevalence of infection probably is underreported.

Continue to: Chlamydia infection can cause serious clinical manifestations...

Chlamydia infection can cause serious clinical manifestations

The 15 serotypes of C trachomatis are grouped into 3 categories according to clinical manifestations:

• Serotypes A, B, Ba, and C cause endemic trachoma, characterized by bilateral irritation of the eyelids that progresses to eyelid thickening and scarring, eventually leading to corneal abrasion and blindness.
• Serotypes D–K manifest as conjunctivitis and pneumonia in newborns, proctitis in men (especially in men who have sex with men), and genitourinary infections in women. Reactive arthritis and inclusion conjunctivitis also can occur with D–K serotypes.
• Serotypes L1–L3 cause lymphogranuloma venereum.

About 70% of women with chlamydia infection are asymptomatic. Those who have symptoms often present with endocervicitis or acute urethral syndrome (acute urethritis). Manifestations of these 2 conditions include a frothy yellow-green vaginal and/or urethral discharge, dysuria, and frequency. Women who engage in rectal intercourse also may notice a purulent discharge from the anus. Untreated, C trachomatis organisms may ascend the reproductive tract, causing both endometritis and pelvic inflammatory disease (PID).

While a single episode of PID increases tubal infertility risk by 10%, a second episode increases the risk by 40%.³ Over time, recurrent and/or chronic PID causes scarring and adhesion formation, which may result in chronic pelvic pain. In addition, chronic infection is the single most important risk factor for ectopic pregnancy. Finally, chlamydia infection is a risk factor for Fitz-Hugh-Cutis syndrome (perihepatitis). In this condition, organisms ascend from the site of pelvic infection along the pericolic gutter to ultimately infect the liver capsule.

Specific complications in pregnancy

Chlamydia infection in pregnant women is associated with preterm delivery and preterm premature rupture of membranes. Infants born to mothers with untreated chlamydia infection are at risk for pneumonia, conjunctivitis, and even perinatal death.² Acquisition of infection occurs at the time of delivery rather than in the antepartum period.

The significant morbidity associated with chlamydia infection underscores the importance of regular screening, especially in pregnant women. The current United States Preventive Service Task Force guidelines recommend annual screening of all sexually active women who are 24 years of age or younger, as well as of older, high-risk women.

The CDC recommends routine screening of all pregnant women for chlamydia at the first prenatal visit. Repeat screening is recommended in the third trimester for all pregnant women younger than 25 years, those at increased risk, and those infected within the past 3 to 6 months or during the first trimester. Those who test positive should be retested 3 weeks after completion of treatment.¹

Chlamydia screening strategies

Historically, a chlamydia diagnosis was made by isolating the organisms in tissue culture. In the 1990s, however, that extremely time-consuming and resource-intensive procedure was replaced by nucleic acid amplification testing (NAAT).

NAAT methodology. NAAT is the gold standard for diagnosing C trachomatis infection; this methodology utilizes various assays, including polymerase chain reaction, ligase chain reaction, and transcription-mediated amplification.

Continue to: Compared with previous culture and antigen detection techniques...

Compared with previous culture and antigen detection techniques, NAAT’s advantages include excellent sensitivity and specificity (>90% and ≥99%, respectively), enabling detection of a low inoculum of organisms in a sample obtained by noninvasive methods, such as first-void urine collection or vaginal swab.^2,4,5 Furthermore, NAAT does not impose any specific storage regulations on collected specimens, is cost effective, and can jointly test for Neisseria gonorrhoeae, which commonly co-infects with C trachomatis.⁶

Screening in pregnancy. In 2012, Blatt and colleagues examined testing patterns in nearly 1.3 million obstetric patients and found that only 59% (761,315) of women were tested for chlamydia at least once in pregnancy.⁷ Only 1 in 3 women were tested during the first prenatal visit, as CDC guidelines recommend. Testing rates declined with increasing age. Of women screened, 3.5% tested positive for chlamydia.⁷ Of these, 3 of 4 were retested at least once, with almost 20% having at least 1 subsequent positive result.⁷

Of note, in a study of women who reported receptive anal intercourse (n = 2,818), 292 women tested positive for chlamydia; 10.4% tested positive in genital-only sites, 58.6% in genital and rectal sites, and 20.5% at the rectal site only.⁸

It is alarming that only 59% of pregnant women are screened for chlamydia given the significant perinatal complications associated with this infection. Barriers to screening pregnant women may include clinician discomfort in discussing STDs and patient refusal of screening. Furthermore, clinicians should routinely ask women about receptive anal sex. Women who report this risk factor should be tested for chlamydia in both the endocervix and rectum.

Retesting and follow-up. After the initial diagnosis of chlamydia, a test of cure 3 weeks after treatment is an important aspect of care. Thus, identifying and overcoming barriers to retesting is important. Clinicians should educate patients about the importance of follow-up. Also consider incorporating the use of home-based, self-obtained vaginal swabs for retesting. Results from 2 randomized trials showed that eliminating a patient’s transportation barriers and providing a home-based alternative to a follow-up visit significantly increased rescreening rates by 33% in STD clinic patients and by 59.2% in family planning clinic patients.⁹

Reinfection risk. The rate of venereal chlamydia transmission in heterosexual partners is 70%. Since sexually active chlamydia-positive patients are at risk for reinfection by their partner after treatment completion, clinicians should refer the sex partners for evaluation. If the sex partners are reluctant to have testing, it is reasonable to provide empiric antibiotic treatment to decrease the risk of re-infection in the patient.⁷ Before doing so, however, make certain that state law permits this practice, and be sure to document the prescribed treatment in the patient’s record.

Continue to: Treatment options...

