Within hospital medicine, there has been a recent increase in programs that provide virtual or telehealth hospitalists, primarily to hospitals that are small, remote, and/or understaffed. According to a 2013 Cisco health care customer experience report, the number of telehealth consumers will likely markedly increase to at least 7 million by 2018.¹

Since telehospitalist programs are still relatively new, there are many questions about why and how they exist and how they are (and can be) funded. Questions also remain about some limitations of telehospitalist programs for both the “givers” and the “receivers” of the services. I tackle some of these questions in this article.

What is a telehospitalist?

A telehospitalist is a hospitalist who provides remote services to patients and providers in need of such services. These services can range from initial encounters, follow-up encounters, post-acute care visits, home visits, consultations, and emergency care.

What are the drivers of telehospitalist programs?

One primary driver of telehealth (and specifically telehospitalist) programs is an ongoing shortage of hospitalists, especially in remote areas and critical access hospitals where coverage issues are especially prominent at night and/or on weekends. In many hospitals, there is also a growing unwillingness on the part of physicians to be routinely on call at night. Although working on call used to be on par with being a physician, many younger-generation physicians are less willing to blur “work and life.” This increases the need for dedicated night coverage in many hospitals.

Another driver for some programs (especially at tertiary care medical centers) is a desire to more thoroughly assess patients prior to transfer to their respective centers (the alternative being a phone conversation with the transferring center about the patient’s status). There is also a growing desire to keep patients local if possible, which is usually better for the patient and the family and can decrease the total cost of their care.

Another catalyst to telehospitalist program growth is the growing cultural comfort level with two-way video interactions, such as Skype and FaceTime. Since videoconferencing has permeated most of our professional and personal lives, telehealth seems familiar and comfortable for both providers and patients. In a recent consumer survey, three out of every four consumers responded that they are very comfortable communicating with providers via technology, as opposed to seeing them in person.¹

Another driver for some programs is financial. Depending on the way the program is structured, it can be not only financially feasible but financially beneficial, especially if the program can consolidate coverage across multiple sites (more on this later).

One other driver for some health care systems is the need to cover areas with on-site nurse practitioners and physician assistants. Using a telehospitalist makes it easier to get appropriate and required oversight for this coverage model across time and space.

What are the advantages of being a telehospitalist?

Some of the career advantages of being a telehospitalist include the shift flexibility and convenience. This work allows a hospitalist to serve a shift from anywhere in the world and from the convenience of their home. Some telehospitalists can easily work local night shifts when they live many time zones away (and therefore, don’t actually have to work a night shift). Many programs are designed to have a single hospitalist cover many hospitals over a wide geography, which would be logistically impossible to do in person. This is especially appealing for multihospital systems that cannot afford to have a hospitalist on site at each location.

The earning potential can also be appealing, depending on the number of shifts a hospitalist is willing to work.

What are the limitations of being a telehospitalist?

There are limits to what a telehospitalist can perform, many of which depend on the manner in which the program and the technology are arranged. Telehealth can vary from a cart-based videoconferencing system that is transported into a patient’s room to an independent robot that travels throughout sites. The primary limitation is the need to rely on someone in the patient’s room to act as virtual hands. This usually falls to the bedside nurse and requires a good working relationship and patience on their part. The bedside nurses have to “buy into” the program in advance and may need to have scripting for how to explain the process to the patients.

Another major challenge is interacting with different electronic health record systems. Becoming agile with a single EHR is challenging enough, but maneuvering several of them in a single shift can be extremely trying. Telehospitalists can also be challenged by technology glitches or failures that need troubleshooting both on their end and on-site. Although these problems are rare, there will always be a concern that the patient will not get his or her needs met if the technology fails.

 

How does the financing work?

Although this is a rapidly changing landscape, telehospitalists are not currently able to generate much revenue from professional billing. Unlike in-person visits, Medicare will not reimburse professional fees for telehospitalist visits. Although each payer is unique, most other (nonMedicare) payers are also not willing to reimburse for televisits. This may change in the future, however, as Medicare does pay for virtual specialty services such as telestroke. In addition, many states have enacted telemedicine parity laws, which require private payers to pay for all health care services equally, regardless of modality (audio, video, or in person).

For now, the financial case for employing telehospitalists for most programs has to be made using benfits other than the generation of professional fees. For telehospitalist programs that can cover several sites, the cost is substantially less than employing individual on-site hospitalists to do low-volume work. Telehospitalist programs are also, likely, less costly than is locum tenens staffing. For programs that evaluate the need for transfers, a case can be made that keeping a patient in a smaller, low-cost venue, rather than transferring them to a larger, higher-cost venue, can also reduce overall cost for a health care system.

What about licensing and credentialing?

Telehospitalists can be hindered by the need to have a license in several states and to be credentialed in several systems. This can be cumbersome, time-consuming, and expensive. To ease the multistate licensing burden, the Interstate Medical Licensure Compact has been established.² This is an accelerated licensure process for eligible physicians that improves license portability across states. There are currently 18 states that participate, and the number continues to increase.

For credentialing, most hospitals require initial credentialing and full recredentialing every 2 years. Maintaining credentials at several sites can be extremely time consuming. To ease this burden, some hospitals with telehealth programs have adopted “credentialing by proxy,” which means that one hospital will accept the credentialing process of another facility.

What next?

In summary, there has been and will likely continue to be explosive growth of telehospitalist programs and providers for all the reasons outlined above. Although some barriers to efficient and effective practice do exist, many of those barriers are being overcome quite rapidly. I expect this growth to continue for the betterment of hospitalists, our patients, and the systems in which we work. For a more in-depth look into telemedicine in hospital medicine, view a report created by a work group of SHM's Practice Management Committee.

Dr. Scheurer is a hospitalist and chief quality officer at the Medical University of South Carolina in Charleston. She is physician editor of The Hospitalist. Email her at [email protected].

References

1.Cisco. (2013 March 4). Cisco Study Reveals 74 Percent of Consumers Open to Virtual Doctor Visit. Cisco: The Network. Retrieved from https://newsroom.cisco.com/press-release-content?type=webcontent&articleId=1148539.

2. Interstate Medical Licensure Compact Commission. (2017). Interstate Medical Licensure Compact. Retrieved from http://www.licenseportability.org/index.html.

 

Within hospital medicine, there has been a recent increase in programs that provide virtual or telehealth hospitalists, primarily to hospitals that are small, remote, and/or understaffed. According to a 2013 Cisco health care customer experience report, the number of telehealth consumers will likely markedly increase to at least 7 million by 2018.¹

Since telehospitalist programs are still relatively new, there are many questions about why and how they exist and how they are (and can be) funded. Questions also remain about some limitations of telehospitalist programs for both the “givers” and the “receivers” of the services. I tackle some of these questions in this article.

What is a telehospitalist?

A telehospitalist is a hospitalist who provides remote services to patients and providers in need of such services. These services can range from initial encounters, follow-up encounters, post-acute care visits, home visits, consultations, and emergency care.

What are the drivers of telehospitalist programs?

One primary driver of telehealth (and specifically telehospitalist) programs is an ongoing shortage of hospitalists, especially in remote areas and critical access hospitals where coverage issues are especially prominent at night and/or on weekends. In many hospitals, there is also a growing unwillingness on the part of physicians to be routinely on call at night. Although working on call used to be on par with being a physician, many younger-generation physicians are less willing to blur “work and life.” This increases the need for dedicated night coverage in many hospitals.

Another driver for some programs (especially at tertiary care medical centers) is a desire to more thoroughly assess patients prior to transfer to their respective centers (the alternative being a phone conversation with the transferring center about the patient’s status). There is also a growing desire to keep patients local if possible, which is usually better for the patient and the family and can decrease the total cost of their care.

Another catalyst to telehospitalist program growth is the growing cultural comfort level with two-way video interactions, such as Skype and FaceTime. Since videoconferencing has permeated most of our professional and personal lives, telehealth seems familiar and comfortable for both providers and patients. In a recent consumer survey, three out of every four consumers responded that they are very comfortable communicating with providers via technology, as opposed to seeing them in person.¹

Another driver for some programs is financial. Depending on the way the program is structured, it can be not only financially feasible but financially beneficial, especially if the program can consolidate coverage across multiple sites (more on this later).

One other driver for some health care systems is the need to cover areas with on-site nurse practitioners and physician assistants. Using a telehospitalist makes it easier to get appropriate and required oversight for this coverage model across time and space.

What are the advantages of being a telehospitalist?

Some of the career advantages of being a telehospitalist include the shift flexibility and convenience. This work allows a hospitalist to serve a shift from anywhere in the world and from the convenience of their home. Some telehospitalists can easily work local night shifts when they live many time zones away (and therefore, don’t actually have to work a night shift). Many programs are designed to have a single hospitalist cover many hospitals over a wide geography, which would be logistically impossible to do in person. This is especially appealing for multihospital systems that cannot afford to have a hospitalist on site at each location.

The earning potential can also be appealing, depending on the number of shifts a hospitalist is willing to work.

What are the limitations of being a telehospitalist?

