The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

A version of this article first appeared on Medscape.com.

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

A version of this article first appeared on Medscape.com.

*This story was updated 2/1/2023.

The first biosimilar for Humira, adalimumab-atto (Amjevita), is now available in the United States, according to an announcement on Jan. 31 by the manufacturer, Amgen. At least seven other U.S. Food and Drug Administration–approved Humira biosimilars are expected to become available later in 2023.

Amjevita was approved by the FDA in September 2016 for multiple inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The delayed launch was part of a global settlement with Humira’s manufacturer, AbbVie.

Humira (adalimumab) has been available since 2002 and is consistently one of the top-selling drugs in the United States. A single 40-mg Amjevita pen device will be available at two prices: a list price (wholesale acquisition cost) of $1,557.59, 55% below the current Humira list price, and a list price of $3,288.24, 5% below the current Humira list price, according to Amgen.

“Amgen’s goal is to provide broad access for patients by offering two options to health plans and pharmacy benefit managers,” the company said in the press release.

Patients are less likely to benefit from the more significant discount, said Marta Wosinska, PhD, a health care economist at the Brookings Institute in Washington, DC. It's expected that insurance companies will use the higher list price for Amjevita, she said, as this higher price will also likely have higher rebates. Rebates are payments to health insurance payers provided by drug manufacturers to promote use of an expensive drug. Some pharmacy benefit managers have already said that they plan to charge patients the same amount for Humira as its biosimilars, Dr. Wosinska said.

"For an existing patient, there's really no incentive for them to switch," she said in an interview.

So far only one insurance company, Kaiser Permanente, has plans to switch patients over to biosimilars, according to the health policy podcast Tradeoffs, and the insurer will stop covering Humira by the end of this year.

A version of this article first appeared on Medscape.com.

*This story was updated 2/1/2023.

Most doctors in primary care would agree that lymphedema is a difficult and frustrating disorder to treat. Despite treatments, patients still continue to suffer with symptoms such as pain and leg heaviness, and get only mild improvement. Patients receiving treatments rarely become symptom free.

According to the National Institutes of Health (NIH), primary or congenital lymphedema is a rare disorder occurring in 1 out of 100,00 Americans. On the other hand, secondary or acquired lymphedema is seen in 1 out of every 1,000 and is a complication of many cancers. For example, 1 out of every 5 women who survive breast cancer will develop lymphedema.

Given the statistics, primary care doctors will likely be responsible for treating patients with this disorder. It is important to note that the American Venous Forum consensus statement concluded that the diagnosis can be made based on clinical exam alone.

Given this fact, practitioners should be able to distinguish lymphedema from other similar diseases. As primary care doctors, we are likely to be the first ones to evaluate and diagnose this disease and need to be proficient on physical findings. We should also know the risk factors. No tests need to be performed, and this is a positive in this time of rising health care costs.

Another important conclusion of the consensus statement is that patients with chronic venous insufficiency should be treated the same as patients with lymphedema, especially given the fact that it can be a secondary cause of lymphedema. However, those disagreeing with this in the panel that developed the consensus statement endorsed doing a venous ultrasound to establish the cause.

Chronic venous insufficiency and lymphedema are often confused for each other, and the fact that they should be treated the same further establishes the fact that no further testing is needed. It can be argued that if we order a test when we suspect lymphedema, it serves only to drive up the cost and delays the initiation of treatment.

One area in which the panel of experts who developed the consensus statement showed some variability was in their recommendations for the treatment of lymphedema. Regular use of compression stockings to reduce lymphedema progression and manual lymphatic drainage were favored by most of the panel members, while Velcro devices and surgery were not.

While it is worthwhile to note this conclusion, determining how to treat a patient in clinical practice is often much more difficult. For one thing, some of these treatments are hard to get covered by insurance companies. Also, there is no objective data, unlike blood pressure or diabetic readings, to show the efficacy of a therapy for lymphedema. Instead, a diagnosis of lymphedema is based on a patient’s subjective symptoms. Many patients experience no substantial improvement from treatment, and even modest improvements can be considered a failure to them.

Another obstacle to treatment is that many patients find the treatment modalities uncomfortable or unsustainable. Some find the compression devices painful, for example. But often, they are given ones that have not been custom fitted to them, especially in the days of COVID when these are most often shipped to the patients’ homes. Also, manual drainage can be very time-consuming. To be effective, some patients need to do it more than once a day and it can take 30-60 minutes. Patients have jobs to go to and just don’t have the downtime to be able to do it effectively.

While this consensus statement does a good job analyzing current diagnosis and treatment of lymphedema, further research is needed to find new treatments and better education of clinicians needs to be done.

Lymphedema is an often-overlooked diagnosis despite having obvious clinical findings. There is currently no cure for lymphedema and the treatments that we do have available are not going to eliminate symptoms.

Patients are often frustrated by the lack of clinical improvement and there is little left to offer them. If we truly want to make an impact in our lymphedema patients, we need a better treatment. For now, we can offer them what is proven by the best evidence to reduce symptoms and support them in their suffering. Sometimes a listening ear and kind heart can make an even larger impact than just offering a treatment that doesn’t cure their disease.

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Most doctors in primary care would agree that lymphedema is a difficult and frustrating disorder to treat. Despite treatments, patients still continue to suffer with symptoms such as pain and leg heaviness, and get only mild improvement. Patients receiving treatments rarely become symptom free.

According to the National Institutes of Health (NIH), primary or congenital lymphedema is a rare disorder occurring in 1 out of 100,00 Americans. On the other hand, secondary or acquired lymphedema is seen in 1 out of every 1,000 and is a complication of many cancers. For example, 1 out of every 5 women who survive breast cancer will develop lymphedema.

Given the statistics, primary care doctors will likely be responsible for treating patients with this disorder. It is important to note that the American Venous Forum consensus statement concluded that the diagnosis can be made based on clinical exam alone.

Given this fact, practitioners should be able to distinguish lymphedema from other similar diseases. As primary care doctors, we are likely to be the first ones to evaluate and diagnose this disease and need to be proficient on physical findings. We should also know the risk factors. No tests need to be performed, and this is a positive in this time of rising health care costs.

Another important conclusion of the consensus statement is that patients with chronic venous insufficiency should be treated the same as patients with lymphedema, especially given the fact that it can be a secondary cause of lymphedema. However, those disagreeing with this in the panel that developed the consensus statement endorsed doing a venous ultrasound to establish the cause.

Chronic venous insufficiency and lymphedema are often confused for each other, and the fact that they should be treated the same further establishes the fact that no further testing is needed. It can be argued that if we order a test when we suspect lymphedema, it serves only to drive up the cost and delays the initiation of treatment.

One area in which the panel of experts who developed the consensus statement showed some variability was in their recommendations for the treatment of lymphedema. Regular use of compression stockings to reduce lymphedema progression and manual lymphatic drainage were favored by most of the panel members, while Velcro devices and surgery were not.

While it is worthwhile to note this conclusion, determining how to treat a patient in clinical practice is often much more difficult. For one thing, some of these treatments are hard to get covered by insurance companies. Also, there is no objective data, unlike blood pressure or diabetic readings, to show the efficacy of a therapy for lymphedema. Instead, a diagnosis of lymphedema is based on a patient’s subjective symptoms. Many patients experience no substantial improvement from treatment, and even modest improvements can be considered a failure to them.

Another obstacle to treatment is that many patients find the treatment modalities uncomfortable or unsustainable. Some find the compression devices painful, for example. But often, they are given ones that have not been custom fitted to them, especially in the days of COVID when these are most often shipped to the patients’ homes. Also, manual drainage can be very time-consuming. To be effective, some patients need to do it more than once a day and it can take 30-60 minutes. Patients have jobs to go to and just don’t have the downtime to be able to do it effectively.

While this consensus statement does a good job analyzing current diagnosis and treatment of lymphedema, further research is needed to find new treatments and better education of clinicians needs to be done.

Lymphedema is an often-overlooked diagnosis despite having obvious clinical findings. There is currently no cure for lymphedema and the treatments that we do have available are not going to eliminate symptoms.