Treatment options

Prompt treatment of C trachomatis infection is essential to decrease the risk of disease sequelae. Nonpregnant adults can be treated with oral doxycycline 100 mg twice daily for 7 days.

In a head-to-head study performed in a controlled environment that ensured treatment adherence, 97% efficacy was achieved with one oral dose of azithromycin (1 g) compared with 100% efficacy with doxycycline.¹⁰ However, in the real-world setting, imperfect adherence to the multi-day doxycycline regimen is associated with treatment failures. Thus, a single dose of azithromycin is preferable for patients with questionable compliance.¹¹

In obstetric patients, azithromycin and amoxicillin are preferred as first-line agents for treatment of C trachomatis due to their improved safety profile in this demographic. Amoxicillin 500 mg orally 3 times daily for 7 days has 95% efficacy.²

Women allergic to these agents may be treated with an alternative regimen of erythromycin base, 500 mg orally 4 times daily for 7 days, or erythromycin ethylsuccinate, 800 mg orally 4 times daily for 7 days. Erythromycin should be reserved for second-line therapy because of its lower efficacy (64%) and frequent gastrointestinal adverse effects.² Doxycycline is contraindicated in pregnancy because of possible teratogenic effects on the teeth and bone of the fetus.

Reference

1. US Preventive Services Task Force. Final recommendation statement: cognitive impairment in older adults: screening. www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cognitive-impairment-in-older-adults-screening. Published February 2020. Accessed March 19, 2020.

Reference

1. US Preventive Services Task Force. Final recommendation statement: cognitive impairment in older adults: screening. www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cognitive-impairment-in-older-adults-screening. Published February 2020. Accessed March 19, 2020.

Reference

1. US Preventive Services Task Force. Final recommendation statement: cognitive impairment in older adults: screening. www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cognitive-impairment-in-older-adults-screening. Published February 2020. Accessed March 19, 2020.

For much of the past 50 years, many of the drugs used in dermatology have been adopted – and often adapted – from other specialties and used for dermatologic conditions.

“Almost every drug was more or less a hand-me-down” developed first for cancer or other diseases and found later, often serendipitously, to be useful for the skin, said William Eaglstein, MD, thinking back to the 1970s and recalling steroids, tetracyclines, methotrexate, and 5-flourouracil. “The perception always was that skin diseases weren’t serious, that the market was small.”

Much has changed. Knowledge about the pathophysiology of dermatologic diseases has exponentially increased, largely because of basic and translational research by dermatologist investigators, and “more and more companies are recognizing the importance of our diseases and the ability to get a return on investment,” said Dr. Eaglstein, past professor and chair of the departments of dermatology at the University of Miami and the University of Pittsburgh, who worked in industry after his academic career.

Psoriasis was a game changer, he and other dermatologists said in interviews. The tumor necrosis factor (TNF)–alpha blockers were first used for other indications, but their marked follow-on success in psoriasis “offered proof of concept clinically – showing that by targeting immune pathways in the skin we could achieve a clinical effect – and proof of concept commercially” that dermatology drugs are worth pursuing by pharmaceutical companies, said William Ju, MD, a cofounder and president of Advancing Innovation in Dermatology, a nonprofit organization that brings together stakeholders to develop novel dermatologic drugs and products.

This resulted in the approval of subsequent biologics, such as ustekinumab (Stelara) which inhibits the signaling of interleukin (IL)–12/IL-23, for psoriasis as their initial indication. Then, biologics targeting IL-17 followed this dermatology-first approach. “Researchers have continued further dissecting out the immunopathological pathways, and antibody drugs targeting IL-23p19 have been approved for psoriasis as the lead indication,” said Dr. Ju, a dermatologist who has worked in industry.

Seth Orlow, MD, PhD, who chairs the department of dermatology at NYU Langone Health, remembers the 1970s through the 1990s as the “era of topicals” developed for dermatologic conditions – topical antifungals, topical corticosteroids, and topical retinoids. The next decade was characterized by formulation tweaks and few novel treatments for dermatology, said Dr. Orlow, who is also professor of pediatric dermatology and director of the program in cutaneous biology at New York University.

Now, given the succession of psoriasis discoveries in the last decade, “large companies are interested in dermatology,” he said in an interview. “There’s an explosion of interest in atopic dermatitis. … and companies are dipping their toes in the water for alopecia areata and vitiligo. That’s amazing.”

Rare diseases like epidermolysis bullosa, ichthyosis, and basal cell nevus syndrome are getting attention as well, boosted by the Orphan Drug Act of 1983, in addition to increased research on disease pathways and growing appreciation of skin diseases. “There’s a lot under development, from small molecules to biologics to gene-based therapies,” Dr. Orlow commented.


 

The new frontier of atopic dermatitis

The approval in 2017 of dupilumab (Dupixent), a monoclonal antibody that inhibits the signaling of both IL-4 and IL-13) for moderate-severe atopic dermatitis (AD) in adults illustrates the new standing of dermatologic diseases in the field of drug development and commercialization. “Atopic dermatitis had always been the forgotten chronic disease in dermatology. … We’ve had no good treatments,” said Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland. “Dupilumab coming to the forefront [as a dermatology-first indication] has changed the entire perspective of the field. … Everyone is now trying to find the next best drug.”

As with psoriasis, a targeted therapy for AD was made possible by the development in the 1990s of monoclonal antibody technology and the ensuing ability to create biologics that target specific molecules in the body – as well as bedside-to-bench research that homed in on the involvement of particular cytokines.