There are limits to what a telehospitalist can perform, many of which depend on the manner in which the program and the technology are arranged. Telehealth can vary from a cart-based videoconferencing system that is transported into a patient’s room to an independent robot that travels throughout sites. The primary limitation is the need to rely on someone in the patient’s room to act as virtual hands. This usually falls to the bedside nurse and requires a good working relationship and patience on their part. The bedside nurses have to “buy into” the program in advance and may need to have scripting for how to explain the process to the patients.

Another major challenge is interacting with different electronic health record systems. Becoming agile with a single EHR is challenging enough, but maneuvering several of them in a single shift can be extremely trying. Telehospitalists can also be challenged by technology glitches or failures that need troubleshooting both on their end and on-site. Although these problems are rare, there will always be a concern that the patient will not get his or her needs met if the technology fails.

 

How does the financing work?

Although this is a rapidly changing landscape, telehospitalists are not currently able to generate much revenue from professional billing. Unlike in-person visits, Medicare will not reimburse professional fees for telehospitalist visits. Although each payer is unique, most other (nonMedicare) payers are also not willing to reimburse for televisits. This may change in the future, however, as Medicare does pay for virtual specialty services such as telestroke. In addition, many states have enacted telemedicine parity laws, which require private payers to pay for all health care services equally, regardless of modality (audio, video, or in person).

For now, the financial case for employing telehospitalists for most programs has to be made using benfits other than the generation of professional fees. For telehospitalist programs that can cover several sites, the cost is substantially less than employing individual on-site hospitalists to do low-volume work. Telehospitalist programs are also, likely, less costly than is locum tenens staffing. For programs that evaluate the need for transfers, a case can be made that keeping a patient in a smaller, low-cost venue, rather than transferring them to a larger, higher-cost venue, can also reduce overall cost for a health care system.

What about licensing and credentialing?

Telehospitalists can be hindered by the need to have a license in several states and to be credentialed in several systems. This can be cumbersome, time-consuming, and expensive. To ease the multistate licensing burden, the Interstate Medical Licensure Compact has been established.² This is an accelerated licensure process for eligible physicians that improves license portability across states. There are currently 18 states that participate, and the number continues to increase.

For credentialing, most hospitals require initial credentialing and full recredentialing every 2 years. Maintaining credentials at several sites can be extremely time consuming. To ease this burden, some hospitals with telehealth programs have adopted “credentialing by proxy,” which means that one hospital will accept the credentialing process of another facility.

What next?

In summary, there has been and will likely continue to be explosive growth of telehospitalist programs and providers for all the reasons outlined above. Although some barriers to efficient and effective practice do exist, many of those barriers are being overcome quite rapidly. I expect this growth to continue for the betterment of hospitalists, our patients, and the systems in which we work. For a more in-depth look into telemedicine in hospital medicine, view a report created by a work group of SHM's Practice Management Committee.

Dr. Scheurer is a hospitalist and chief quality officer at the Medical University of South Carolina in Charleston. She is physician editor of The Hospitalist. Email her at [email protected].

References

1.Cisco. (2013 March 4). Cisco Study Reveals 74 Percent of Consumers Open to Virtual Doctor Visit. Cisco: The Network. Retrieved from https://newsroom.cisco.com/press-release-content?type=webcontent&articleId=1148539.

2. Interstate Medical Licensure Compact Commission. (2017). Interstate Medical Licensure Compact. Retrieved from http://www.licenseportability.org/index.html.

 

Within hospital medicine, there has been a recent increase in programs that provide virtual or telehealth hospitalists, primarily to hospitals that are small, remote, and/or understaffed. According to a 2013 Cisco health care customer experience report, the number of telehealth consumers will likely markedly increase to at least 7 million by 2018.¹

Since telehospitalist programs are still relatively new, there are many questions about why and how they exist and how they are (and can be) funded. Questions also remain about some limitations of telehospitalist programs for both the “givers” and the “receivers” of the services. I tackle some of these questions in this article.

What is a telehospitalist?

A telehospitalist is a hospitalist who provides remote services to patients and providers in need of such services. These services can range from initial encounters, follow-up encounters, post-acute care visits, home visits, consultations, and emergency care.

What are the drivers of telehospitalist programs?

One primary driver of telehealth (and specifically telehospitalist) programs is an ongoing shortage of hospitalists, especially in remote areas and critical access hospitals where coverage issues are especially prominent at night and/or on weekends. In many hospitals, there is also a growing unwillingness on the part of physicians to be routinely on call at night. Although working on call used to be on par with being a physician, many younger-generation physicians are less willing to blur “work and life.” This increases the need for dedicated night coverage in many hospitals.

Another driver for some programs (especially at tertiary care medical centers) is a desire to more thoroughly assess patients prior to transfer to their respective centers (the alternative being a phone conversation with the transferring center about the patient’s status). There is also a growing desire to keep patients local if possible, which is usually better for the patient and the family and can decrease the total cost of their care.

Another catalyst to telehospitalist program growth is the growing cultural comfort level with two-way video interactions, such as Skype and FaceTime. Since videoconferencing has permeated most of our professional and personal lives, telehealth seems familiar and comfortable for both providers and patients. In a recent consumer survey, three out of every four consumers responded that they are very comfortable communicating with providers via technology, as opposed to seeing them in person.¹

Another driver for some programs is financial. Depending on the way the program is structured, it can be not only financially feasible but financially beneficial, especially if the program can consolidate coverage across multiple sites (more on this later).

One other driver for some health care systems is the need to cover areas with on-site nurse practitioners and physician assistants. Using a telehospitalist makes it easier to get appropriate and required oversight for this coverage model across time and space.

What are the advantages of being a telehospitalist?

Some of the career advantages of being a telehospitalist include the shift flexibility and convenience. This work allows a hospitalist to serve a shift from anywhere in the world and from the convenience of their home. Some telehospitalists can easily work local night shifts when they live many time zones away (and therefore, don’t actually have to work a night shift). Many programs are designed to have a single hospitalist cover many hospitals over a wide geography, which would be logistically impossible to do in person. This is especially appealing for multihospital systems that cannot afford to have a hospitalist on site at each location.

The earning potential can also be appealing, depending on the number of shifts a hospitalist is willing to work.

What are the limitations of being a telehospitalist?

There are limits to what a telehospitalist can perform, many of which depend on the manner in which the program and the technology are arranged. Telehealth can vary from a cart-based videoconferencing system that is transported into a patient’s room to an independent robot that travels throughout sites. The primary limitation is the need to rely on someone in the patient’s room to act as virtual hands. This usually falls to the bedside nurse and requires a good working relationship and patience on their part. The bedside nurses have to “buy into” the program in advance and may need to have scripting for how to explain the process to the patients.

Another major challenge is interacting with different electronic health record systems. Becoming agile with a single EHR is challenging enough, but maneuvering several of them in a single shift can be extremely trying. Telehospitalists can also be challenged by technology glitches or failures that need troubleshooting both on their end and on-site. Although these problems are rare, there will always be a concern that the patient will not get his or her needs met if the technology fails.

 

How does the financing work?

Although this is a rapidly changing landscape, telehospitalists are not currently able to generate much revenue from professional billing. Unlike in-person visits, Medicare will not reimburse professional fees for telehospitalist visits. Although each payer is unique, most other (nonMedicare) payers are also not willing to reimburse for televisits. This may change in the future, however, as Medicare does pay for virtual specialty services such as telestroke. In addition, many states have enacted telemedicine parity laws, which require private payers to pay for all health care services equally, regardless of modality (audio, video, or in person).

For now, the financial case for employing telehospitalists for most programs has to be made using benfits other than the generation of professional fees. For telehospitalist programs that can cover several sites, the cost is substantially less than employing individual on-site hospitalists to do low-volume work. Telehospitalist programs are also, likely, less costly than is locum tenens staffing. For programs that evaluate the need for transfers, a case can be made that keeping a patient in a smaller, low-cost venue, rather than transferring them to a larger, higher-cost venue, can also reduce overall cost for a health care system.

What about licensing and credentialing?

Telehospitalists can be hindered by the need to have a license in several states and to be credentialed in several systems. This can be cumbersome, time-consuming, and expensive. To ease the multistate licensing burden, the Interstate Medical Licensure Compact has been established.² This is an accelerated licensure process for eligible physicians that improves license portability across states. There are currently 18 states that participate, and the number continues to increase.

For credentialing, most hospitals require initial credentialing and full recredentialing every 2 years. Maintaining credentials at several sites can be extremely time consuming. To ease this burden, some hospitals with telehealth programs have adopted “credentialing by proxy,” which means that one hospital will accept the credentialing process of another facility.

What next?

In summary, there has been and will likely continue to be explosive growth of telehospitalist programs and providers for all the reasons outlined above. Although some barriers to efficient and effective practice do exist, many of those barriers are being overcome quite rapidly. I expect this growth to continue for the betterment of hospitalists, our patients, and the systems in which we work. For a more in-depth look into telemedicine in hospital medicine, view a report created by a work group of SHM's Practice Management Committee.

Dr. Scheurer is a hospitalist and chief quality officer at the Medical University of South Carolina in Charleston. She is physician editor of The Hospitalist. Email her at [email protected].