Patients are often frustrated by the lack of clinical improvement and there is little left to offer them. If we truly want to make an impact in our lymphedema patients, we need a better treatment. For now, we can offer them what is proven by the best evidence to reduce symptoms and support them in their suffering. Sometimes a listening ear and kind heart can make an even larger impact than just offering a treatment that doesn’t cure their disease.

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Most doctors in primary care would agree that lymphedema is a difficult and frustrating disorder to treat. Despite treatments, patients still continue to suffer with symptoms such as pain and leg heaviness, and get only mild improvement. Patients receiving treatments rarely become symptom free.

According to the National Institutes of Health (NIH), primary or congenital lymphedema is a rare disorder occurring in 1 out of 100,00 Americans. On the other hand, secondary or acquired lymphedema is seen in 1 out of every 1,000 and is a complication of many cancers. For example, 1 out of every 5 women who survive breast cancer will develop lymphedema.

Given the statistics, primary care doctors will likely be responsible for treating patients with this disorder. It is important to note that the American Venous Forum consensus statement concluded that the diagnosis can be made based on clinical exam alone.

Given this fact, practitioners should be able to distinguish lymphedema from other similar diseases. As primary care doctors, we are likely to be the first ones to evaluate and diagnose this disease and need to be proficient on physical findings. We should also know the risk factors. No tests need to be performed, and this is a positive in this time of rising health care costs.

Another important conclusion of the consensus statement is that patients with chronic venous insufficiency should be treated the same as patients with lymphedema, especially given the fact that it can be a secondary cause of lymphedema. However, those disagreeing with this in the panel that developed the consensus statement endorsed doing a venous ultrasound to establish the cause.

Chronic venous insufficiency and lymphedema are often confused for each other, and the fact that they should be treated the same further establishes the fact that no further testing is needed. It can be argued that if we order a test when we suspect lymphedema, it serves only to drive up the cost and delays the initiation of treatment.

One area in which the panel of experts who developed the consensus statement showed some variability was in their recommendations for the treatment of lymphedema. Regular use of compression stockings to reduce lymphedema progression and manual lymphatic drainage were favored by most of the panel members, while Velcro devices and surgery were not.

While it is worthwhile to note this conclusion, determining how to treat a patient in clinical practice is often much more difficult. For one thing, some of these treatments are hard to get covered by insurance companies. Also, there is no objective data, unlike blood pressure or diabetic readings, to show the efficacy of a therapy for lymphedema. Instead, a diagnosis of lymphedema is based on a patient’s subjective symptoms. Many patients experience no substantial improvement from treatment, and even modest improvements can be considered a failure to them.

Another obstacle to treatment is that many patients find the treatment modalities uncomfortable or unsustainable. Some find the compression devices painful, for example. But often, they are given ones that have not been custom fitted to them, especially in the days of COVID when these are most often shipped to the patients’ homes. Also, manual drainage can be very time-consuming. To be effective, some patients need to do it more than once a day and it can take 30-60 minutes. Patients have jobs to go to and just don’t have the downtime to be able to do it effectively.

While this consensus statement does a good job analyzing current diagnosis and treatment of lymphedema, further research is needed to find new treatments and better education of clinicians needs to be done.

Lymphedema is an often-overlooked diagnosis despite having obvious clinical findings. There is currently no cure for lymphedema and the treatments that we do have available are not going to eliminate symptoms.

Patients are often frustrated by the lack of clinical improvement and there is little left to offer them. If we truly want to make an impact in our lymphedema patients, we need a better treatment. For now, we can offer them what is proven by the best evidence to reduce symptoms and support them in their suffering. Sometimes a listening ear and kind heart can make an even larger impact than just offering a treatment that doesn’t cure their disease.

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

Transferring from one residency program to another is rare but not unheard of. According to the most recent Accreditation Council for Graduate Medical Education Data Resource Book, there were 1020 residents who transferred residency programs in the 2020-2021 academic year.¹ With a total of 126,759 active residents in specialty programs, the percentage of transferring residents was less than 1%. The specialties with the highest number of transferring residents included psychiatry, general surgery, internal medicine, and family medicine. In dermatology programs, there were only 2 resident transfers during the 2019-2020 academic year and 6 transfers in the 2020-2021 academic year.^1,2 A resident contemplating transferring training programs must carefully consider the advantages and disadvantages before undertaking the uncertain transfer process, but transferring residency programs can be achieved successfully with planning and luck.

Deciding to Transfer

The decision to transfer residency programs may be a difficult one that is wrought with anxiety. There are many reasons why a trainee may wish to pursue transferring training programs. A transfer to another geographic area may be necessary for personal or family reasons, such as to reunite with a spouse and children or to care for a sick family member. A resident may find their program to be a poor fit and may wish to train in a different educational environment. Occasionally, a program can lose its accreditation, and its residents will be tasked with finding a new position elsewhere. A trainee also may realize that the specialty they matched into initially does not align with their true passions. It is important for the potential transfer applicant to be levelheaded about their decision. Residency is a demanding period for every trainee; switching programs may not be the best solution for every problem and should only be considered if essential.

Transfer Timing

A trainee may have thoughts of leaving a program soon after starting residency or perhaps even before starting if their National Resident Matching Program (NRMP) Match result was a disappointment; however, there are certain rules related to transfer timing. The NRMP Match represents a binding commitment for both the applicant and program. If for any reason an applicant will not honor the binding commitment, the NRMP requires the applicant to initiate a waiver review, which can be requested for unanticipated serious and extreme hardship, change of specialty, or ineligibility. According to the NRMP rules and regulations, applicants cannot apply for, discuss, interview for, or accept a position in another program until a waiver has been granted.³ Waivers based on change of specialty must be requested by mid-January prior to the start of training, which means most applicants who match to positions that begin in the same year of the Match do not qualify for change of specialty waivers. However, those who matched to an advanced position and are doing a preliminary year position may consider this option if they have a change of heart during their internship. The NRMP may consider a 1-year deferral to delay training if mutually agreed upon by both the matched applicant and the program.³ The binding commitment is in place for the first 45 days of training, and applicants who resign within 45 days or a program that tries to solicit the transfer of a resident prior to that date could be in violation of the Match and can face consequences such as being barred from entering the matching process in future cycles. Of the 1020 transfers that occurred among residents in specialty programs during the 2020-2021 academic year, 354 (34.7%) occurred during the first year of the training program; 228 (22.4%) occurred during the second year; 389 (38.1%) occurred during the third year; and 49 (4.8%) occurred in the fourth, fifth, or sixth year of the program.¹ Unlike other jobs/occupations in which one can simply give notice, in medical training even if a transfer position is accepted, the transition date between programs must be mutually agreed upon. Often, this may coincide with the start of the new academic year.

The Transfer Process

Transferring residency programs is a substantial undertaking. Unlike the Match, a trainee seeking to transfer programs does so without a standardized application system or structured support through the process; the transfer applicant must be prepared to navigate the transfer process on their own. The first step after making the decision to transfer is for the resident to meet with the program leadership (ie, program director[s], coordinator, designated official) at their home program to discuss the decision—a nerve-wracking but imperative first step. A receiving program may not favor an applicant secretly applying to a new program without the knowledge of their home program and often will require the home program’s blessing to proceed. The receiving program also would want to ensure the applicant is in good standing and not leaving due to misconduct. Once given the go-ahead, the process is largely in the hands of the applicant. The transfer applicant should identify locations or programs of interest and then take initiative to reach out to potential programs. FREIDA (Fellowship and Residency Electronic Interactive Database Access) is the American Medical Association’s residency and fellowship database that allows vacant position listings to be posted online.⁴ Additionally, the Association of American Medical Colleges’ FindAResident website is a year-round search tool designed to help find open residency and fellowship positions.⁵ Various specialties also may have program director listserves that communicate vacant positions. On occasion, there are spots in the main NRMP Match that are reserved positions (“R”). These are postgraduate year 2 positions in specialty programs that begin in the year of the Match and are reserved for physicians with prior graduate medical education; these also are known as “Physician Positions.”⁶ Ultimately, advertisements for vacancies may be few and far between, requiring the resident to send unsolicited emails with curriculum vitae attached to the program directors at programs of interest to inquire about any vacancies and hope for a favorable response. Even if the transfer applicant is qualified, luck that the right spot will be available at the right time may be the deciding factor in transferring programs.