But there also is a “new understanding of the burden of the disease,” Dr. Simpson observed. In the last 5 years, he said, research funded by the National Eczema Association documented that AD “not only causes inflammation of the skin … but that it affects people at school and in the workplace, that people have multiple mental health comorbidities and skin infections, and that the disease profoundly affects the entire patient in ways that weren’t really recognized or appreciated.”

Having evolved in the footsteps of psoriasis, AD is at a higher starting point in terms of the safety and efficacy of its first biologic, sources said. On the other hand, AD is a much more complex and heterogeneous disease, and researchers are trying to determine which immune pathways and cytokines are most important – and in which populations.

“We’re at the beginning. We’re trying to figure out how to get 80% of patients clear or almost clear [as we can now with psoriasis biologics] rather than almost 40% [as in the dupilumab pivotal trials],” said Dr. Simpson, former cochair of the National Eczema Association’s scientific committee. Public data from ongoing phase 2 and 3 trials of other Th2 cytokine inhibitors suggest that 25%-45% of enrolled patients achieve high levels of clearance, he noted.

Emma Guttman-Yassky, MD, PhD, Sol and Clara Kest Professor and vice-chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said that AD’s heterogeneity involves “many factors, like ethnicity, age … and whether they have an atopic background such as asthma.”

Bruce Jancin/MDedge News

Her research is showing, for instance, that AD in Asian and black patients is different than AD in European-American patients, and that the presence of comorbidities may well have treatment implications. She has also shown that children may have a different phenotype than adults, with greater activation of the Th17 axis that typifies psoriasis.

“For certain patients, we may need to target more than one pathway, or target a different pathway than the Th2 pathway. And treatment may be different in the setting of comorbidities,” said Dr. Guttman-Yassky, who is also director of the laboratory of inflammatory skin diseases at Mount Sinai. “We may think of one treatment – dupilumab, for example – for someone who has asthma and AD. But for patients who don’t have asthma and are Asian, for instance, or for children, we may need additional agents.”

Her research over the years on AD has taught her the importance of human studies over mouse model studies; it was in humans, she noted, that she and other investigators demonstrated “without doubt” that AD is an immune disease and not simply a barrier disease. The Th2 cytokine pathway appears to play the predominant role in AD, though “there still is a strong Th1 component,” she said.

“We’re in a better position to figure this out today [than in the past 20 or even 10 years],” said Dr. Guttman-Yassky, who recalls being told years ago that AD was a “dead end,” that it “would kill [her] career.” Given the evolution of science and the recognition of comorbidities and seriousness of dermatologic diseases, “the stars are aligned to get more [therapies] to these patients.”

Janus kinase (JAK) inhibitors are among these therapies. Three JAK inhibitors are in or have recently completed phase 3 studies for AD; two are currently approved for rheumatoid arthritis, and the other has been designed specifically for AD, Dr. Simpson pointed out. The drugs are oral small molecule drugs that block the JAK signaling pathways for certain proinflammatory cytokines.

“The JAK inhibitors are a real exciting story for dermatology,” he said. “Theoretically, by blocking more cytokines than biologics do, there could be some safety issues – that’s why we’re awaiting big phase 3 study results so we can figure out the risk-benefit balance and guide our patients as to which drug is best.”

Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center in Portland – a stand-alone dermatology clinical trial center founded in 1998 – likes to envision the evolution of drugs for dermatologic conditions as a funnel, with the most broad-acting drugs at the wide top of the funnel and the most targeted drugs at the bottom tip.

JAK inhibitors, he said, sit near the middle – more targeted and safer than cyclosporine and methotrexate, for instance, but not as targeted as the biologics now available for psoriasis and being developed for AD. “The oral medications that have been developed for psoriasis and those coming for AD are not quite as targeted to the disease,” he noted. “JAK inhibitors have great efficacy – it’s more a question of safety and being able to treat without causing collateral damage.”

Dr. Blauvelt expects the armamentarium of new drugs approved for AD to go from one (dupilumab) to seven within the next 2 years. This will include three new biologics and three new oral JAK inhibitors, he predicts. As the specialty sorts through and integrates these new drugs into practice, dermatologists will increasingly personalize treatment and will face the “nonscientific” challenge of the cost of new therapies and patient access to them, he noted.

In the meantime, said Dr. Simpson, recent drug discoveries have driven more non–pharmaceutical-funded translational research aimed at understanding the underlying biology of AD. The National Institutes of Health, for instance, “is interested in dupilumab and its impact on the skin barrier and skin defense mechanisms,” he said. “We’ll learn a lot more [in coming years].”
 

Spillover to other diseases

JAK inhibitors – some in oral and some in topical form – are showing efficacy in ongoing research for alopecia areata (AA) and vitiligo as well, Dr. Blauvelt said.

“We’re understanding more about the pathophysiology of these diseases, which historically have been tough diseases for dermatologists to treat,” he said. “The successes in alopecia areata and vitiligo are incredibly exciting actually – it’s very exciting to see hair and pigment coming back. And as we learn more, we should be able to develop [additional] drugs that are more disease targeted than the JAK inhibitors.”

Already, some of the biologics used to treat psoriasis have been studied in patients with hidradenitis suppurativa (HS), a disease in which painful lumps and sometimes tunnels form under the skin, with some success; adalimumab (Humira), a TNF-inhibitor, is now FDA approved for the treatment of moderate-severe HS, and studies are ongoing of IL-17 and IL-23 blockers for the disease.

“The pathophysiology [of HS] is very complex; it’s not nearly as straightforward as psoriasis, and there haven’t been any major breakthroughs yet,” Dr. Blauvelt said. “But the drugs seem to be working better than historical alternatives.”