References

1.Cisco. (2013 March 4). Cisco Study Reveals 74 Percent of Consumers Open to Virtual Doctor Visit. Cisco: The Network. Retrieved from https://newsroom.cisco.com/press-release-content?type=webcontent&articleId=1148539.

2. Interstate Medical Licensure Compact Commission. (2017). Interstate Medical Licensure Compact. Retrieved from http://www.licenseportability.org/index.html.

The FDA has made it easier and faster for health care professionals (HCPs) to get up-to-date drug safety information for the more than 18,000 approved drugs via its Drug Safety Labeling Changes (SLCs) database. The FDA Center for Drug Evaluation and Research recently launched a new searchable and downloadable database for SLCs information (http://www.fda.gov/slc). In most cases, the improved website provides supplemental labeling information within days of a safety label change. Now when a physician or other HCP prescribes a medicine using an e-prescribing system, the updated drug safety information displays much faster than it did with the previous safety labeling changes system. Here’s how.

Shortly after FDA approval of the new drug safety information for an existing drug, the information is entered into the safety labeling changes database. Health information technology (IT) vendors that provide clinical and drug information support for hospitals and pharmacies are then alerted to integrate the updated data into their systems as well. Instead of waiting weeks for the monthly release of all safety labeling updates, this information now is accessible within days.

Although SLCs have been available online for many years, previously they were aggregated and posted only monthly. This time frame meant that if a new safety concern was reflected in an approved labeling change early in a month, then the information was not publicly posted until the following month—4 to 5 weeks later. The FDA recognized the need to apply new digital functionalities to shorten the time between an SLC approval and the public availability of the safety information. Between January 2015 and July 2016, FDA made more than 1,500 SLCs (Table).

As health care professionals know, the “labeling” of a medicine includes detailed information provided in the package insert that accompanies the drug whether it’s on the box, inside the product box, or folded and glued to the lid of a bottle. The product labeling includes a summary for the safe and effective use of the drug and is generally intended for use by prescribers and pharmacists.

However, when a drug is approved, not every safety concern or risk potential can be identified or known. Safety information can change multiple times over the lifetime of a drug as the FDA learns about new risks, interactions with other medications, and adverse effects.

After the FDA becomes aware of new safety information, changes to the product labeling may be required. That’s why postmarketing safety oversight is essential to learn more about the effects of medicines when they are used by a large number of people over a long period. If new safety concerns emerge after a medicine is used in a real-world setting, the FDA may require a “Safety Labeling Change.” The FDA’s new, faster connection between updated safety information and safety alerts on the pharmacy computer system can help build improved confidence into each drug prescription.

The new SLCs website contains a database of changed safety information from all sections of the label that addresses a drug’s safety, including:

• Boxed warning
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Patient counseling information/patient information/medication guide

Health care providers, health IT vendors, and the public now have access to critical safety data that can impact the health of a patient faster than before.

Providing drug safety labeling changes quickly to health care vendors facilitates having the data further integrated into systems frequently accessed by HCPs. It also carries SLC data downstream for integration into drug information systems and other electronic venues, such as social media, news feeds, and websites, with vast reach among health care professionals, patients, and consumers. Some of these include WebMD, Medscape, American Society of Health-System Pharmacists, PDR.net, Epocrates, First Databank, and Yahoo Health.

The data files are downloadable in a comma-separated values format—a feature that allows information to be gathered faster. There also are hyperlinks to the labeling revisions at Drugs@FDA, and notifications are sent to subscribers via an RSS feed.

The FDA continues to pursue and provide innovative ways to rapidly access important information that protects and advances public health and will work to better identify class labeling changes. The FDA’s primary goal for the redesigned SLC Internet interface is to deliver drug safety labeling changes as quickly and efficiently as possible, to help create and promote better patient health.

The FDA has made it easier and faster for health care professionals (HCPs) to get up-to-date drug safety information for the more than 18,000 approved drugs via its Drug Safety Labeling Changes (SLCs) database. The FDA Center for Drug Evaluation and Research recently launched a new searchable and downloadable database for SLCs information (http://www.fda.gov/slc). In most cases, the improved website provides supplemental labeling information within days of a safety label change. Now when a physician or other HCP prescribes a medicine using an e-prescribing system, the updated drug safety information displays much faster than it did with the previous safety labeling changes system. Here’s how.

Shortly after FDA approval of the new drug safety information for an existing drug, the information is entered into the safety labeling changes database. Health information technology (IT) vendors that provide clinical and drug information support for hospitals and pharmacies are then alerted to integrate the updated data into their systems as well. Instead of waiting weeks for the monthly release of all safety labeling updates, this information now is accessible within days.

Although SLCs have been available online for many years, previously they were aggregated and posted only monthly. This time frame meant that if a new safety concern was reflected in an approved labeling change early in a month, then the information was not publicly posted until the following month—4 to 5 weeks later. The FDA recognized the need to apply new digital functionalities to shorten the time between an SLC approval and the public availability of the safety information. Between January 2015 and July 2016, FDA made more than 1,500 SLCs (Table).

As health care professionals know, the “labeling” of a medicine includes detailed information provided in the package insert that accompanies the drug whether it’s on the box, inside the product box, or folded and glued to the lid of a bottle. The product labeling includes a summary for the safe and effective use of the drug and is generally intended for use by prescribers and pharmacists.

However, when a drug is approved, not every safety concern or risk potential can be identified or known. Safety information can change multiple times over the lifetime of a drug as the FDA learns about new risks, interactions with other medications, and adverse effects.

After the FDA becomes aware of new safety information, changes to the product labeling may be required. That’s why postmarketing safety oversight is essential to learn more about the effects of medicines when they are used by a large number of people over a long period. If new safety concerns emerge after a medicine is used in a real-world setting, the FDA may require a “Safety Labeling Change.” The FDA’s new, faster connection between updated safety information and safety alerts on the pharmacy computer system can help build improved confidence into each drug prescription.

The new SLCs website contains a database of changed safety information from all sections of the label that addresses a drug’s safety, including:

• Boxed warning
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Patient counseling information/patient information/medication guide

Health care providers, health IT vendors, and the public now have access to critical safety data that can impact the health of a patient faster than before.

Providing drug safety labeling changes quickly to health care vendors facilitates having the data further integrated into systems frequently accessed by HCPs. It also carries SLC data downstream for integration into drug information systems and other electronic venues, such as social media, news feeds, and websites, with vast reach among health care professionals, patients, and consumers. Some of these include WebMD, Medscape, American Society of Health-System Pharmacists, PDR.net, Epocrates, First Databank, and Yahoo Health.

The data files are downloadable in a comma-separated values format—a feature that allows information to be gathered faster. There also are hyperlinks to the labeling revisions at Drugs@FDA, and notifications are sent to subscribers via an RSS feed.

The FDA continues to pursue and provide innovative ways to rapidly access important information that protects and advances public health and will work to better identify class labeling changes. The FDA’s primary goal for the redesigned SLC Internet interface is to deliver drug safety labeling changes as quickly and efficiently as possible, to help create and promote better patient health.

The FDA has made it easier and faster for health care professionals (HCPs) to get up-to-date drug safety information for the more than 18,000 approved drugs via its Drug Safety Labeling Changes (SLCs) database. The FDA Center for Drug Evaluation and Research recently launched a new searchable and downloadable database for SLCs information (http://www.fda.gov/slc). In most cases, the improved website provides supplemental labeling information within days of a safety label change. Now when a physician or other HCP prescribes a medicine using an e-prescribing system, the updated drug safety information displays much faster than it did with the previous safety labeling changes system. Here’s how.

Shortly after FDA approval of the new drug safety information for an existing drug, the information is entered into the safety labeling changes database. Health information technology (IT) vendors that provide clinical and drug information support for hospitals and pharmacies are then alerted to integrate the updated data into their systems as well. Instead of waiting weeks for the monthly release of all safety labeling updates, this information now is accessible within days.

Although SLCs have been available online for many years, previously they were aggregated and posted only monthly. This time frame meant that if a new safety concern was reflected in an approved labeling change early in a month, then the information was not publicly posted until the following month—4 to 5 weeks later. The FDA recognized the need to apply new digital functionalities to shorten the time between an SLC approval and the public availability of the safety information. Between January 2015 and July 2016, FDA made more than 1,500 SLCs (Table).

As health care professionals know, the “labeling” of a medicine includes detailed information provided in the package insert that accompanies the drug whether it’s on the box, inside the product box, or folded and glued to the lid of a bottle. The product labeling includes a summary for the safe and effective use of the drug and is generally intended for use by prescribers and pharmacists.

However, when a drug is approved, not every safety concern or risk potential can be identified or known. Safety information can change multiple times over the lifetime of a drug as the FDA learns about new risks, interactions with other medications, and adverse effects.

After the FDA becomes aware of new safety information, changes to the product labeling may be required. That’s why postmarketing safety oversight is essential to learn more about the effects of medicines when they are used by a large number of people over a long period. If new safety concerns emerge after a medicine is used in a real-world setting, the FDA may require a “Safety Labeling Change.” The FDA’s new, faster connection between updated safety information and safety alerts on the pharmacy computer system can help build improved confidence into each drug prescription.