The next step is interviewing for the position. There likely will be fewer candidates interviewing for an open spot but that does not make the process less competitive. The candidate should highlight their strengths and achievements and discuss why the new program would be a great fit both personally and professionally. Even if an applicant is seeking a transfer due to discontent with a prior program, it is best to act graciously and not speak poorly about another training program.

Prior to selection, the candidate may be asked to provide information such as diplomas, US Medical Licensing Examination Step and residency in-service training examination scores, and academic reviews from their current residency program. The interview process may take several weeks as the graduate medical education office often will need to officially approve of an applicant before a formal offer to transfer is extended.

Finally, once an offer is made and accepted, there still is a great amount of paperwork to complete before the transition. The applicant should stay on track with all off-boarding and on-boarding requirements, such as signing a contract, obtaining background checks, and applying for a new license to ensure the switch is not delayed.

The transfer process is not easy to navigate and can be a source of stress for the applicant. It is natural to fear resentment from colleagues and co-residents. Although transferring programs might be in the best interest of the trainee, it may leave a large gap in the program that they are leaving, which can place a burden on the remaining residents.

There are many adjustments to be made after transferring programs. The transferring resident will again start from scratch, needing to learn the ropes and adapt to the growing pains of being at a new institution. This may require learning a completely new electronic medical record, adapting to a new culture, and in many cases stepping in as a senior resident without fully knowing the ins and outs of the program.

Advantages of Transferring Programs

Successfully transferring programs is something to celebrate. There may be great benefits to transferring to a program that is better suited to the trainee—either personally or professionally. Ameliorating the adversity that led to the decision to transfer such as reuniting a long-distance family or realizing one’s true passion can allow the resident to thrive as a trainee and maximize their potential. Transferring programs can give a resident a more well-rounded training experience, as different programs may have different strengths, patient populations, and practice settings. Working with different faculty members with varied niches and practice styles can create a more comprehensive residency experience.

Final Thoughts

Ultimately, transferring residency programs is not easy but also is not impossible. Successfully switching residency programs can be a rewarding experience providing greater well-being and fulfillment.

Transferring from one residency program to another is rare but not unheard of. According to the most recent Accreditation Council for Graduate Medical Education Data Resource Book, there were 1020 residents who transferred residency programs in the 2020-2021 academic year.¹ With a total of 126,759 active residents in specialty programs, the percentage of transferring residents was less than 1%. The specialties with the highest number of transferring residents included psychiatry, general surgery, internal medicine, and family medicine. In dermatology programs, there were only 2 resident transfers during the 2019-2020 academic year and 6 transfers in the 2020-2021 academic year.^1,2 A resident contemplating transferring training programs must carefully consider the advantages and disadvantages before undertaking the uncertain transfer process, but transferring residency programs can be achieved successfully with planning and luck.

Deciding to Transfer

The decision to transfer residency programs may be a difficult one that is wrought with anxiety. There are many reasons why a trainee may wish to pursue transferring training programs. A transfer to another geographic area may be necessary for personal or family reasons, such as to reunite with a spouse and children or to care for a sick family member. A resident may find their program to be a poor fit and may wish to train in a different educational environment. Occasionally, a program can lose its accreditation, and its residents will be tasked with finding a new position elsewhere. A trainee also may realize that the specialty they matched into initially does not align with their true passions. It is important for the potential transfer applicant to be levelheaded about their decision. Residency is a demanding period for every trainee; switching programs may not be the best solution for every problem and should only be considered if essential.

Transfer Timing

A trainee may have thoughts of leaving a program soon after starting residency or perhaps even before starting if their National Resident Matching Program (NRMP) Match result was a disappointment; however, there are certain rules related to transfer timing. The NRMP Match represents a binding commitment for both the applicant and program. If for any reason an applicant will not honor the binding commitment, the NRMP requires the applicant to initiate a waiver review, which can be requested for unanticipated serious and extreme hardship, change of specialty, or ineligibility. According to the NRMP rules and regulations, applicants cannot apply for, discuss, interview for, or accept a position in another program until a waiver has been granted.³ Waivers based on change of specialty must be requested by mid-January prior to the start of training, which means most applicants who match to positions that begin in the same year of the Match do not qualify for change of specialty waivers. However, those who matched to an advanced position and are doing a preliminary year position may consider this option if they have a change of heart during their internship. The NRMP may consider a 1-year deferral to delay training if mutually agreed upon by both the matched applicant and the program.³ The binding commitment is in place for the first 45 days of training, and applicants who resign within 45 days or a program that tries to solicit the transfer of a resident prior to that date could be in violation of the Match and can face consequences such as being barred from entering the matching process in future cycles. Of the 1020 transfers that occurred among residents in specialty programs during the 2020-2021 academic year, 354 (34.7%) occurred during the first year of the training program; 228 (22.4%) occurred during the second year; 389 (38.1%) occurred during the third year; and 49 (4.8%) occurred in the fourth, fifth, or sixth year of the program.¹ Unlike other jobs/occupations in which one can simply give notice, in medical training even if a transfer position is accepted, the transition date between programs must be mutually agreed upon. Often, this may coincide with the start of the new academic year.

The Transfer Process

Transferring residency programs is a substantial undertaking. Unlike the Match, a trainee seeking to transfer programs does so without a standardized application system or structured support through the process; the transfer applicant must be prepared to navigate the transfer process on their own. The first step after making the decision to transfer is for the resident to meet with the program leadership (ie, program director[s], coordinator, designated official) at their home program to discuss the decision—a nerve-wracking but imperative first step. A receiving program may not favor an applicant secretly applying to a new program without the knowledge of their home program and often will require the home program’s blessing to proceed. The receiving program also would want to ensure the applicant is in good standing and not leaving due to misconduct. Once given the go-ahead, the process is largely in the hands of the applicant. The transfer applicant should identify locations or programs of interest and then take initiative to reach out to potential programs. FREIDA (Fellowship and Residency Electronic Interactive Database Access) is the American Medical Association’s residency and fellowship database that allows vacant position listings to be posted online.⁴ Additionally, the Association of American Medical Colleges’ FindAResident website is a year-round search tool designed to help find open residency and fellowship positions.⁵ Various specialties also may have program director listserves that communicate vacant positions. On occasion, there are spots in the main NRMP Match that are reserved positions (“R”). These are postgraduate year 2 positions in specialty programs that begin in the year of the Match and are reserved for physicians with prior graduate medical education; these also are known as “Physician Positions.”⁶ Ultimately, advertisements for vacancies may be few and far between, requiring the resident to send unsolicited emails with curriculum vitae attached to the program directors at programs of interest to inquire about any vacancies and hope for a favorable response. Even if the transfer applicant is qualified, luck that the right spot will be available at the right time may be the deciding factor in transferring programs.

The next step is interviewing for the position. There likely will be fewer candidates interviewing for an open spot but that does not make the process less competitive. The candidate should highlight their strengths and achievements and discuss why the new program would be a great fit both personally and professionally. Even if an applicant is seeking a transfer due to discontent with a prior program, it is best to act graciously and not speak poorly about another training program.

Prior to selection, the candidate may be asked to provide information such as diplomas, US Medical Licensing Examination Step and residency in-service training examination scores, and academic reviews from their current residency program. The interview process may take several weeks as the graduate medical education office often will need to officially approve of an applicant before a formal offer to transfer is extended.

Finally, once an offer is made and accepted, there still is a great amount of paperwork to complete before the transition. The applicant should stay on track with all off-boarding and on-boarding requirements, such as signing a contract, obtaining background checks, and applying for a new license to ensure the switch is not delayed.

The transfer process is not easy to navigate and can be a source of stress for the applicant. It is natural to fear resentment from colleagues and co-residents. Although transferring programs might be in the best interest of the trainee, it may leave a large gap in the program that they are leaving, which can place a burden on the remaining residents.

There are many adjustments to be made after transferring programs. The transferring resident will again start from scratch, needing to learn the ropes and adapt to the growing pains of being at a new institution. This may require learning a completely new electronic medical record, adapting to a new culture, and in many cases stepping in as a senior resident without fully knowing the ins and outs of the program.