Regarding AA, Dr. Guttman-Yassky, who is participating in a study of dupilumab for AA, recently found in a retrospective cross-sectional study that patients with the condition are more likely to have atopic comorbidities – asthma, allergic rhinitis, and AD, for instance. “The more comorbid conditions, the greater the risk of developing alopecia areata,” she said. “That could point to a potential pathogenic role of the Th2 axis in the disorder [challenging the traditional view of AA as a singularly Th1-centered disease.] The future will tell.”
 

Action on rare skin diseases

Both large and small companies have moved into the orphan drug space, investing in research and pursuing orphan drug indications for dermatologic conditions, because “it’s clear now in the marketplace that companies can develop effective drugs for rare disorders and be quite successful,” Dr. Orlow said.

According to a recent analysis, as a result of incentives for rare disease drug development contained in the Orphan Drug Act, 72 indications have been approved for rare skin disease, skin-related cancers, and hereditary disorders with prominent dermatologic manifestations since the law was passed in 1983 (J. Am. Acad. Dermatol. 2019;81[3]:867-77).

Epidermolysis bullosa (EB) is a good example, he and other sources said, of commercial interests merging with growing knowledge of disease pathogenesis as well as the tools needed to develop new treatments.

Research by dermatology scientists and others over the past 40 years, Dr. Ju explained, shed light on the molecular basis underlying the structure and function of the junction between the epidermis and dermis, including the pivotal role that type VII collagen plays in the normal adhesion of these two layers. Researchers then learned that, in EB, the family of genetic diseases characterized by skin fragility, “dystrophic types are caused by mutations in the gene encoding type VII collagen,” he said.

“Just as the advent of monoclonal antibodies allowed us to start attacking psoriasis and atopic dermatitis in unprecedented ways, the advent of gene therapy allows us to potentially address the fundamental molecular genetic defect of various types of EB,” Dr. Ju said.

While gene therapy is “still in its infancy,” companies have begun using the tools to address EB. One gene therapy in the pipeline – in phase 3 clinical trial testing – involves grafting back into patients with recessive dystrophic EB their skin cells that have been genetically modified to produce a correct (nonmutated) type VII collagen, he said.

Basal cell nevus syndrome, or Gorlin syndrome, a rare disease in which patients develop a multitude of basal cell carcinoma tumors, is another example of a “dermatology first” approach, Dr. Ju said. Research identified a genetic mutation that causes the hedgehog signaling pathway to be inappropriately activated in the disease, and a drug, vismodegib, was developed to inhibit this pathway. The drug was initially approved for patients with metastatic basal cell cancer and types of advanced basal cell cancer, and is now being tested in cancers affecting other organs, he said.

Basal cell cancer “is a huge market, but it was really unrecognized in the past,” Dr. Eaglstein said. “Seeing drugs come to market for basal cell cancer – this wouldn’t have happened [decades ago].”

Dr. Ju has worked in the pharmaceutical industry; all other sources in this story have worked with pharmaceutical manufacturers of treatments that are being developed or have been approved to treat dermatologic diseases mentioned in this story. In addition to Dr. Ju, Dr. Eaglstein and Dr. Orlow are cofounders of the Advancing Innovation in Dermatology group; Dr. Orlow is a member of the program committee for the organization’s dermatology summit conference.

 

For much of the past 50 years, many of the drugs used in dermatology have been adopted – and often adapted – from other specialties and used for dermatologic conditions.

“Almost every drug was more or less a hand-me-down” developed first for cancer or other diseases and found later, often serendipitously, to be useful for the skin, said William Eaglstein, MD, thinking back to the 1970s and recalling steroids, tetracyclines, methotrexate, and 5-flourouracil. “The perception always was that skin diseases weren’t serious, that the market was small.”

Much has changed. Knowledge about the pathophysiology of dermatologic diseases has exponentially increased, largely because of basic and translational research by dermatologist investigators, and “more and more companies are recognizing the importance of our diseases and the ability to get a return on investment,” said Dr. Eaglstein, past professor and chair of the departments of dermatology at the University of Miami and the University of Pittsburgh, who worked in industry after his academic career.

Psoriasis was a game changer, he and other dermatologists said in interviews. The tumor necrosis factor (TNF)–alpha blockers were first used for other indications, but their marked follow-on success in psoriasis “offered proof of concept clinically – showing that by targeting immune pathways in the skin we could achieve a clinical effect – and proof of concept commercially” that dermatology drugs are worth pursuing by pharmaceutical companies, said William Ju, MD, a cofounder and president of Advancing Innovation in Dermatology, a nonprofit organization that brings together stakeholders to develop novel dermatologic drugs and products.

This resulted in the approval of subsequent biologics, such as ustekinumab (Stelara) which inhibits the signaling of interleukin (IL)–12/IL-23, for psoriasis as their initial indication. Then, biologics targeting IL-17 followed this dermatology-first approach. “Researchers have continued further dissecting out the immunopathological pathways, and antibody drugs targeting IL-23p19 have been approved for psoriasis as the lead indication,” said Dr. Ju, a dermatologist who has worked in industry.

Seth Orlow, MD, PhD, who chairs the department of dermatology at NYU Langone Health, remembers the 1970s through the 1990s as the “era of topicals” developed for dermatologic conditions – topical antifungals, topical corticosteroids, and topical retinoids. The next decade was characterized by formulation tweaks and few novel treatments for dermatology, said Dr. Orlow, who is also professor of pediatric dermatology and director of the program in cutaneous biology at New York University.

Now, given the succession of psoriasis discoveries in the last decade, “large companies are interested in dermatology,” he said in an interview. “There’s an explosion of interest in atopic dermatitis. … and companies are dipping their toes in the water for alopecia areata and vitiligo. That’s amazing.”