The new SLCs website contains a database of changed safety information from all sections of the label that addresses a drug’s safety, including:

• Boxed warning
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Patient counseling information/patient information/medication guide

Health care providers, health IT vendors, and the public now have access to critical safety data that can impact the health of a patient faster than before.

Providing drug safety labeling changes quickly to health care vendors facilitates having the data further integrated into systems frequently accessed by HCPs. It also carries SLC data downstream for integration into drug information systems and other electronic venues, such as social media, news feeds, and websites, with vast reach among health care professionals, patients, and consumers. Some of these include WebMD, Medscape, American Society of Health-System Pharmacists, PDR.net, Epocrates, First Databank, and Yahoo Health.

The data files are downloadable in a comma-separated values format—a feature that allows information to be gathered faster. There also are hyperlinks to the labeling revisions at Drugs@FDA, and notifications are sent to subscribers via an RSS feed.

The FDA continues to pursue and provide innovative ways to rapidly access important information that protects and advances public health and will work to better identify class labeling changes. The FDA’s primary goal for the redesigned SLC Internet interface is to deliver drug safety labeling changes as quickly and efficiently as possible, to help create and promote better patient health.

UC San Diego

Engineers say they have developed biomimetic bone tissues that could one day provide new bone marrow for patients requiring transplants.

The team created bone tissues with functional bone marrow that can be filled with donor cells and implanted under the skin of mice.

The implant gives donor cells their own space to live and grow without competition, eliminating the need for a conditioning regimen to wipe out the host’s pre-existing cells prior to transplant.

“We’ve made an accessory bone that can separately accommodate donor cells,” explained Shyni Varghese, PhD, of the University of California, San Diego.

“This way, we can keep the host cells and bypass irradiation.”

In mice that received the engineered bone tissue, donor hematopoietic cells survived for at least 6 months and supplied the mice with new blood cells.

“In the future, our work could contribute to improved therapies for bone marrow disease,” said Yu-Ru Vernon Shih, PhD, a researcher in Dr Varghese’s lab.

The researchers noted that these implants would be limited to patients with non-malignant bone marrow diseases, such as aplastic anemia, where there aren’t any cancerous cells that need to be eliminated prior to transplant.

The team described their bone tissue implants in PNAS.

The implants mimic the structure of long bones in the body, consisting of an outer bone compartment and an inner marrow compartment.

The implants are made of a porous hydrogel matrix. The outer matrix contains calcium phosphate minerals. Stem cells grown in this mineralized matrix differentiate into bone-building cells. The inner matrix houses donor stem cells that produce blood cells.

When implanted beneath the skin of mice, the structures matured into bone tissues that have a working blood vessel network and a bone marrow that supplies new blood cells.

After 4 weeks, the implanted marrow contained a mix of host and donor blood cells. This mix was still circulating in the bloodstream after 24 weeks.

The researchers said these findings suggest the implanted marrow is functional, donor cells can grow and survive for long time periods in the presence of host cells, and host and donor cells can travel between the implanted marrow and the host’s circulating blood via the blood vessel network formed in the implanted bone tissue.

In another set of experiments, the researchers took hematopoietic stem cells from the implanted marrow and transplanted them into a second group of mice that had their stem cells destroyed by radiation and drugs. The team found the transplanted cells had diffused into the bloodstream of these mice.

“We did these experiments to show that the bone marrow cells from the engineered bone tissues function similar to native bone,” Dr Shih said.

“We’re working on making this a platform to generate more bone marrow stem cells,” Dr Varghese added. “That would have useful applications for cell transplantations in the clinic.” 

UC San Diego

Engineers say they have developed biomimetic bone tissues that could one day provide new bone marrow for patients requiring transplants.

The team created bone tissues with functional bone marrow that can be filled with donor cells and implanted under the skin of mice.

The implant gives donor cells their own space to live and grow without competition, eliminating the need for a conditioning regimen to wipe out the host’s pre-existing cells prior to transplant.

“We’ve made an accessory bone that can separately accommodate donor cells,” explained Shyni Varghese, PhD, of the University of California, San Diego.

“This way, we can keep the host cells and bypass irradiation.”

In mice that received the engineered bone tissue, donor hematopoietic cells survived for at least 6 months and supplied the mice with new blood cells.

“In the future, our work could contribute to improved therapies for bone marrow disease,” said Yu-Ru Vernon Shih, PhD, a researcher in Dr Varghese’s lab.

The researchers noted that these implants would be limited to patients with non-malignant bone marrow diseases, such as aplastic anemia, where there aren’t any cancerous cells that need to be eliminated prior to transplant.

The team described their bone tissue implants in PNAS.

The implants mimic the structure of long bones in the body, consisting of an outer bone compartment and an inner marrow compartment.

The implants are made of a porous hydrogel matrix. The outer matrix contains calcium phosphate minerals. Stem cells grown in this mineralized matrix differentiate into bone-building cells. The inner matrix houses donor stem cells that produce blood cells.

When implanted beneath the skin of mice, the structures matured into bone tissues that have a working blood vessel network and a bone marrow that supplies new blood cells.

After 4 weeks, the implanted marrow contained a mix of host and donor blood cells. This mix was still circulating in the bloodstream after 24 weeks.

The researchers said these findings suggest the implanted marrow is functional, donor cells can grow and survive for long time periods in the presence of host cells, and host and donor cells can travel between the implanted marrow and the host’s circulating blood via the blood vessel network formed in the implanted bone tissue.

In another set of experiments, the researchers took hematopoietic stem cells from the implanted marrow and transplanted them into a second group of mice that had their stem cells destroyed by radiation and drugs. The team found the transplanted cells had diffused into the bloodstream of these mice.

“We did these experiments to show that the bone marrow cells from the engineered bone tissues function similar to native bone,” Dr Shih said.

“We’re working on making this a platform to generate more bone marrow stem cells,” Dr Varghese added. “That would have useful applications for cell transplantations in the clinic.” 

UC San Diego

Engineers say they have developed biomimetic bone tissues that could one day provide new bone marrow for patients requiring transplants.

The team created bone tissues with functional bone marrow that can be filled with donor cells and implanted under the skin of mice.

The implant gives donor cells their own space to live and grow without competition, eliminating the need for a conditioning regimen to wipe out the host’s pre-existing cells prior to transplant.

“We’ve made an accessory bone that can separately accommodate donor cells,” explained Shyni Varghese, PhD, of the University of California, San Diego.

“This way, we can keep the host cells and bypass irradiation.”

In mice that received the engineered bone tissue, donor hematopoietic cells survived for at least 6 months and supplied the mice with new blood cells.

“In the future, our work could contribute to improved therapies for bone marrow disease,” said Yu-Ru Vernon Shih, PhD, a researcher in Dr Varghese’s lab.

The researchers noted that these implants would be limited to patients with non-malignant bone marrow diseases, such as aplastic anemia, where there aren’t any cancerous cells that need to be eliminated prior to transplant.

The team described their bone tissue implants in PNAS.

The implants mimic the structure of long bones in the body, consisting of an outer bone compartment and an inner marrow compartment.

The implants are made of a porous hydrogel matrix. The outer matrix contains calcium phosphate minerals. Stem cells grown in this mineralized matrix differentiate into bone-building cells. The inner matrix houses donor stem cells that produce blood cells.

When implanted beneath the skin of mice, the structures matured into bone tissues that have a working blood vessel network and a bone marrow that supplies new blood cells.

After 4 weeks, the implanted marrow contained a mix of host and donor blood cells. This mix was still circulating in the bloodstream after 24 weeks.

The researchers said these findings suggest the implanted marrow is functional, donor cells can grow and survive for long time periods in the presence of host cells, and host and donor cells can travel between the implanted marrow and the host’s circulating blood via the blood vessel network formed in the implanted bone tissue.

In another set of experiments, the researchers took hematopoietic stem cells from the implanted marrow and transplanted them into a second group of mice that had their stem cells destroyed by radiation and drugs. The team found the transplanted cells had diffused into the bloodstream of these mice.

“We did these experiments to show that the bone marrow cells from the engineered bone tissues function similar to native bone,” Dr Shih said.

“We’re working on making this a platform to generate more bone marrow stem cells,” Dr Varghese added. “That would have useful applications for cell transplantations in the clinic.” 

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

Baseline EPO (IU/L)	RS status	IWG HI-E, n=82 n (%)	RBC-TI, n=56 n (%)
≤ 500	RS+	30/46 (65%)	16/29 (55%)
	RS-	6/14 (43%)	4/7 (57%)
> 500	RS+	5/9 (56%)	2/9 (22%)
	RS-	1/11 (9%)	0/9 (0%)
	Unknown	0/2 (0%)	0/2 (0%)

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

Baseline EPO (IU/L)	RS status	IWG HI-E, n=82 n (%)	RBC-TI, n=56 n (%)
≤ 500	RS+	30/46 (65%)	16/29 (55%)
	RS-	6/14 (43%)	4/7 (57%)
> 500	RS+	5/9 (56%)	2/9 (22%)
	RS-	1/11 (9%)	0/9 (0%)
	Unknown	0/2 (0%)	0/2 (0%)

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

Baseline EPO (IU/L)	RS status	IWG HI-E, n=82 n (%)	RBC-TI, n=56 n (%)
≤ 500	RS+	30/46 (65%)	16/29 (55%)
	RS-	6/14 (43%)	4/7 (57%)
> 500	RS+	5/9 (56%)	2/9 (22%)
	RS-	1/11 (9%)	0/9 (0%)
	Unknown	0/2 (0%)	0/2 (0%)

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Photo courtesy of FDA

New research suggests postmarket safety events are common for therapeutics approved by the US Food and Drug Administration (FDA).