Advantages of Transferring Programs

Successfully transferring programs is something to celebrate. There may be great benefits to transferring to a program that is better suited to the trainee—either personally or professionally. Ameliorating the adversity that led to the decision to transfer such as reuniting a long-distance family or realizing one’s true passion can allow the resident to thrive as a trainee and maximize their potential. Transferring programs can give a resident a more well-rounded training experience, as different programs may have different strengths, patient populations, and practice settings. Working with different faculty members with varied niches and practice styles can create a more comprehensive residency experience.

Final Thoughts

Ultimately, transferring residency programs is not easy but also is not impossible. Successfully switching residency programs can be a rewarding experience providing greater well-being and fulfillment.

Transferring from one residency program to another is rare but not unheard of. According to the most recent Accreditation Council for Graduate Medical Education Data Resource Book, there were 1020 residents who transferred residency programs in the 2020-2021 academic year.¹ With a total of 126,759 active residents in specialty programs, the percentage of transferring residents was less than 1%. The specialties with the highest number of transferring residents included psychiatry, general surgery, internal medicine, and family medicine. In dermatology programs, there were only 2 resident transfers during the 2019-2020 academic year and 6 transfers in the 2020-2021 academic year.^1,2 A resident contemplating transferring training programs must carefully consider the advantages and disadvantages before undertaking the uncertain transfer process, but transferring residency programs can be achieved successfully with planning and luck.

Deciding to Transfer

The decision to transfer residency programs may be a difficult one that is wrought with anxiety. There are many reasons why a trainee may wish to pursue transferring training programs. A transfer to another geographic area may be necessary for personal or family reasons, such as to reunite with a spouse and children or to care for a sick family member. A resident may find their program to be a poor fit and may wish to train in a different educational environment. Occasionally, a program can lose its accreditation, and its residents will be tasked with finding a new position elsewhere. A trainee also may realize that the specialty they matched into initially does not align with their true passions. It is important for the potential transfer applicant to be levelheaded about their decision. Residency is a demanding period for every trainee; switching programs may not be the best solution for every problem and should only be considered if essential.

Transfer Timing

A trainee may have thoughts of leaving a program soon after starting residency or perhaps even before starting if their National Resident Matching Program (NRMP) Match result was a disappointment; however, there are certain rules related to transfer timing. The NRMP Match represents a binding commitment for both the applicant and program. If for any reason an applicant will not honor the binding commitment, the NRMP requires the applicant to initiate a waiver review, which can be requested for unanticipated serious and extreme hardship, change of specialty, or ineligibility. According to the NRMP rules and regulations, applicants cannot apply for, discuss, interview for, or accept a position in another program until a waiver has been granted.³ Waivers based on change of specialty must be requested by mid-January prior to the start of training, which means most applicants who match to positions that begin in the same year of the Match do not qualify for change of specialty waivers. However, those who matched to an advanced position and are doing a preliminary year position may consider this option if they have a change of heart during their internship. The NRMP may consider a 1-year deferral to delay training if mutually agreed upon by both the matched applicant and the program.³ The binding commitment is in place for the first 45 days of training, and applicants who resign within 45 days or a program that tries to solicit the transfer of a resident prior to that date could be in violation of the Match and can face consequences such as being barred from entering the matching process in future cycles. Of the 1020 transfers that occurred among residents in specialty programs during the 2020-2021 academic year, 354 (34.7%) occurred during the first year of the training program; 228 (22.4%) occurred during the second year; 389 (38.1%) occurred during the third year; and 49 (4.8%) occurred in the fourth, fifth, or sixth year of the program.¹ Unlike other jobs/occupations in which one can simply give notice, in medical training even if a transfer position is accepted, the transition date between programs must be mutually agreed upon. Often, this may coincide with the start of the new academic year.

The Transfer Process

Transferring residency programs is a substantial undertaking. Unlike the Match, a trainee seeking to transfer programs does so without a standardized application system or structured support through the process; the transfer applicant must be prepared to navigate the transfer process on their own. The first step after making the decision to transfer is for the resident to meet with the program leadership (ie, program director[s], coordinator, designated official) at their home program to discuss the decision—a nerve-wracking but imperative first step. A receiving program may not favor an applicant secretly applying to a new program without the knowledge of their home program and often will require the home program’s blessing to proceed. The receiving program also would want to ensure the applicant is in good standing and not leaving due to misconduct. Once given the go-ahead, the process is largely in the hands of the applicant. The transfer applicant should identify locations or programs of interest and then take initiative to reach out to potential programs. FREIDA (Fellowship and Residency Electronic Interactive Database Access) is the American Medical Association’s residency and fellowship database that allows vacant position listings to be posted online.⁴ Additionally, the Association of American Medical Colleges’ FindAResident website is a year-round search tool designed to help find open residency and fellowship positions.⁵ Various specialties also may have program director listserves that communicate vacant positions. On occasion, there are spots in the main NRMP Match that are reserved positions (“R”). These are postgraduate year 2 positions in specialty programs that begin in the year of the Match and are reserved for physicians with prior graduate medical education; these also are known as “Physician Positions.”⁶ Ultimately, advertisements for vacancies may be few and far between, requiring the resident to send unsolicited emails with curriculum vitae attached to the program directors at programs of interest to inquire about any vacancies and hope for a favorable response. Even if the transfer applicant is qualified, luck that the right spot will be available at the right time may be the deciding factor in transferring programs.

The next step is interviewing for the position. There likely will be fewer candidates interviewing for an open spot but that does not make the process less competitive. The candidate should highlight their strengths and achievements and discuss why the new program would be a great fit both personally and professionally. Even if an applicant is seeking a transfer due to discontent with a prior program, it is best to act graciously and not speak poorly about another training program.

Prior to selection, the candidate may be asked to provide information such as diplomas, US Medical Licensing Examination Step and residency in-service training examination scores, and academic reviews from their current residency program. The interview process may take several weeks as the graduate medical education office often will need to officially approve of an applicant before a formal offer to transfer is extended.

Finally, once an offer is made and accepted, there still is a great amount of paperwork to complete before the transition. The applicant should stay on track with all off-boarding and on-boarding requirements, such as signing a contract, obtaining background checks, and applying for a new license to ensure the switch is not delayed.

The transfer process is not easy to navigate and can be a source of stress for the applicant. It is natural to fear resentment from colleagues and co-residents. Although transferring programs might be in the best interest of the trainee, it may leave a large gap in the program that they are leaving, which can place a burden on the remaining residents.

There are many adjustments to be made after transferring programs. The transferring resident will again start from scratch, needing to learn the ropes and adapt to the growing pains of being at a new institution. This may require learning a completely new electronic medical record, adapting to a new culture, and in many cases stepping in as a senior resident without fully knowing the ins and outs of the program.

Advantages of Transferring Programs

Successfully transferring programs is something to celebrate. There may be great benefits to transferring to a program that is better suited to the trainee—either personally or professionally. Ameliorating the adversity that led to the decision to transfer such as reuniting a long-distance family or realizing one’s true passion can allow the resident to thrive as a trainee and maximize their potential. Transferring programs can give a resident a more well-rounded training experience, as different programs may have different strengths, patient populations, and practice settings. Working with different faculty members with varied niches and practice styles can create a more comprehensive residency experience.

Final Thoughts

Ultimately, transferring residency programs is not easy but also is not impossible. Successfully switching residency programs can be a rewarding experience providing greater well-being and fulfillment.

To the Editor:

Hemorrhagic lacrimation and epistaxis are dramatic presentations with a narrow differential diagnosis. It rarely has been reported to present alongside the more typical features of acute hemorrhagic edema of infancy (AHEI), which is a benign self-limited leukocytoclastic vasculitis most often seen in children aged 4 months to 2 years. Extracutaneous involvement rarely is seen in AHEI, though joint, gastrointestinal tract, and renal involvement have been reported.¹ Most patients present with edematous, annular, or cockade purpuric vasculitic lesions classically involving the face and distal extremities with relative sparing of the trunk. We present a case of a well-appearing, 10-month-old infant boy with hemorrhagic vasculitic lesions, acral edema, and an associated episode of hemorrhagic lacrimation and epistaxis.