Rare diseases like epidermolysis bullosa, ichthyosis, and basal cell nevus syndrome are getting attention as well, boosted by the Orphan Drug Act of 1983, in addition to increased research on disease pathways and growing appreciation of skin diseases. “There’s a lot under development, from small molecules to biologics to gene-based therapies,” Dr. Orlow commented.


 

The new frontier of atopic dermatitis

The approval in 2017 of dupilumab (Dupixent), a monoclonal antibody that inhibits the signaling of both IL-4 and IL-13) for moderate-severe atopic dermatitis (AD) in adults illustrates the new standing of dermatologic diseases in the field of drug development and commercialization. “Atopic dermatitis had always been the forgotten chronic disease in dermatology. … We’ve had no good treatments,” said Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland. “Dupilumab coming to the forefront [as a dermatology-first indication] has changed the entire perspective of the field. … Everyone is now trying to find the next best drug.”

As with psoriasis, a targeted therapy for AD was made possible by the development in the 1990s of monoclonal antibody technology and the ensuing ability to create biologics that target specific molecules in the body – as well as bedside-to-bench research that homed in on the involvement of particular cytokines.

But there also is a “new understanding of the burden of the disease,” Dr. Simpson observed. In the last 5 years, he said, research funded by the National Eczema Association documented that AD “not only causes inflammation of the skin … but that it affects people at school and in the workplace, that people have multiple mental health comorbidities and skin infections, and that the disease profoundly affects the entire patient in ways that weren’t really recognized or appreciated.”

Having evolved in the footsteps of psoriasis, AD is at a higher starting point in terms of the safety and efficacy of its first biologic, sources said. On the other hand, AD is a much more complex and heterogeneous disease, and researchers are trying to determine which immune pathways and cytokines are most important – and in which populations.

“We’re at the beginning. We’re trying to figure out how to get 80% of patients clear or almost clear [as we can now with psoriasis biologics] rather than almost 40% [as in the dupilumab pivotal trials],” said Dr. Simpson, former cochair of the National Eczema Association’s scientific committee. Public data from ongoing phase 2 and 3 trials of other Th2 cytokine inhibitors suggest that 25%-45% of enrolled patients achieve high levels of clearance, he noted.

Emma Guttman-Yassky, MD, PhD, Sol and Clara Kest Professor and vice-chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said that AD’s heterogeneity involves “many factors, like ethnicity, age … and whether they have an atopic background such as asthma.”

Bruce Jancin/MDedge News

Her research is showing, for instance, that AD in Asian and black patients is different than AD in European-American patients, and that the presence of comorbidities may well have treatment implications. She has also shown that children may have a different phenotype than adults, with greater activation of the Th17 axis that typifies psoriasis.

“For certain patients, we may need to target more than one pathway, or target a different pathway than the Th2 pathway. And treatment may be different in the setting of comorbidities,” said Dr. Guttman-Yassky, who is also director of the laboratory of inflammatory skin diseases at Mount Sinai. “We may think of one treatment – dupilumab, for example – for someone who has asthma and AD. But for patients who don’t have asthma and are Asian, for instance, or for children, we may need additional agents.”

Her research over the years on AD has taught her the importance of human studies over mouse model studies; it was in humans, she noted, that she and other investigators demonstrated “without doubt” that AD is an immune disease and not simply a barrier disease. The Th2 cytokine pathway appears to play the predominant role in AD, though “there still is a strong Th1 component,” she said.

“We’re in a better position to figure this out today [than in the past 20 or even 10 years],” said Dr. Guttman-Yassky, who recalls being told years ago that AD was a “dead end,” that it “would kill [her] career.” Given the evolution of science and the recognition of comorbidities and seriousness of dermatologic diseases, “the stars are aligned to get more [therapies] to these patients.”

Janus kinase (JAK) inhibitors are among these therapies. Three JAK inhibitors are in or have recently completed phase 3 studies for AD; two are currently approved for rheumatoid arthritis, and the other has been designed specifically for AD, Dr. Simpson pointed out. The drugs are oral small molecule drugs that block the JAK signaling pathways for certain proinflammatory cytokines.

“The JAK inhibitors are a real exciting story for dermatology,” he said. “Theoretically, by blocking more cytokines than biologics do, there could be some safety issues – that’s why we’re awaiting big phase 3 study results so we can figure out the risk-benefit balance and guide our patients as to which drug is best.”

Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center in Portland – a stand-alone dermatology clinical trial center founded in 1998 – likes to envision the evolution of drugs for dermatologic conditions as a funnel, with the most broad-acting drugs at the wide top of the funnel and the most targeted drugs at the bottom tip.

JAK inhibitors, he said, sit near the middle – more targeted and safer than cyclosporine and methotrexate, for instance, but not as targeted as the biologics now available for psoriasis and being developed for AD. “The oral medications that have been developed for psoriasis and those coming for AD are not quite as targeted to the disease,” he noted. “JAK inhibitors have great efficacy – it’s more a question of safety and being able to treat without causing collateral damage.”

Dr. Blauvelt expects the armamentarium of new drugs approved for AD to go from one (dupilumab) to seven within the next 2 years. This will include three new biologics and three new oral JAK inhibitors, he predicts. As the specialty sorts through and integrates these new drugs into practice, dermatologists will increasingly personalize treatment and will face the “nonscientific” challenge of the cost of new therapies and patient access to them, he noted.

In the meantime, said Dr. Simpson, recent drug discoveries have driven more non–pharmaceutical-funded translational research aimed at understanding the underlying biology of AD. The National Institutes of Health, for instance, “is interested in dupilumab and its impact on the skin barrier and skin defense mechanisms,” he said. “We’ll learn a lot more [in coming years].”
 