Researchers evaluated more than 200 pharmaceuticals and biologics approved by the FDA from 2001 through 2010 and found that nearly a third of these products were affected by a postmarket safety event.

Most of the events were boxed warnings or safety communications, but there were a few products withdrawn from the market due to safety issues.

Joseph S. Ross, MD, of the Yale University School of Medicine in New Haven, Connecticut, and his colleagues reported these findings in JAMA.

The researchers noted that most pivotal trials that form the basis for FDA approval enroll fewer than 1000 patients and have follow-up of 6 months or less.

Therefore, uncommon or long-term serious safety risks may only become evident after approval, when new therapeutics are used in larger patient populations and for longer periods of time.

With this in mind, Dr Ross and his colleagues examined postmarket safety events for all novel therapeutics approved by the FDA between January 2001 and December 2010 (followed-up through February 2017).

Safety events included withdrawals due to safety concerns, FDA issuance of incremental boxed warnings added in the postmarket period, and FDA issuance of safety communications.

From 2001 through 2010, the FDA approved 222 novel therapeutics—183 pharmaceuticals and 39 biologics.

During a median follow-up of 11.7 years, there were 123 postmarket safety events—3 withdrawals, 61 boxed warnings, and 59 safety communications.

“The fact that the FDA is issuing safety communications means it is doing a good job of following newly approved drugs and evaluating their safety up in the postmarket period,” Dr Ross said.

The 123 safety events identified affected 71 (32%) of the 222 therapeutics.

The median time from FDA approval to the first postmarket safety event was 4.2 years. And 31% of the therapeutics were still affected by a postmarket safety event at 10 years.

The researchers found that postmarket safety events were significantly more frequent in biologics (P=0.03), drugs used to treat psychiatric disease (P<0.001), products approved near their regulatory deadline (P=0.008), and therapeutics granted accelerated approval (P=0.02).

“[The accelerated approval finding] shows that there is the potential for compromising patient safety when drug evaluation is persistently sped up,” Dr Ross said.

On the other hand, the researchers also found that postmarket safety events were significantly less frequent in therapeutics the FDA reviewed in less than 200 days (P=0.02).

The researchers said these findings should be interpreted cautiously, but they can be used to inform ongoing surveillance efforts. 

Photo courtesy of FDA

New research suggests postmarket safety events are common for therapeutics approved by the US Food and Drug Administration (FDA).

Researchers evaluated more than 200 pharmaceuticals and biologics approved by the FDA from 2001 through 2010 and found that nearly a third of these products were affected by a postmarket safety event.

Most of the events were boxed warnings or safety communications, but there were a few products withdrawn from the market due to safety issues.

Joseph S. Ross, MD, of the Yale University School of Medicine in New Haven, Connecticut, and his colleagues reported these findings in JAMA.

The researchers noted that most pivotal trials that form the basis for FDA approval enroll fewer than 1000 patients and have follow-up of 6 months or less.

Therefore, uncommon or long-term serious safety risks may only become evident after approval, when new therapeutics are used in larger patient populations and for longer periods of time.

With this in mind, Dr Ross and his colleagues examined postmarket safety events for all novel therapeutics approved by the FDA between January 2001 and December 2010 (followed-up through February 2017).

Safety events included withdrawals due to safety concerns, FDA issuance of incremental boxed warnings added in the postmarket period, and FDA issuance of safety communications.

From 2001 through 2010, the FDA approved 222 novel therapeutics—183 pharmaceuticals and 39 biologics.

During a median follow-up of 11.7 years, there were 123 postmarket safety events—3 withdrawals, 61 boxed warnings, and 59 safety communications.

“The fact that the FDA is issuing safety communications means it is doing a good job of following newly approved drugs and evaluating their safety up in the postmarket period,” Dr Ross said.

The 123 safety events identified affected 71 (32%) of the 222 therapeutics.

The median time from FDA approval to the first postmarket safety event was 4.2 years. And 31% of the therapeutics were still affected by a postmarket safety event at 10 years.

The researchers found that postmarket safety events were significantly more frequent in biologics (P=0.03), drugs used to treat psychiatric disease (P<0.001), products approved near their regulatory deadline (P=0.008), and therapeutics granted accelerated approval (P=0.02).

“[The accelerated approval finding] shows that there is the potential for compromising patient safety when drug evaluation is persistently sped up,” Dr Ross said.

On the other hand, the researchers also found that postmarket safety events were significantly less frequent in therapeutics the FDA reviewed in less than 200 days (P=0.02).

The researchers said these findings should be interpreted cautiously, but they can be used to inform ongoing surveillance efforts. 

Photo courtesy of FDA

New research suggests postmarket safety events are common for therapeutics approved by the US Food and Drug Administration (FDA).

Researchers evaluated more than 200 pharmaceuticals and biologics approved by the FDA from 2001 through 2010 and found that nearly a third of these products were affected by a postmarket safety event.

Most of the events were boxed warnings or safety communications, but there were a few products withdrawn from the market due to safety issues.

Joseph S. Ross, MD, of the Yale University School of Medicine in New Haven, Connecticut, and his colleagues reported these findings in JAMA.

The researchers noted that most pivotal trials that form the basis for FDA approval enroll fewer than 1000 patients and have follow-up of 6 months or less.

Therefore, uncommon or long-term serious safety risks may only become evident after approval, when new therapeutics are used in larger patient populations and for longer periods of time.

With this in mind, Dr Ross and his colleagues examined postmarket safety events for all novel therapeutics approved by the FDA between January 2001 and December 2010 (followed-up through February 2017).

Safety events included withdrawals due to safety concerns, FDA issuance of incremental boxed warnings added in the postmarket period, and FDA issuance of safety communications.

From 2001 through 2010, the FDA approved 222 novel therapeutics—183 pharmaceuticals and 39 biologics.

During a median follow-up of 11.7 years, there were 123 postmarket safety events—3 withdrawals, 61 boxed warnings, and 59 safety communications.

“The fact that the FDA is issuing safety communications means it is doing a good job of following newly approved drugs and evaluating their safety up in the postmarket period,” Dr Ross said.

The 123 safety events identified affected 71 (32%) of the 222 therapeutics.

The median time from FDA approval to the first postmarket safety event was 4.2 years. And 31% of the therapeutics were still affected by a postmarket safety event at 10 years.

The researchers found that postmarket safety events were significantly more frequent in biologics (P=0.03), drugs used to treat psychiatric disease (P<0.001), products approved near their regulatory deadline (P=0.008), and therapeutics granted accelerated approval (P=0.02).

“[The accelerated approval finding] shows that there is the potential for compromising patient safety when drug evaluation is persistently sped up,” Dr Ross said.

On the other hand, the researchers also found that postmarket safety events were significantly less frequent in therapeutics the FDA reviewed in less than 200 days (P=0.02).

The researchers said these findings should be interpreted cautiously, but they can be used to inform ongoing surveillance efforts. 

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

 

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

 

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.

IN THIS ARTICLE

• Staging endometriosis
• Medications for treating endometriosis
• Complications

Endometriosis is a gynecologic disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity (ie, endometrial implants), most commonly found on the ovaries. Although its pathophysiology is not completely understood, the disease is associated with dysmenorrhea, dyspareunia, and infertility.^1,2 Endometriosis is an estrogen-dependent disorder, predominantly affecting women of childbearing age. It occurs in 10% to 15% of the general female population, but prevalence is even higher (35% to 50%) among women who experience pelvic pain and/or infertility.^1-4 Although endometriosis mainly affects women in their mid-to-late 20s, it can also manifest in adolescence.^3,5 Nearly half of all adolescents with intractable dysmenorrhea are diagnosed with endometriosis.⁵

ETIOLOGY

The etiology of endometriosis, while not completely understood, is likely multifactorial. Factors that may influence its development include gene expression, tissue response to hormones, neuronal tissue involvement, lack of protective factors, inflammation, and cellular oxidative stress.^6,7

Several theories regarding the etiology of endometriosis have been proposed; the most widely accepted is the transplantation theory, which suggests that endometriosis results from retrograde flow of menstrual tissue through the fallopian tubes. During menstruation, fragments of the endometrium are driven through the fallopian tubes and into the pelvic cavity, where they can implant onto the pelvic structures, leading to further growth and invasion.^2,6,8 Women who have polymenorrhea, prolonged menses, and early menarche therefore have an increased risk for endometriosis.⁸ This theory does not account for the fact that although nearly 90% of women have some elements of retrograde menstrual flow, only a fraction of them develop endometriosis.⁶