A 10-month-old infant boy who was otherwise healthy presented to the emergency department (ED) with an acute-onset, progressively worsening cutaneous eruption of 2 days’ duration. A thorough history revealed that the eruption initially had presented as several small, bright-red papules on the thighs. The eruption subsequently spread to involve the buttocks, legs, and arms (Figures 1 and 2). The parents also noted that the patient had experienced an episode of bloody tears and epistaxis that lasted a few minutes at the pediatrician’s office earlier that morning, a finding that prompted the urgent referral to the ED.

Dermatology was then consulted. A review of systems was notable for rhinorrhea and diarrhea during the week leading to the eruption. The patient’s parents denied fevers, decreased oral intake, or a recent course of antibiotics. The patient’s medical history was notable only for atopic dermatitis treated with emollients and occasional topical steroids. The parents denied recent travel or vaccinations. Physical examination showed an afebrile, well-appearing infant with multiple nontender, slightly edematous, circular, purpuric papules and plaques scattered on the buttocks and extremities with edema on the dorsal feet. The remainder of the patient’s workup in the ED was notable for mild elevations in C-reactive protein levels (1.4 mg/dL [reference range, 0–1.2 mg/dL]) and an elevated erythrocyte sedimentation rate (22 mm/h [reference range, 2–12 mm/h]). A complete blood cell count; liver function tests; urinalysis; and coagulation studies, including prothrombin, partial thromboplastin time, and international normalized ratio, were unremarkable. Acute hemorrhagic edema of infancy was diagnosed based on the clinical manifestations.

Acute hemorrhagic edema of infancy (also known as Finkelstein disease, medallionlike purpura, Seidemayer syndrome, infantile postinfectious irislike purpura and edema, and purpura en cocarde avec oedeme) is believed to result from an immune complex–related reaction, often in the setting of an upper respiratory tract infection; medications, especially antibiotics; or vaccinations. The condition previously was considered a benign form of Henoch-Schönlein purpura; however, it is now recognized as its own clinical entity. Acute hemorrhagic edema of infancy commonly affects children between the ages of 4 months and 2 years. The incidence peaks in the winter months, and males tend to be more affected than females.¹

Acute hemorrhagic edema of infancy is clinically characterized by a triad of large purpuric lesions, low-grade fever, and peripheral acral edema. Edema can develop on the hands, feet, and genitalia. Importantly, facial edema has been noted to precede skin lesions.² Coin-shaped or targetoid hemorrhagic and purpuric lesions in a cockade or rosette pattern with scalloped margins typically begin on the distal extremities and tend to spread proximally. The lesions are variable in size but have been reported to be as large as 5 cm in diameter. Although joint pain, bloody diarrhea, hematuria, and proteinuria can accompany AHEI, most cases are devoid of systemic symptoms.³ Hemorrhagic lacrimation and epistaxis—both present in our patient—are rare findings with AHEI. It is likely that most providers, including dermatologists, may be unfamiliar with these striking clinical findings. Although the pathophysiology of hemorrhagic lacrimation and epistaxis has not been formally investigated, we postulate that it likely is related to the formation of immune complexes that lead to small vessel vasculitis, underpinning the characteristic findings in AHEI.^4,5 This reasoning is supported by the complete resolution of symptoms corresponding with clinical clearance of the cutaneous vasculitis in 2 prior cases^4,5 as well as in our patient who did not have a relapse of symptoms following cessation of the cutaneous eruption at a pediatric follow-up appointment 2 weeks later.

Acute hemorrhagic edema of infancy is a clinical diagnosis; however, a skin biopsy can be performed to confirm the clinical suspicion and rule out more serious conditions. Histopathologic examination reveals a leukocytoclastic vasculitis involving the capillaries and postcapillary venules of the upper and mid dermis. Laboratory test results usually are nonspecific but can help distinguish AHEI from more serious diseases. The erythrocyte sedimentation rate and C-reactive protein level may be slightly elevated in infants with AHEI. Urinalysis and stool guaiac tests also can be performed to evaluate for any renal or gastrointestinal involvement.⁶

The differential diagnosis includes IgA vasculitis, erythema multiforme, acute meningococcemia, urticarial vasculitis, Kawasaki disease, and child abuse. IgA vasculitis often presents with more systemic involvement, with abdominal pain, vomiting, hematemesis, diarrhea, and hematochezia occurring in up to 50% of patients. The cutaneous findings of erythema multiforme classically are confined to the limbs and face, and edema of the extremities typically is not seen. Patients with acute meningococcemia appear toxic with high fevers, malaise, and possible septic shock.⁵

Acute hemorrhagic edema of infancy is a self-limited condition typically lasting 1 to 3 weeks and requires only supportive care.⁷ Antibiotics should be given to treat concurrent bacterial infections, and antihistamines and steroids may be useful for symptomatic relief. Importantly, however, systemic corticosteroids do not appear to conclusively alter the disease course.⁸

Acute hemorrhagic edema of infancy is a rare benign leukocytoclastic vasculitis with a striking presentation often seen following an upper respiratory tract infection or course of antibiotics. Our case demonstrates that on rare occasions, AHEI may be accompanied by hemorrhagic lacrimation and epistaxis—findings that can be quite alarming to both parents and medical providers. Nonetheless, patients and their caretakers should be assured that the condition is self-limited and resolves without permanent sequalae.

To the Editor:

Hemorrhagic lacrimation and epistaxis are dramatic presentations with a narrow differential diagnosis. It rarely has been reported to present alongside the more typical features of acute hemorrhagic edema of infancy (AHEI), which is a benign self-limited leukocytoclastic vasculitis most often seen in children aged 4 months to 2 years. Extracutaneous involvement rarely is seen in AHEI, though joint, gastrointestinal tract, and renal involvement have been reported.¹ Most patients present with edematous, annular, or cockade purpuric vasculitic lesions classically involving the face and distal extremities with relative sparing of the trunk. We present a case of a well-appearing, 10-month-old infant boy with hemorrhagic vasculitic lesions, acral edema, and an associated episode of hemorrhagic lacrimation and epistaxis.

A 10-month-old infant boy who was otherwise healthy presented to the emergency department (ED) with an acute-onset, progressively worsening cutaneous eruption of 2 days’ duration. A thorough history revealed that the eruption initially had presented as several small, bright-red papules on the thighs. The eruption subsequently spread to involve the buttocks, legs, and arms (Figures 1 and 2). The parents also noted that the patient had experienced an episode of bloody tears and epistaxis that lasted a few minutes at the pediatrician’s office earlier that morning, a finding that prompted the urgent referral to the ED.

Dermatology was then consulted. A review of systems was notable for rhinorrhea and diarrhea during the week leading to the eruption. The patient’s parents denied fevers, decreased oral intake, or a recent course of antibiotics. The patient’s medical history was notable only for atopic dermatitis treated with emollients and occasional topical steroids. The parents denied recent travel or vaccinations. Physical examination showed an afebrile, well-appearing infant with multiple nontender, slightly edematous, circular, purpuric papules and plaques scattered on the buttocks and extremities with edema on the dorsal feet. The remainder of the patient’s workup in the ED was notable for mild elevations in C-reactive protein levels (1.4 mg/dL [reference range, 0–1.2 mg/dL]) and an elevated erythrocyte sedimentation rate (22 mm/h [reference range, 2–12 mm/h]). A complete blood cell count; liver function tests; urinalysis; and coagulation studies, including prothrombin, partial thromboplastin time, and international normalized ratio, were unremarkable. Acute hemorrhagic edema of infancy was diagnosed based on the clinical manifestations.