Spillover to other diseases

JAK inhibitors – some in oral and some in topical form – are showing efficacy in ongoing research for alopecia areata (AA) and vitiligo as well, Dr. Blauvelt said.

“We’re understanding more about the pathophysiology of these diseases, which historically have been tough diseases for dermatologists to treat,” he said. “The successes in alopecia areata and vitiligo are incredibly exciting actually – it’s very exciting to see hair and pigment coming back. And as we learn more, we should be able to develop [additional] drugs that are more disease targeted than the JAK inhibitors.”

Already, some of the biologics used to treat psoriasis have been studied in patients with hidradenitis suppurativa (HS), a disease in which painful lumps and sometimes tunnels form under the skin, with some success; adalimumab (Humira), a TNF-inhibitor, is now FDA approved for the treatment of moderate-severe HS, and studies are ongoing of IL-17 and IL-23 blockers for the disease.

“The pathophysiology [of HS] is very complex; it’s not nearly as straightforward as psoriasis, and there haven’t been any major breakthroughs yet,” Dr. Blauvelt said. “But the drugs seem to be working better than historical alternatives.”

Regarding AA, Dr. Guttman-Yassky, who is participating in a study of dupilumab for AA, recently found in a retrospective cross-sectional study that patients with the condition are more likely to have atopic comorbidities – asthma, allergic rhinitis, and AD, for instance. “The more comorbid conditions, the greater the risk of developing alopecia areata,” she said. “That could point to a potential pathogenic role of the Th2 axis in the disorder [challenging the traditional view of AA as a singularly Th1-centered disease.] The future will tell.”
 

Action on rare skin diseases

Both large and small companies have moved into the orphan drug space, investing in research and pursuing orphan drug indications for dermatologic conditions, because “it’s clear now in the marketplace that companies can develop effective drugs for rare disorders and be quite successful,” Dr. Orlow said.

According to a recent analysis, as a result of incentives for rare disease drug development contained in the Orphan Drug Act, 72 indications have been approved for rare skin disease, skin-related cancers, and hereditary disorders with prominent dermatologic manifestations since the law was passed in 1983 (J. Am. Acad. Dermatol. 2019;81[3]:867-77).

Epidermolysis bullosa (EB) is a good example, he and other sources said, of commercial interests merging with growing knowledge of disease pathogenesis as well as the tools needed to develop new treatments.

Research by dermatology scientists and others over the past 40 years, Dr. Ju explained, shed light on the molecular basis underlying the structure and function of the junction between the epidermis and dermis, including the pivotal role that type VII collagen plays in the normal adhesion of these two layers. Researchers then learned that, in EB, the family of genetic diseases characterized by skin fragility, “dystrophic types are caused by mutations in the gene encoding type VII collagen,” he said.

“Just as the advent of monoclonal antibodies allowed us to start attacking psoriasis and atopic dermatitis in unprecedented ways, the advent of gene therapy allows us to potentially address the fundamental molecular genetic defect of various types of EB,” Dr. Ju said.

While gene therapy is “still in its infancy,” companies have begun using the tools to address EB. One gene therapy in the pipeline – in phase 3 clinical trial testing – involves grafting back into patients with recessive dystrophic EB their skin cells that have been genetically modified to produce a correct (nonmutated) type VII collagen, he said.

Basal cell nevus syndrome, or Gorlin syndrome, a rare disease in which patients develop a multitude of basal cell carcinoma tumors, is another example of a “dermatology first” approach, Dr. Ju said. Research identified a genetic mutation that causes the hedgehog signaling pathway to be inappropriately activated in the disease, and a drug, vismodegib, was developed to inhibit this pathway. The drug was initially approved for patients with metastatic basal cell cancer and types of advanced basal cell cancer, and is now being tested in cancers affecting other organs, he said.

Basal cell cancer “is a huge market, but it was really unrecognized in the past,” Dr. Eaglstein said. “Seeing drugs come to market for basal cell cancer – this wouldn’t have happened [decades ago].”

Dr. Ju has worked in the pharmaceutical industry; all other sources in this story have worked with pharmaceutical manufacturers of treatments that are being developed or have been approved to treat dermatologic diseases mentioned in this story. In addition to Dr. Ju, Dr. Eaglstein and Dr. Orlow are cofounders of the Advancing Innovation in Dermatology group; Dr. Orlow is a member of the program committee for the organization’s dermatology summit conference.

 

For much of the past 50 years, many of the drugs used in dermatology have been adopted – and often adapted – from other specialties and used for dermatologic conditions.

“Almost every drug was more or less a hand-me-down” developed first for cancer or other diseases and found later, often serendipitously, to be useful for the skin, said William Eaglstein, MD, thinking back to the 1970s and recalling steroids, tetracyclines, methotrexate, and 5-flourouracil. “The perception always was that skin diseases weren’t serious, that the market was small.”

Much has changed. Knowledge about the pathophysiology of dermatologic diseases has exponentially increased, largely because of basic and translational research by dermatologist investigators, and “more and more companies are recognizing the importance of our diseases and the ability to get a return on investment,” said Dr. Eaglstein, past professor and chair of the departments of dermatology at the University of Miami and the University of Pittsburgh, who worked in industry after his academic career.

Psoriasis was a game changer, he and other dermatologists said in interviews. The tumor necrosis factor (TNF)–alpha blockers were first used for other indications, but their marked follow-on success in psoriasis “offered proof of concept clinically – showing that by targeting immune pathways in the skin we could achieve a clinical effect – and proof of concept commercially” that dermatology drugs are worth pursuing by pharmaceutical companies, said William Ju, MD, a cofounder and president of Advancing Innovation in Dermatology, a nonprofit organization that brings together stakeholders to develop novel dermatologic drugs and products.