Two other plausible explanations are the coelomic metaplasia and embryonic rest theories. In the coelomic metaplasia theory, the mesothelium (coelomic epithelium)—which encases the ovaries—invaginates into the ovaries and undergoes a metaplastic change to endometrial tissue. This could explain the development of endometriosis in patients with the congenital malformation Müllerian agenesis. In the embryonic rest theory, Müllerian remnants in the rectovaginal area, left behind by the Müllerian duct system, have the potential to differentiate into endometrial tissue.^2,5,6,8

Another theory involving lymphatic or hematologic spread has been proposed, which would explain the presence of endometrial implants at sites distant from the uterus (eg, the pleural cavity and brain). However, this theory is not widely understood.⁶

The two most recent hypotheses on endometriosis are associated with an abnormal immune system and a possible genetic predisposition. The peritoneal fluid of women with endometriosis has different levels of prostanoids, cytokines, growth factors, and interleukins than that of women who do not have the condition. It is uncertain whether the relationship between peritoneal fluid changes and endometriosis is causal.⁶ A genetic correlation has been suggested, based on an increased prevalence of endometriosis in women with an affected first-degree relative; in a case-control study on family incidence of endometriosis, 5.9% to 9.6% of first-degree relatives and 1.3% of second-degree relatives were affected.⁹ The Oxford Endometriosis Gene (OXEGENE) study is currently investigating susceptible loci for endometriosis genes, which could provide a better understanding of the disease process.⁶

CLINICAL PRESENTATION

The most common symptoms of endometriosis are dysmenorrhea, deep dyspareunia, chronic pelvic pain, and infertility, but 20% to 25% of affected women are asymptomatic.^4,10,11 Pelvic pain in women most often heralds onset of menses and worsens during menstruation.¹ Other symptoms include back pain, dyschezia, dysuria, nausea, lethargy, and chronic fatigue.^4,8,10

Endometriosis is concomitant with infertility; endometrial adhesions that attach to pelvic organs cause distortion of pelvic structures and impaired ovum release and pick-up, and are believed to reduce fecundity. Additionally, women with endometriosis have low ovarian reserve and low-quality oocytes.^6,8 Altered chemical elements (ie, prostanoids, cytokines, growth factors, and interleukins) may also contribute to endometrial-related infertility; intrapelvic growth factors could affect the fallopian tubes or pelvic environment, and thus the oocytes in a similar fashion.⁶

In adolescents, endometriosis can present as cyclic or acyclic pain; severe dysmenorrhea; dysmenorrhea that responds poorly to medications (eg, oral contraceptive pills [OCPs] or NSAIDs); and prolonged menstruation with premenstrual spotting.¹

The physical exam may reveal tender nodules in the posterior vaginal fornix; cervical motion tenderness; a fixed uterus, cervix, or adnexa; uterine motion tenderness; thickening, pain, tenderness, or nodularity of the uterosacral ligament; or tender adnexal masses due to endometriomas.^8,10

PATHOLOGIC CHARACTERISTICS AND STAGING

Gross pathology of endometriosis varies based on duration of disease and depth of implants or lesions. Implants range from punctate foci to small stellate patches that vary in color but typically measure less than 2 cm. They manifest most commonly in the ovaries, followed by the anterior and posterior cul-de-sac, posterior broad ligament, and uterosacral ligament. Implants can also be located on the uterus, fallopian tubes, sigmoid colon, ureter, small intestine, lungs, and brain (see Figure).³

 

Due to recurrent cyclic hemorrhage within a deep implant, endometriomas typically appear in the ovaries, entirely replacing normal ovarian tissue. Endometriomas are composed of dark, thick, degenerated blood products that result in a brown cyst—hence their designation as chocolate cysts. Microscopically, they are comprised of endometrial glands, stroma, and sometimes smooth muscle.³

Staging of endometriosis is determined by the volume, depth, location, and size of the implants (see Table 1). It is important to note that staging does not necessarily reflect symptom severity.¹²

DIAGNOSIS

There are several approaches to the diagnostic evaluation of endometriosis, all of which should be guided by the clinical presentation and physical examination. Clinical characteristics can be nonspecific and highly variable, warranting more reliable diagnostic methods.

Laparoscopy is the diagnostic gold standard for endometriosis, and biopsy of implants revealing endometrial tissue is confirmatory. Less invasive diagnostic methods include ultrasound and MRI—but without confirmatory histologic sampling, these only yield a presumptive diagnosis.

With ultrasonography, a transvaginal approach should be taken. While endometriomas have a variety of presentations on ultrasound, most appear as a homogenous, hypoechoic, focal lesion within the ovary. MRI has greater specificity than ultrasound for diagnosis of endometriomas. However, “shading,” or loss of signal, within an endometrioma is a feature commonly found on MRI.³

Other tests that aid in the diagnosis, but are not definitive, include sedimentation rate and tumor marker CA-125. These are both commonly elevated in patients with endometriosis. Measurement of CA-125 is helpful for identifying patients with infertility and severe endometriosis, who would therefore benefit from early surgical intervention.⁸

TREATMENT

There is no permanent cure for endometriosis; treatment entails nonsurgical and surgical approaches to symptom resolution. Treatment is directed by the patient’s desire to maintain fertility.

Conservative treatment of pelvic pain with NSAIDs is a common approach. Progestins are also used to treat pelvic pain; they create an acyclic, hypo-estrogenic environment by blocking ovarian estrogen secretion and subsequent endometrial cell proliferation. In addition to alleviating pain, progestins also prevent disease recurrence after surgery.^2,13 Options include combination OCPs, levonorgestrel intrauterine devices, medroxyprogesterone acetate, and etonogestrel implants. Combination OCPs and medroxyprogesterone acetate are considered to be firstline treatment.⁸

Gonadotropin-releasing hormone agonists (GnRH-a), such as leuprolide acetate, and androgenic agents, such as danocrine, are also indicated for relief of pain resulting from biopsy-confirmed endometriosis. Danocrine has been shown to ameliorate pain in up to 92% of patients.^3,8 Other unconventional treatment modalities include aromatase inhibitors, selective estrogen receptor modulators, anti-inflammatory agents, and immunomodulators.² For an outline of the medication choices and their mechanisms of action, see Table 2.

Surgery, or ablation of the implants, is another viable treatment option; it can be performed via laparoscopy or laparotomy. Although the success rate is high, implants recur in 28% of patients 18 months after surgery and in 40% of patients after nine years; 40% to 50% of patients have adhesion recurrence.³

Patients who have concomitant infertility can be treated with advanced reproductive techniques, including intrauterine insemination and ovarian hyperstimulation. The monthly fecundity rate with such techniques is 9% to 18%.³ Laparoscopic surgery with ablation of endometrial implants may increase fertility in patients with endometriosis.⁸

Hysterectomy and bilateral salpingo-oophorectomy are definitive treatment options reserved for patients with intractable pain and those who do not wish to maintain fertility.^3,8 Recurrent symptoms occur in 10% of patients 10 years after hysterectomy with bilateral salpingectomy, compared with 62% of those who have hysterectomy alone.⁸ Complete surgical removal of endometriomas, and ovary if affected, can reduce risk for epithelial ovarian cancer in the future.²

COMPLICATIONS

Adhesions are a common complication of endometriosis. Ultrasound can be used for diagnosis and to determine whether pelvic organs are fixed (ie, fixed retroverted uterus). MRI may also be used; adhesions appear as “speculated low-signal-intensity stranding that obscures organ interfaces.”³ Other suggestive findings on MRI include posterior displacement of the pelvic organs, elevation of the posterior vaginal fornix, hydrosalpinx, loculated fluid collections, and angulated bowel loops.³

Malignant transformation is rare, affecting fewer than 1% of patients with endometriosis. Most malignancies arise from ovarian endometriosis and can be related to unopposed estrogen therapy; they are typically large and have a solid component. The most common endometriosis-related malignant neoplasm is endometrioid carcinoma, followed by clear-cell carcinoma.³

CONCLUSION

Patients with endometriosis often present with complaints such as dysmenorrhea, deep dyspareunia, and chronic pelvic pain, but surgical and histologic findings indicate that symptom severity does not necessarily equate to disease severity. Definitive diagnosis requires an invasive surgical procedure.

In the absence of a cure, endometriosis treatment focuses on symptom control and improvement in quality of life. Familiarity with the disease process and knowledge of treatment options will help health care providers achieve this goal for patients who experience the potentially life-altering effects of endometriosis.

 

Aluminum hydroxide–adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) were noninferior to standard inactivated poliovirus vaccine (IPV) in a large trial in the Dominican Republic, said Luis Rivera, MD, of the Hospital Maternidad Nuestra Señora de la Altagracia, Santo Domingo, Dominican Republic, and his associates.

If these findings are replicated in phase III trials and regulatory approval follows, such vaccines could be low-cost replacements for standard IPV and oral poliovirus vaccines in low-resource countries, the study authors suggested.

designer491/Thinkstock

Statens Serum Institut has developed three reduced-dose IPV-Al formulations to be given intramuscularly containing poliovirus type 1, type 2, and type 3. A 3-times reduced dose (1/3 IPV-Al), 5-times reduced dose (1/5 IPV-Al), and 10-times reduced dose (1/10 IPV-Al) vaccines have been developed.