Acute hemorrhagic edema of infancy (also known as Finkelstein disease, medallionlike purpura, Seidemayer syndrome, infantile postinfectious irislike purpura and edema, and purpura en cocarde avec oedeme) is believed to result from an immune complex–related reaction, often in the setting of an upper respiratory tract infection; medications, especially antibiotics; or vaccinations. The condition previously was considered a benign form of Henoch-Schönlein purpura; however, it is now recognized as its own clinical entity. Acute hemorrhagic edema of infancy commonly affects children between the ages of 4 months and 2 years. The incidence peaks in the winter months, and males tend to be more affected than females.¹

Acute hemorrhagic edema of infancy is clinically characterized by a triad of large purpuric lesions, low-grade fever, and peripheral acral edema. Edema can develop on the hands, feet, and genitalia. Importantly, facial edema has been noted to precede skin lesions.² Coin-shaped or targetoid hemorrhagic and purpuric lesions in a cockade or rosette pattern with scalloped margins typically begin on the distal extremities and tend to spread proximally. The lesions are variable in size but have been reported to be as large as 5 cm in diameter. Although joint pain, bloody diarrhea, hematuria, and proteinuria can accompany AHEI, most cases are devoid of systemic symptoms.³ Hemorrhagic lacrimation and epistaxis—both present in our patient—are rare findings with AHEI. It is likely that most providers, including dermatologists, may be unfamiliar with these striking clinical findings. Although the pathophysiology of hemorrhagic lacrimation and epistaxis has not been formally investigated, we postulate that it likely is related to the formation of immune complexes that lead to small vessel vasculitis, underpinning the characteristic findings in AHEI.^4,5 This reasoning is supported by the complete resolution of symptoms corresponding with clinical clearance of the cutaneous vasculitis in 2 prior cases^4,5 as well as in our patient who did not have a relapse of symptoms following cessation of the cutaneous eruption at a pediatric follow-up appointment 2 weeks later.

Acute hemorrhagic edema of infancy is a clinical diagnosis; however, a skin biopsy can be performed to confirm the clinical suspicion and rule out more serious conditions. Histopathologic examination reveals a leukocytoclastic vasculitis involving the capillaries and postcapillary venules of the upper and mid dermis. Laboratory test results usually are nonspecific but can help distinguish AHEI from more serious diseases. The erythrocyte sedimentation rate and C-reactive protein level may be slightly elevated in infants with AHEI. Urinalysis and stool guaiac tests also can be performed to evaluate for any renal or gastrointestinal involvement.⁶

The differential diagnosis includes IgA vasculitis, erythema multiforme, acute meningococcemia, urticarial vasculitis, Kawasaki disease, and child abuse. IgA vasculitis often presents with more systemic involvement, with abdominal pain, vomiting, hematemesis, diarrhea, and hematochezia occurring in up to 50% of patients. The cutaneous findings of erythema multiforme classically are confined to the limbs and face, and edema of the extremities typically is not seen. Patients with acute meningococcemia appear toxic with high fevers, malaise, and possible septic shock.⁵

Acute hemorrhagic edema of infancy is a self-limited condition typically lasting 1 to 3 weeks and requires only supportive care.⁷ Antibiotics should be given to treat concurrent bacterial infections, and antihistamines and steroids may be useful for symptomatic relief. Importantly, however, systemic corticosteroids do not appear to conclusively alter the disease course.⁸

Acute hemorrhagic edema of infancy is a rare benign leukocytoclastic vasculitis with a striking presentation often seen following an upper respiratory tract infection or course of antibiotics. Our case demonstrates that on rare occasions, AHEI may be accompanied by hemorrhagic lacrimation and epistaxis—findings that can be quite alarming to both parents and medical providers. Nonetheless, patients and their caretakers should be assured that the condition is self-limited and resolves without permanent sequalae.

To the Editor:

Hemorrhagic lacrimation and epistaxis are dramatic presentations with a narrow differential diagnosis. It rarely has been reported to present alongside the more typical features of acute hemorrhagic edema of infancy (AHEI), which is a benign self-limited leukocytoclastic vasculitis most often seen in children aged 4 months to 2 years. Extracutaneous involvement rarely is seen in AHEI, though joint, gastrointestinal tract, and renal involvement have been reported.¹ Most patients present with edematous, annular, or cockade purpuric vasculitic lesions classically involving the face and distal extremities with relative sparing of the trunk. We present a case of a well-appearing, 10-month-old infant boy with hemorrhagic vasculitic lesions, acral edema, and an associated episode of hemorrhagic lacrimation and epistaxis.

A 10-month-old infant boy who was otherwise healthy presented to the emergency department (ED) with an acute-onset, progressively worsening cutaneous eruption of 2 days’ duration. A thorough history revealed that the eruption initially had presented as several small, bright-red papules on the thighs. The eruption subsequently spread to involve the buttocks, legs, and arms (Figures 1 and 2). The parents also noted that the patient had experienced an episode of bloody tears and epistaxis that lasted a few minutes at the pediatrician’s office earlier that morning, a finding that prompted the urgent referral to the ED.

Dermatology was then consulted. A review of systems was notable for rhinorrhea and diarrhea during the week leading to the eruption. The patient’s parents denied fevers, decreased oral intake, or a recent course of antibiotics. The patient’s medical history was notable only for atopic dermatitis treated with emollients and occasional topical steroids. The parents denied recent travel or vaccinations. Physical examination showed an afebrile, well-appearing infant with multiple nontender, slightly edematous, circular, purpuric papules and plaques scattered on the buttocks and extremities with edema on the dorsal feet. The remainder of the patient’s workup in the ED was notable for mild elevations in C-reactive protein levels (1.4 mg/dL [reference range, 0–1.2 mg/dL]) and an elevated erythrocyte sedimentation rate (22 mm/h [reference range, 2–12 mm/h]). A complete blood cell count; liver function tests; urinalysis; and coagulation studies, including prothrombin, partial thromboplastin time, and international normalized ratio, were unremarkable. Acute hemorrhagic edema of infancy was diagnosed based on the clinical manifestations.

Acute hemorrhagic edema of infancy (also known as Finkelstein disease, medallionlike purpura, Seidemayer syndrome, infantile postinfectious irislike purpura and edema, and purpura en cocarde avec oedeme) is believed to result from an immune complex–related reaction, often in the setting of an upper respiratory tract infection; medications, especially antibiotics; or vaccinations. The condition previously was considered a benign form of Henoch-Schönlein purpura; however, it is now recognized as its own clinical entity. Acute hemorrhagic edema of infancy commonly affects children between the ages of 4 months and 2 years. The incidence peaks in the winter months, and males tend to be more affected than females.¹

Acute hemorrhagic edema of infancy is clinically characterized by a triad of large purpuric lesions, low-grade fever, and peripheral acral edema. Edema can develop on the hands, feet, and genitalia. Importantly, facial edema has been noted to precede skin lesions.² Coin-shaped or targetoid hemorrhagic and purpuric lesions in a cockade or rosette pattern with scalloped margins typically begin on the distal extremities and tend to spread proximally. The lesions are variable in size but have been reported to be as large as 5 cm in diameter. Although joint pain, bloody diarrhea, hematuria, and proteinuria can accompany AHEI, most cases are devoid of systemic symptoms.³ Hemorrhagic lacrimation and epistaxis—both present in our patient—are rare findings with AHEI. It is likely that most providers, including dermatologists, may be unfamiliar with these striking clinical findings. Although the pathophysiology of hemorrhagic lacrimation and epistaxis has not been formally investigated, we postulate that it likely is related to the formation of immune complexes that lead to small vessel vasculitis, underpinning the characteristic findings in AHEI.^4,5 This reasoning is supported by the complete resolution of symptoms corresponding with clinical clearance of the cutaneous vasculitis in 2 prior cases^4,5 as well as in our patient who did not have a relapse of symptoms following cessation of the cutaneous eruption at a pediatric follow-up appointment 2 weeks later.