This resulted in the approval of subsequent biologics, such as ustekinumab (Stelara) which inhibits the signaling of interleukin (IL)–12/IL-23, for psoriasis as their initial indication. Then, biologics targeting IL-17 followed this dermatology-first approach. “Researchers have continued further dissecting out the immunopathological pathways, and antibody drugs targeting IL-23p19 have been approved for psoriasis as the lead indication,” said Dr. Ju, a dermatologist who has worked in industry.

Seth Orlow, MD, PhD, who chairs the department of dermatology at NYU Langone Health, remembers the 1970s through the 1990s as the “era of topicals” developed for dermatologic conditions – topical antifungals, topical corticosteroids, and topical retinoids. The next decade was characterized by formulation tweaks and few novel treatments for dermatology, said Dr. Orlow, who is also professor of pediatric dermatology and director of the program in cutaneous biology at New York University.

Now, given the succession of psoriasis discoveries in the last decade, “large companies are interested in dermatology,” he said in an interview. “There’s an explosion of interest in atopic dermatitis. … and companies are dipping their toes in the water for alopecia areata and vitiligo. That’s amazing.”

Rare diseases like epidermolysis bullosa, ichthyosis, and basal cell nevus syndrome are getting attention as well, boosted by the Orphan Drug Act of 1983, in addition to increased research on disease pathways and growing appreciation of skin diseases. “There’s a lot under development, from small molecules to biologics to gene-based therapies,” Dr. Orlow commented.


 

The new frontier of atopic dermatitis

The approval in 2017 of dupilumab (Dupixent), a monoclonal antibody that inhibits the signaling of both IL-4 and IL-13) for moderate-severe atopic dermatitis (AD) in adults illustrates the new standing of dermatologic diseases in the field of drug development and commercialization. “Atopic dermatitis had always been the forgotten chronic disease in dermatology. … We’ve had no good treatments,” said Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland. “Dupilumab coming to the forefront [as a dermatology-first indication] has changed the entire perspective of the field. … Everyone is now trying to find the next best drug.”

As with psoriasis, a targeted therapy for AD was made possible by the development in the 1990s of monoclonal antibody technology and the ensuing ability to create biologics that target specific molecules in the body – as well as bedside-to-bench research that homed in on the involvement of particular cytokines.

But there also is a “new understanding of the burden of the disease,” Dr. Simpson observed. In the last 5 years, he said, research funded by the National Eczema Association documented that AD “not only causes inflammation of the skin … but that it affects people at school and in the workplace, that people have multiple mental health comorbidities and skin infections, and that the disease profoundly affects the entire patient in ways that weren’t really recognized or appreciated.”

Having evolved in the footsteps of psoriasis, AD is at a higher starting point in terms of the safety and efficacy of its first biologic, sources said. On the other hand, AD is a much more complex and heterogeneous disease, and researchers are trying to determine which immune pathways and cytokines are most important – and in which populations.

“We’re at the beginning. We’re trying to figure out how to get 80% of patients clear or almost clear [as we can now with psoriasis biologics] rather than almost 40% [as in the dupilumab pivotal trials],” said Dr. Simpson, former cochair of the National Eczema Association’s scientific committee. Public data from ongoing phase 2 and 3 trials of other Th2 cytokine inhibitors suggest that 25%-45% of enrolled patients achieve high levels of clearance, he noted.

Emma Guttman-Yassky, MD, PhD, Sol and Clara Kest Professor and vice-chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said that AD’s heterogeneity involves “many factors, like ethnicity, age … and whether they have an atopic background such as asthma.”

Bruce Jancin/MDedge News

Her research is showing, for instance, that AD in Asian and black patients is different than AD in European-American patients, and that the presence of comorbidities may well have treatment implications. She has also shown that children may have a different phenotype than adults, with greater activation of the Th17 axis that typifies psoriasis.

“For certain patients, we may need to target more than one pathway, or target a different pathway than the Th2 pathway. And treatment may be different in the setting of comorbidities,” said Dr. Guttman-Yassky, who is also director of the laboratory of inflammatory skin diseases at Mount Sinai. “We may think of one treatment – dupilumab, for example – for someone who has asthma and AD. But for patients who don’t have asthma and are Asian, for instance, or for children, we may need additional agents.”

Her research over the years on AD has taught her the importance of human studies over mouse model studies; it was in humans, she noted, that she and other investigators demonstrated “without doubt” that AD is an immune disease and not simply a barrier disease. The Th2 cytokine pathway appears to play the predominant role in AD, though “there still is a strong Th1 component,” she said.

“We’re in a better position to figure this out today [than in the past 20 or even 10 years],” said Dr. Guttman-Yassky, who recalls being told years ago that AD was a “dead end,” that it “would kill [her] career.” Given the evolution of science and the recognition of comorbidities and seriousness of dermatologic diseases, “the stars are aligned to get more [therapies] to these patients.”

Janus kinase (JAK) inhibitors are among these therapies. Three JAK inhibitors are in or have recently completed phase 3 studies for AD; two are currently approved for rheumatoid arthritis, and the other has been designed specifically for AD, Dr. Simpson pointed out. The drugs are oral small molecule drugs that block the JAK signaling pathways for certain proinflammatory cytokines.

“The JAK inhibitors are a real exciting story for dermatology,” he said. “Theoretically, by blocking more cytokines than biologics do, there could be some safety issues – that’s why we’re awaiting big phase 3 study results so we can figure out the risk-benefit balance and guide our patients as to which drug is best.”

Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center in Portland – a stand-alone dermatology clinical trial center founded in 1998 – likes to envision the evolution of drugs for dermatologic conditions as a funnel, with the most broad-acting drugs at the wide top of the funnel and the most targeted drugs at the bottom tip.

JAK inhibitors, he said, sit near the middle – more targeted and safer than cyclosporine and methotrexate, for instance, but not as targeted as the biologics now available for psoriasis and being developed for AD. “The oral medications that have been developed for psoriasis and those coming for AD are not quite as targeted to the disease,” he noted. “JAK inhibitors have great efficacy – it’s more a question of safety and being able to treat without causing collateral damage.”

Dr. Blauvelt expects the armamentarium of new drugs approved for AD to go from one (dupilumab) to seven within the next 2 years. This will include three new biologics and three new oral JAK inhibitors, he predicts. As the specialty sorts through and integrates these new drugs into practice, dermatologists will increasingly personalize treatment and will face the “nonscientific” challenge of the cost of new therapies and patient access to them, he noted.

In the meantime, said Dr. Simpson, recent drug discoveries have driven more non–pharmaceutical-funded translational research aimed at understanding the underlying biology of AD. The National Institutes of Health, for instance, “is interested in dupilumab and its impact on the skin barrier and skin defense mechanisms,” he said. “We’ll learn a lot more [in coming years].”
 

Spillover to other diseases

JAK inhibitors – some in oral and some in topical form – are showing efficacy in ongoing research for alopecia areata (AA) and vitiligo as well, Dr. Blauvelt said.

“We’re understanding more about the pathophysiology of these diseases, which historically have been tough diseases for dermatologists to treat,” he said. “The successes in alopecia areata and vitiligo are incredibly exciting actually – it’s very exciting to see hair and pigment coming back. And as we learn more, we should be able to develop [additional] drugs that are more disease targeted than the JAK inhibitors.”

Already, some of the biologics used to treat psoriasis have been studied in patients with hidradenitis suppurativa (HS), a disease in which painful lumps and sometimes tunnels form under the skin, with some success; adalimumab (Humira), a TNF-inhibitor, is now FDA approved for the treatment of moderate-severe HS, and studies are ongoing of IL-17 and IL-23 blockers for the disease.

“The pathophysiology [of HS] is very complex; it’s not nearly as straightforward as psoriasis, and there haven’t been any major breakthroughs yet,” Dr. Blauvelt said. “But the drugs seem to be working better than historical alternatives.”

Regarding AA, Dr. Guttman-Yassky, who is participating in a study of dupilumab for AA, recently found in a retrospective cross-sectional study that patients with the condition are more likely to have atopic comorbidities – asthma, allergic rhinitis, and AD, for instance. “The more comorbid conditions, the greater the risk of developing alopecia areata,” she said. “That could point to a potential pathogenic role of the Th2 axis in the disorder [challenging the traditional view of AA as a singularly Th1-centered disease.] The future will tell.”
 

Action on rare skin diseases

Both large and small companies have moved into the orphan drug space, investing in research and pursuing orphan drug indications for dermatologic conditions, because “it’s clear now in the marketplace that companies can develop effective drugs for rare disorders and be quite successful,” Dr. Orlow said.

According to a recent analysis, as a result of incentives for rare disease drug development contained in the Orphan Drug Act, 72 indications have been approved for rare skin disease, skin-related cancers, and hereditary disorders with prominent dermatologic manifestations since the law was passed in 1983 (J. Am. Acad. Dermatol. 2019;81[3]:867-77).

Epidermolysis bullosa (EB) is a good example, he and other sources said, of commercial interests merging with growing knowledge of disease pathogenesis as well as the tools needed to develop new treatments.

Research by dermatology scientists and others over the past 40 years, Dr. Ju explained, shed light on the molecular basis underlying the structure and function of the junction between the epidermis and dermis, including the pivotal role that type VII collagen plays in the normal adhesion of these two layers. Researchers then learned that, in EB, the family of genetic diseases characterized by skin fragility, “dystrophic types are caused by mutations in the gene encoding type VII collagen,” he said.

“Just as the advent of monoclonal antibodies allowed us to start attacking psoriasis and atopic dermatitis in unprecedented ways, the advent of gene therapy allows us to potentially address the fundamental molecular genetic defect of various types of EB,” Dr. Ju said.

While gene therapy is “still in its infancy,” companies have begun using the tools to address EB. One gene therapy in the pipeline – in phase 3 clinical trial testing – involves grafting back into patients with recessive dystrophic EB their skin cells that have been genetically modified to produce a correct (nonmutated) type VII collagen, he said.

Basal cell nevus syndrome, or Gorlin syndrome, a rare disease in which patients develop a multitude of basal cell carcinoma tumors, is another example of a “dermatology first” approach, Dr. Ju said. Research identified a genetic mutation that causes the hedgehog signaling pathway to be inappropriately activated in the disease, and a drug, vismodegib, was developed to inhibit this pathway. The drug was initially approved for patients with metastatic basal cell cancer and types of advanced basal cell cancer, and is now being tested in cancers affecting other organs, he said.

Basal cell cancer “is a huge market, but it was really unrecognized in the past,” Dr. Eaglstein said. “Seeing drugs come to market for basal cell cancer – this wouldn’t have happened [decades ago].”

Dr. Ju has worked in the pharmaceutical industry; all other sources in this story have worked with pharmaceutical manufacturers of treatments that are being developed or have been approved to treat dermatologic diseases mentioned in this story. In addition to Dr. Ju, Dr. Eaglstein and Dr. Orlow are cofounders of the Advancing Innovation in Dermatology group; Dr. Orlow is a member of the program committee for the organization’s dermatology summit conference.