In this phase II, blinded, randomized trial with three investigational IPV-Al groups and one IPV group, the vaccines were given at 6 weeks, 10 weeks, 14 weeks, and 18 weeks to 823 infants who had not previously received any polio vaccination. The three new IPV-Al vaccines all proved to be noninferior to IPV for poliovirus types 1, 2, and 3.

For 1/10 IPV-Al, the seroconversion rates for the different poliovirus types were 98.5% (type 1), 94.6% (type 2), and 99.5% (type 3), compared with 100% (type 1), 98.5% (type 2), and 100% (type 3) for IPV.

This and the results from other studies “have paved the way for further clinical investigations of IPV-Al in phase III trials,” Dr. Rivera and his associates wrote.

“The low frequency of adverse events in this phase II trial suggests that a safety evaluation is not necessarily justified,” they concluded.

The Bill & Melinda Gates Foundation funded the study. The authors had no disclosures.

Read more in the Lancet Infectious Diseases (2017 Apr 25. doi: 10.1016/S1473-3099(17)30177-9).

[email protected]

 

Aluminum hydroxide–adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) were noninferior to standard inactivated poliovirus vaccine (IPV) in a large trial in the Dominican Republic, said Luis Rivera, MD, of the Hospital Maternidad Nuestra Señora de la Altagracia, Santo Domingo, Dominican Republic, and his associates.

If these findings are replicated in phase III trials and regulatory approval follows, such vaccines could be low-cost replacements for standard IPV and oral poliovirus vaccines in low-resource countries, the study authors suggested.

designer491/Thinkstock

Statens Serum Institut has developed three reduced-dose IPV-Al formulations to be given intramuscularly containing poliovirus type 1, type 2, and type 3. A 3-times reduced dose (1/3 IPV-Al), 5-times reduced dose (1/5 IPV-Al), and 10-times reduced dose (1/10 IPV-Al) vaccines have been developed.

In this phase II, blinded, randomized trial with three investigational IPV-Al groups and one IPV group, the vaccines were given at 6 weeks, 10 weeks, 14 weeks, and 18 weeks to 823 infants who had not previously received any polio vaccination. The three new IPV-Al vaccines all proved to be noninferior to IPV for poliovirus types 1, 2, and 3.

For 1/10 IPV-Al, the seroconversion rates for the different poliovirus types were 98.5% (type 1), 94.6% (type 2), and 99.5% (type 3), compared with 100% (type 1), 98.5% (type 2), and 100% (type 3) for IPV.

This and the results from other studies “have paved the way for further clinical investigations of IPV-Al in phase III trials,” Dr. Rivera and his associates wrote.

“The low frequency of adverse events in this phase II trial suggests that a safety evaluation is not necessarily justified,” they concluded.

The Bill & Melinda Gates Foundation funded the study. The authors had no disclosures.

Read more in the Lancet Infectious Diseases (2017 Apr 25. doi: 10.1016/S1473-3099(17)30177-9).

[email protected]

 

Aluminum hydroxide–adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) were noninferior to standard inactivated poliovirus vaccine (IPV) in a large trial in the Dominican Republic, said Luis Rivera, MD, of the Hospital Maternidad Nuestra Señora de la Altagracia, Santo Domingo, Dominican Republic, and his associates.

If these findings are replicated in phase III trials and regulatory approval follows, such vaccines could be low-cost replacements for standard IPV and oral poliovirus vaccines in low-resource countries, the study authors suggested.

designer491/Thinkstock

Statens Serum Institut has developed three reduced-dose IPV-Al formulations to be given intramuscularly containing poliovirus type 1, type 2, and type 3. A 3-times reduced dose (1/3 IPV-Al), 5-times reduced dose (1/5 IPV-Al), and 10-times reduced dose (1/10 IPV-Al) vaccines have been developed.

In this phase II, blinded, randomized trial with three investigational IPV-Al groups and one IPV group, the vaccines were given at 6 weeks, 10 weeks, 14 weeks, and 18 weeks to 823 infants who had not previously received any polio vaccination. The three new IPV-Al vaccines all proved to be noninferior to IPV for poliovirus types 1, 2, and 3.

For 1/10 IPV-Al, the seroconversion rates for the different poliovirus types were 98.5% (type 1), 94.6% (type 2), and 99.5% (type 3), compared with 100% (type 1), 98.5% (type 2), and 100% (type 3) for IPV.

This and the results from other studies “have paved the way for further clinical investigations of IPV-Al in phase III trials,” Dr. Rivera and his associates wrote.

“The low frequency of adverse events in this phase II trial suggests that a safety evaluation is not necessarily justified,” they concluded.

The Bill & Melinda Gates Foundation funded the study. The authors had no disclosures.

Read more in the Lancet Infectious Diseases (2017 Apr 25. doi: 10.1016/S1473-3099(17)30177-9).

[email protected]

 

SYDNEY – Think twice before prescribing oral steroids for patients who have urticarial dermatitis, diarrhea, and cough, especially if they have lived in or recently traveled to tropical areas, Ian McCrossin, MD, said at the annual meeting of the Australasian College of Dermatologists.

Strongyloides stercoralis, or threadworm, infection can flare dramatically when patients take oral steroids. “You get thousands of worms, and they punch their way through the bowel wall and take the bowel organisms with them; that’s when you get septicaemia,” Dr. McCrossin, a dermatologist from Liverpool Hospital, Sydney, said in an interview.

Strongyloidiasis is relatively rare in developed countries, but it is endemic in parts of Southeast Asia, Central America, and Africa. The most common way of becoming infected with Strongyloides is by walking barefoot in soil that is contaminated with Strongyloides larvae. The parasite, which spreads through sewage-contaminated soil and invades the human host through their feet, has an autoinfection cycle. As a result, individuals can remain infected for decades.

Dr. McCrossin cited an Australian study that found a strongyloides infection was present in 11.6% of 309 Vietnam veterans living in South Australia.

Risk factors for Strongyloides hyperinfection include compromised immunity, human T-cell lymphotropic virus type 1, alcohol use disorder, malnutrition, and oral steroid use. Mortality rates from the resulting sepsis are as high as 87%, Dr. McCrossin said.

IgG ELISA is a reliable test for established strongyloidiasis, but is less effective for recent infection, hyperinfection, and in patients who are immunosuppressed. Eosinophilia has a poor predictive value. Light microscopy of stool samples may require evaluation of multiple stool samples unless the patient had hyperinfection.

Treatment generally consists of ivermectin, 200 mcg/kg orally for 1-2 days. Follow-up stool exams should be performed 2-4 weeks after treatment to confirm clearance of infection. In those patients with hyperinfections, ivermectin 200 mcg/kg orally is given daily until stool and/or sputum exams are negative for 2 weeks.

Dr. McCrossin declared no conflicts of interest.
 

 

SYDNEY – Think twice before prescribing oral steroids for patients who have urticarial dermatitis, diarrhea, and cough, especially if they have lived in or recently traveled to tropical areas, Ian McCrossin, MD, said at the annual meeting of the Australasian College of Dermatologists.

Strongyloides stercoralis, or threadworm, infection can flare dramatically when patients take oral steroids. “You get thousands of worms, and they punch their way through the bowel wall and take the bowel organisms with them; that’s when you get septicaemia,” Dr. McCrossin, a dermatologist from Liverpool Hospital, Sydney, said in an interview.

Strongyloidiasis is relatively rare in developed countries, but it is endemic in parts of Southeast Asia, Central America, and Africa. The most common way of becoming infected with Strongyloides is by walking barefoot in soil that is contaminated with Strongyloides larvae. The parasite, which spreads through sewage-contaminated soil and invades the human host through their feet, has an autoinfection cycle. As a result, individuals can remain infected for decades.

Dr. McCrossin cited an Australian study that found a strongyloides infection was present in 11.6% of 309 Vietnam veterans living in South Australia.

Risk factors for Strongyloides hyperinfection include compromised immunity, human T-cell lymphotropic virus type 1, alcohol use disorder, malnutrition, and oral steroid use. Mortality rates from the resulting sepsis are as high as 87%, Dr. McCrossin said.

IgG ELISA is a reliable test for established strongyloidiasis, but is less effective for recent infection, hyperinfection, and in patients who are immunosuppressed. Eosinophilia has a poor predictive value. Light microscopy of stool samples may require evaluation of multiple stool samples unless the patient had hyperinfection.

Treatment generally consists of ivermectin, 200 mcg/kg orally for 1-2 days. Follow-up stool exams should be performed 2-4 weeks after treatment to confirm clearance of infection. In those patients with hyperinfections, ivermectin 200 mcg/kg orally is given daily until stool and/or sputum exams are negative for 2 weeks.

Dr. McCrossin declared no conflicts of interest.
 

 

SYDNEY – Think twice before prescribing oral steroids for patients who have urticarial dermatitis, diarrhea, and cough, especially if they have lived in or recently traveled to tropical areas, Ian McCrossin, MD, said at the annual meeting of the Australasian College of Dermatologists.

Strongyloides stercoralis, or threadworm, infection can flare dramatically when patients take oral steroids. “You get thousands of worms, and they punch their way through the bowel wall and take the bowel organisms with them; that’s when you get septicaemia,” Dr. McCrossin, a dermatologist from Liverpool Hospital, Sydney, said in an interview.