Acute hemorrhagic edema of infancy is a clinical diagnosis; however, a skin biopsy can be performed to confirm the clinical suspicion and rule out more serious conditions. Histopathologic examination reveals a leukocytoclastic vasculitis involving the capillaries and postcapillary venules of the upper and mid dermis. Laboratory test results usually are nonspecific but can help distinguish AHEI from more serious diseases. The erythrocyte sedimentation rate and C-reactive protein level may be slightly elevated in infants with AHEI. Urinalysis and stool guaiac tests also can be performed to evaluate for any renal or gastrointestinal involvement.⁶

The differential diagnosis includes IgA vasculitis, erythema multiforme, acute meningococcemia, urticarial vasculitis, Kawasaki disease, and child abuse. IgA vasculitis often presents with more systemic involvement, with abdominal pain, vomiting, hematemesis, diarrhea, and hematochezia occurring in up to 50% of patients. The cutaneous findings of erythema multiforme classically are confined to the limbs and face, and edema of the extremities typically is not seen. Patients with acute meningococcemia appear toxic with high fevers, malaise, and possible septic shock.⁵

Acute hemorrhagic edema of infancy is a self-limited condition typically lasting 1 to 3 weeks and requires only supportive care.⁷ Antibiotics should be given to treat concurrent bacterial infections, and antihistamines and steroids may be useful for symptomatic relief. Importantly, however, systemic corticosteroids do not appear to conclusively alter the disease course.⁸

Acute hemorrhagic edema of infancy is a rare benign leukocytoclastic vasculitis with a striking presentation often seen following an upper respiratory tract infection or course of antibiotics. Our case demonstrates that on rare occasions, AHEI may be accompanied by hemorrhagic lacrimation and epistaxis—findings that can be quite alarming to both parents and medical providers. Nonetheless, patients and their caretakers should be assured that the condition is self-limited and resolves without permanent sequalae.

A new “smart patch” composed of microneedles that can detect proinflammatory markers via simulated skin interstitial fluid (ISF) may help diagnose neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease very early on.

Originally developed to deliver medications and vaccines via the skin in a minimally invasive manner, the microneedle arrays were fitted with molecular sensors that, when placed on the skin, detect neuroinflammatory biomarkers such as interleukin-6 in as little as 6 minutes.

The literature suggests that these biomarkers of neurodegenerative disease are present years before patients become symptomatic, said study investigator Sanjiv Sharma, PhD.

“Neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease are [characterized by] progressive loss in nerve cell and brain cells, which leads to memory problems and a loss of mental ability. That is why early diagnosis is key to preventing the loss of brain tissue in dementia, which can go undetected for years,” added Dr. Sharma, who is a lecturer in medical engineering at Swansea (Wales) University.

Dr. Sharma developed the patch with scientists at the Polytechnic of Porto (Portugal) School of Engineering in Portugal. In 2022, they designed, and are currently testing, a microneedle patch that will deliver the COVID vaccine.

The investigators describe their research on the patch’s ability to detect IL-6 in an article published in ACS Omega.
 

At-home diagnosis?

“The skin is the largest organ in the body – it contains more skin interstitial fluid than the total blood volume,” Dr. Sharma noted. “This fluid is an ultrafiltrate of blood and holds biomarkers that complement other biofluids, such as sweat, saliva, and urine. It can be sampled in a minimally invasive manner and used either for point-of-care testing or real-time using microneedle devices.”

Dr. Sharma and associates tested the microneedle patch in artificial ISF that contained the inflammatory cytokine IL-6. They found that the patch accurately detected IL-6 concentrations as low as 1 pg/mL in the fabricated ISF solution.

“In general, the transdermal sensor presented here showed simplicity in designing, short measuring time, high accuracy, and low detection limit. This approach seems a successful tool for the screening of inflammatory biomarkers in point of care testing wherein the skin acts as a window to the body,” the investigators reported.

Dr. Sharma noted that early detection of neurodegenerative diseases is crucial, as once symptoms appear, the disease may have already progressed significantly, and meaningful intervention is challenging.

The device has yet to be tested in humans, which is the next step, said Dr. Sharma.

“We will have to test the hypothesis through extensive preclinical and clinical studies to determine if bloodless, transdermal (skin) diagnostics can offer a cost-effective device that could allow testing in simpler settings such as a clinician’s practice or even home settings,” he noted.
 

Early days

Commenting on the research, David K. Simon, MD, PhD, professor of neurology at Harvard Medical School, Boston, said it is “a promising step regarding validation of a potentially beneficial method for rapidly and accurately measuring IL-6.”

However, he added, “many additional steps are needed to validate the method in actual human skin and to determine whether or not measuring these biomarkers in skin will be useful in studies of neurodegenerative diseases.”

He noted that one study limitation is that inflammatory cytokines such as IL-6 are highly nonspecific, and levels are elevated in various diseases associated with inflammation.

“It is highly unlikely that measuring IL-6 will be useful as a diagnostic tool. However, it does have potential as a biomarker for measuring the impact of treatments aimed at reducing inflammation. As the authors point out, it’s more likely that clinicians will require a panel of biomarkers rather than only measuring IL-6,” he said.

The study was funded by Fundação para a Ciência e Tecnologia. The investigators disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new “smart patch” composed of microneedles that can detect proinflammatory markers via simulated skin interstitial fluid (ISF) may help diagnose neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease very early on.

Originally developed to deliver medications and vaccines via the skin in a minimally invasive manner, the microneedle arrays were fitted with molecular sensors that, when placed on the skin, detect neuroinflammatory biomarkers such as interleukin-6 in as little as 6 minutes.

The literature suggests that these biomarkers of neurodegenerative disease are present years before patients become symptomatic, said study investigator Sanjiv Sharma, PhD.

“Neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease are [characterized by] progressive loss in nerve cell and brain cells, which leads to memory problems and a loss of mental ability. That is why early diagnosis is key to preventing the loss of brain tissue in dementia, which can go undetected for years,” added Dr. Sharma, who is a lecturer in medical engineering at Swansea (Wales) University.

Dr. Sharma developed the patch with scientists at the Polytechnic of Porto (Portugal) School of Engineering in Portugal. In 2022, they designed, and are currently testing, a microneedle patch that will deliver the COVID vaccine.

The investigators describe their research on the patch’s ability to detect IL-6 in an article published in ACS Omega.
 

At-home diagnosis?

“The skin is the largest organ in the body – it contains more skin interstitial fluid than the total blood volume,” Dr. Sharma noted. “This fluid is an ultrafiltrate of blood and holds biomarkers that complement other biofluids, such as sweat, saliva, and urine. It can be sampled in a minimally invasive manner and used either for point-of-care testing or real-time using microneedle devices.”

Dr. Sharma and associates tested the microneedle patch in artificial ISF that contained the inflammatory cytokine IL-6. They found that the patch accurately detected IL-6 concentrations as low as 1 pg/mL in the fabricated ISF solution.

“In general, the transdermal sensor presented here showed simplicity in designing, short measuring time, high accuracy, and low detection limit. This approach seems a successful tool for the screening of inflammatory biomarkers in point of care testing wherein the skin acts as a window to the body,” the investigators reported.

Dr. Sharma noted that early detection of neurodegenerative diseases is crucial, as once symptoms appear, the disease may have already progressed significantly, and meaningful intervention is challenging.

The device has yet to be tested in humans, which is the next step, said Dr. Sharma.

“We will have to test the hypothesis through extensive preclinical and clinical studies to determine if bloodless, transdermal (skin) diagnostics can offer a cost-effective device that could allow testing in simpler settings such as a clinician’s practice or even home settings,” he noted.
 

Early days

Commenting on the research, David K. Simon, MD, PhD, professor of neurology at Harvard Medical School, Boston, said it is “a promising step regarding validation of a potentially beneficial method for rapidly and accurately measuring IL-6.”

However, he added, “many additional steps are needed to validate the method in actual human skin and to determine whether or not measuring these biomarkers in skin will be useful in studies of neurodegenerative diseases.”

He noted that one study limitation is that inflammatory cytokines such as IL-6 are highly nonspecific, and levels are elevated in various diseases associated with inflammation.

“It is highly unlikely that measuring IL-6 will be useful as a diagnostic tool. However, it does have potential as a biomarker for measuring the impact of treatments aimed at reducing inflammation. As the authors point out, it’s more likely that clinicians will require a panel of biomarkers rather than only measuring IL-6,” he said.

The study was funded by Fundação para a Ciência e Tecnologia. The investigators disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new “smart patch” composed of microneedles that can detect proinflammatory markers via simulated skin interstitial fluid (ISF) may help diagnose neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease very early on.