Strongyloidiasis is relatively rare in developed countries, but it is endemic in parts of Southeast Asia, Central America, and Africa. The most common way of becoming infected with Strongyloides is by walking barefoot in soil that is contaminated with Strongyloides larvae. The parasite, which spreads through sewage-contaminated soil and invades the human host through their feet, has an autoinfection cycle. As a result, individuals can remain infected for decades.

Dr. McCrossin cited an Australian study that found a strongyloides infection was present in 11.6% of 309 Vietnam veterans living in South Australia.

Risk factors for Strongyloides hyperinfection include compromised immunity, human T-cell lymphotropic virus type 1, alcohol use disorder, malnutrition, and oral steroid use. Mortality rates from the resulting sepsis are as high as 87%, Dr. McCrossin said.

IgG ELISA is a reliable test for established strongyloidiasis, but is less effective for recent infection, hyperinfection, and in patients who are immunosuppressed. Eosinophilia has a poor predictive value. Light microscopy of stool samples may require evaluation of multiple stool samples unless the patient had hyperinfection.

Treatment generally consists of ivermectin, 200 mcg/kg orally for 1-2 days. Follow-up stool exams should be performed 2-4 weeks after treatment to confirm clearance of infection. In those patients with hyperinfections, ivermectin 200 mcg/kg orally is given daily until stool and/or sputum exams are negative for 2 weeks.

Dr. McCrossin declared no conflicts of interest.
 

 

PORTLAND, ORE. – Clinicians who treat or diagnose ANCA-associated vasculitis should watch for a variety of skin lesions, which can signify severe systemic manifestations of disease, according to the results of a cross-sectional study of 1,184 patients from 130 centers worldwide.

Among patients with granulomatosis with polyangiitis (GPA) or eosinophilic granulomatosis with polyangiitis (EGPA), the presence of skin lesions approximately doubled the likelihood of renal, pulmonary, neurologic, or other severe systemic manifestations of ANCA-associated vasculitis (hazard ratios, 2.0; P less than .03).

Examples of severe systemic manifestations included scleritis, sensorineural deafness, spinal cord lesions, stroke, mesenteric ischemia, alveolar hemorrhage, cranial nerve palsy, respiratory failure, red blood cell casts in the urine, or a greater than 25% drop in creatinine clearance, among others. The results were reported by Robert G. Micheletti, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, together with his associates in a poster presented at the annual meeting of the Society for Investigative Dermatology.

This cohort is part of the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS), which aims to develop classification and diagnostic criteria for primary systemic vasculitis. Fully 35% of patients had cutaneous manifestations of ANCA-associated vasculitis, including 47% of those with EGPA, 34% of those with GPA, and 28% of those with microscopic polyangiitis (MPA).

Petechiae/purpura were the most common cutaneous manifestations of all three subtypes, affecting 15% of the overall cohort, 21% of patients with EGPA, 16% of those with GPA, and 9% of those with MPA (P less than .01 for differences among groups). Petechiae/purpura did not more accurately predict systemic disease than other cutaneous findings, and skin lesions were not significantly associated with severe systemic disease in patients with MPA (HR, 0.63; 95% confidence interval, 0.35-1.14; P = .13), the investigators reported.

Besides petechiae/purpura, patients with EGPA most often presented with allergic and nonspecific cutaneous manifestations, such as pruritus (13% of patients), urticaria (8%), and maculopapular rash (8%), they said. In contrast, patients with GPA most often had painful skin lesions (10%) or maculopapular rash (7%), while those with MPA were more likely to have livedo reticularis or racemosa (7%).

Study participants tended to be in their mid-50s to mid-60s at diagnosis, about 48% were male, and most were Northern European, Southern European, or American whites, while 28% of those with MPA were Han Chinese, of another Chinese ethnicity, or Japanese.

“This study demonstrates that skin lesions are quite common and varied in granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis,” the investigators concluded.

Funders included the American College of Rheumatology, the European League Against Rheumatism, the Vasculitis Foundation, and the Dermatology Foundation. Dr. Micheletti had no conflicts of interest.

 

PORTLAND, ORE. – Clinicians who treat or diagnose ANCA-associated vasculitis should watch for a variety of skin lesions, which can signify severe systemic manifestations of disease, according to the results of a cross-sectional study of 1,184 patients from 130 centers worldwide.

Among patients with granulomatosis with polyangiitis (GPA) or eosinophilic granulomatosis with polyangiitis (EGPA), the presence of skin lesions approximately doubled the likelihood of renal, pulmonary, neurologic, or other severe systemic manifestations of ANCA-associated vasculitis (hazard ratios, 2.0; P less than .03).

Examples of severe systemic manifestations included scleritis, sensorineural deafness, spinal cord lesions, stroke, mesenteric ischemia, alveolar hemorrhage, cranial nerve palsy, respiratory failure, red blood cell casts in the urine, or a greater than 25% drop in creatinine clearance, among others. The results were reported by Robert G. Micheletti, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, together with his associates in a poster presented at the annual meeting of the Society for Investigative Dermatology.

This cohort is part of the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS), which aims to develop classification and diagnostic criteria for primary systemic vasculitis. Fully 35% of patients had cutaneous manifestations of ANCA-associated vasculitis, including 47% of those with EGPA, 34% of those with GPA, and 28% of those with microscopic polyangiitis (MPA).

Petechiae/purpura were the most common cutaneous manifestations of all three subtypes, affecting 15% of the overall cohort, 21% of patients with EGPA, 16% of those with GPA, and 9% of those with MPA (P less than .01 for differences among groups). Petechiae/purpura did not more accurately predict systemic disease than other cutaneous findings, and skin lesions were not significantly associated with severe systemic disease in patients with MPA (HR, 0.63; 95% confidence interval, 0.35-1.14; P = .13), the investigators reported.

Besides petechiae/purpura, patients with EGPA most often presented with allergic and nonspecific cutaneous manifestations, such as pruritus (13% of patients), urticaria (8%), and maculopapular rash (8%), they said. In contrast, patients with GPA most often had painful skin lesions (10%) or maculopapular rash (7%), while those with MPA were more likely to have livedo reticularis or racemosa (7%).

Study participants tended to be in their mid-50s to mid-60s at diagnosis, about 48% were male, and most were Northern European, Southern European, or American whites, while 28% of those with MPA were Han Chinese, of another Chinese ethnicity, or Japanese.

“This study demonstrates that skin lesions are quite common and varied in granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis,” the investigators concluded.

Funders included the American College of Rheumatology, the European League Against Rheumatism, the Vasculitis Foundation, and the Dermatology Foundation. Dr. Micheletti had no conflicts of interest.

 

PORTLAND, ORE. – Clinicians who treat or diagnose ANCA-associated vasculitis should watch for a variety of skin lesions, which can signify severe systemic manifestations of disease, according to the results of a cross-sectional study of 1,184 patients from 130 centers worldwide.

Among patients with granulomatosis with polyangiitis (GPA) or eosinophilic granulomatosis with polyangiitis (EGPA), the presence of skin lesions approximately doubled the likelihood of renal, pulmonary, neurologic, or other severe systemic manifestations of ANCA-associated vasculitis (hazard ratios, 2.0; P less than .03).

Examples of severe systemic manifestations included scleritis, sensorineural deafness, spinal cord lesions, stroke, mesenteric ischemia, alveolar hemorrhage, cranial nerve palsy, respiratory failure, red blood cell casts in the urine, or a greater than 25% drop in creatinine clearance, among others. The results were reported by Robert G. Micheletti, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, together with his associates in a poster presented at the annual meeting of the Society for Investigative Dermatology.

This cohort is part of the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS), which aims to develop classification and diagnostic criteria for primary systemic vasculitis. Fully 35% of patients had cutaneous manifestations of ANCA-associated vasculitis, including 47% of those with EGPA, 34% of those with GPA, and 28% of those with microscopic polyangiitis (MPA).

Petechiae/purpura were the most common cutaneous manifestations of all three subtypes, affecting 15% of the overall cohort, 21% of patients with EGPA, 16% of those with GPA, and 9% of those with MPA (P less than .01 for differences among groups). Petechiae/purpura did not more accurately predict systemic disease than other cutaneous findings, and skin lesions were not significantly associated with severe systemic disease in patients with MPA (HR, 0.63; 95% confidence interval, 0.35-1.14; P = .13), the investigators reported.

Besides petechiae/purpura, patients with EGPA most often presented with allergic and nonspecific cutaneous manifestations, such as pruritus (13% of patients), urticaria (8%), and maculopapular rash (8%), they said. In contrast, patients with GPA most often had painful skin lesions (10%) or maculopapular rash (7%), while those with MPA were more likely to have livedo reticularis or racemosa (7%).

Study participants tended to be in their mid-50s to mid-60s at diagnosis, about 48% were male, and most were Northern European, Southern European, or American whites, while 28% of those with MPA were Han Chinese, of another Chinese ethnicity, or Japanese.

“This study demonstrates that skin lesions are quite common and varied in granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis,” the investigators concluded.

Funders included the American College of Rheumatology, the European League Against Rheumatism, the Vasculitis Foundation, and the Dermatology Foundation. Dr. Micheletti had no conflicts of interest.