Originally developed to deliver medications and vaccines via the skin in a minimally invasive manner, the microneedle arrays were fitted with molecular sensors that, when placed on the skin, detect neuroinflammatory biomarkers such as interleukin-6 in as little as 6 minutes.

The literature suggests that these biomarkers of neurodegenerative disease are present years before patients become symptomatic, said study investigator Sanjiv Sharma, PhD.

“Neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease are [characterized by] progressive loss in nerve cell and brain cells, which leads to memory problems and a loss of mental ability. That is why early diagnosis is key to preventing the loss of brain tissue in dementia, which can go undetected for years,” added Dr. Sharma, who is a lecturer in medical engineering at Swansea (Wales) University.

Dr. Sharma developed the patch with scientists at the Polytechnic of Porto (Portugal) School of Engineering in Portugal. In 2022, they designed, and are currently testing, a microneedle patch that will deliver the COVID vaccine.

The investigators describe their research on the patch’s ability to detect IL-6 in an article published in ACS Omega.
 

At-home diagnosis?

“The skin is the largest organ in the body – it contains more skin interstitial fluid than the total blood volume,” Dr. Sharma noted. “This fluid is an ultrafiltrate of blood and holds biomarkers that complement other biofluids, such as sweat, saliva, and urine. It can be sampled in a minimally invasive manner and used either for point-of-care testing or real-time using microneedle devices.”

Dr. Sharma and associates tested the microneedle patch in artificial ISF that contained the inflammatory cytokine IL-6. They found that the patch accurately detected IL-6 concentrations as low as 1 pg/mL in the fabricated ISF solution.

“In general, the transdermal sensor presented here showed simplicity in designing, short measuring time, high accuracy, and low detection limit. This approach seems a successful tool for the screening of inflammatory biomarkers in point of care testing wherein the skin acts as a window to the body,” the investigators reported.

Dr. Sharma noted that early detection of neurodegenerative diseases is crucial, as once symptoms appear, the disease may have already progressed significantly, and meaningful intervention is challenging.

The device has yet to be tested in humans, which is the next step, said Dr. Sharma.

“We will have to test the hypothesis through extensive preclinical and clinical studies to determine if bloodless, transdermal (skin) diagnostics can offer a cost-effective device that could allow testing in simpler settings such as a clinician’s practice or even home settings,” he noted.
 

Early days

Commenting on the research, David K. Simon, MD, PhD, professor of neurology at Harvard Medical School, Boston, said it is “a promising step regarding validation of a potentially beneficial method for rapidly and accurately measuring IL-6.”

However, he added, “many additional steps are needed to validate the method in actual human skin and to determine whether or not measuring these biomarkers in skin will be useful in studies of neurodegenerative diseases.”

He noted that one study limitation is that inflammatory cytokines such as IL-6 are highly nonspecific, and levels are elevated in various diseases associated with inflammation.

“It is highly unlikely that measuring IL-6 will be useful as a diagnostic tool. However, it does have potential as a biomarker for measuring the impact of treatments aimed at reducing inflammation. As the authors point out, it’s more likely that clinicians will require a panel of biomarkers rather than only measuring IL-6,” he said.

The study was funded by Fundação para a Ciência e Tecnologia. The investigators disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An agent biologically similar to the humanized monoclonal antibody natalizumab is as effective and safe as the original reference drug for relapsing remitting multiple sclerosis (RRMS) – and has a similar level of immunogenicity, new research shows.

The investigators noted that these phase 3 trial findings are the final stage in the regulatory approval process.

“There will be a biosimilar that with respect to all parameters – efficacy, side effects, immunogenicity – doesn’t differ from the original drug and will probably be an option to consider to reduce treatment costs in MS,” said lead investigator Bernhard Hemmer, MD, a professor in the department of neurology, Technical University of Munich (Germany).

The findings were published online in JAMA Neurology.
 

Potential cost savings

Disease-modifying therapies (DMTs), particularly targeted biologics, have revolutionized the treatment of MS, including RRMS. Natalizumab, which was the first targeted biologic therapy approved for RRMS, is very effective and widely used, Dr. Hemmer said.

However, this and other DMTs are costly. Biosimilars, which are medicines clinically similar to an already marketed reference biologic medicine, can address this issue. In the areas of rheumatology and oncology, biosimilars have already demonstrated significant cost savings and improved treatment access.

The biosimilar natalizumab (biosim-NTZ), developed by Polpharma Biologics, is the first biosimilar monoclonal antibody therapy to be developed for MS.

Health authorities such as the Food and Drug Administration require comparative phase 3 studies to confirm there are no clinically relevant differences between a proposed biosimilar and its reference medicine.

The new multicenter, phase 3, double-blind, randomized trial – known as Antelope – included 264 adult patients with RRMS at 48 centers in seven Eastern European countries. Most study participants were women (61.4%), and their mean age was 36.7 years.

All study participants were randomly assigned to receive intravenous infusions every 4 weeks of 300 mg of biosim-NTZ or reference natalizumab (ref-NTZ) for a total of 12 infusions.

At week 24, 30 patients were switched from ref-NTZ to biosim-NTZ for the remainder of their infusions. Including such a population is required by regulatory agencies to ensure switching patients from a drug they’ve been taking to a new biosimilar does not introduce any concerns, said Dr. Hemmer.
 

Comparable efficacy, safety profile

The primary efficacy endpoint was the cumulative number of new active brain lesions on MRI.

At baseline, 48.1% of the biosimilar group and 45.9% of the reference drug group had at least one gadolinium-enhancing lesion. In addition, 96.9% of the biosimilar group had more than 15 T2 lesions, compared with 96.2% of the reference group.

At week 24, the mean difference between biosim-NTZ and ref-NTZ in the cumulative number of new active lesions was 0.17 (least square means, 0.34 vs. 0.45), with a 95% confidence interval of –0.61 to 0.94 and a point estimate within the prespecified margins of ± 2.1.

The annualized relapse rate for biosim-NTZ and ref-NTZ was similar at 24 weeks (0.21 vs. 0.15), as well as at 48 weeks (0.17 vs. 0.13). For Expanded Disability Status Scale scores, which were similar between treatment groups at baseline (mean, 3.4 vs. 3.2), change at 24 and 48 weeks was minimal and similar in both groups.

The safety profile was as expected for patients with RRMS receiving natalizumab. There were few adverse events of special interest, with similar proportions across all treatment groups.

The overall adverse-event profile for patients who switched from ref-NTZ to biosim-NTZ was similar to patients continuing ref-NTZ treatment and did not indicate any new or increased risks associated with switching.

Rates of treatment-emergent adverse events (TEAEs) were similar, at 64.9% for biosim-NTZ, 68.9% for ref-NTZ, and 73.3% for the switch group. The most-reported TEAEs among all treatment groups were nervous system disorders and infections and infestations.

Progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal demyelinating disease of the central nervous system, is associated with some DMTs – notably ref-NTZ. It is caused by infection with the John Cunningham virus (JCV) (also referred to as human polyomavirus), the researchers noted.

As per the study protocol, no participant had a JCV-positive index of more than 1.5 at baseline. Proportions of patients positive for anti-JCV antibodies were similarly distributed between treatment groups throughout the study.
 

Similar immunogenicity

There was strong concordance regarding positivity for treatment-emergent antidrug antibodies between the biosim-NTZ and ref-NTZ groups (79.4% and 74.0%). This was also the case for antinatalizumab-neutralizing antibodies (69.0% and 66.2%).

“There was nothing that indicated immunogenicity is different” between the two agents, said Dr. Hemmer.

While this might change “when you look at longer time periods,” antibodies to natalizumab usually develop “very early on,” he added.

Dr. Hemmer noted that this comparison of the proposed biosimilar with the reference drug had no real surprises.

“If the immunogenicity is the same, the mode of action is the same, and the dose is the same, you would expect to have a similar clinical effect and also a similar side-effect profile, which is indeed the case,” he said.

Dr. Hemmer added that he has no insight as to when the drug might be approved but believes developers expect that to occur sometime this year.
 

Welcome results

Commenting on the study results, Torge Rempe, MD, assistant professor in the department of neurology, University of Florida, Gainesville, and the William T. And Janice M. Neely professor for research in MS, said he welcomes these new results showing the biosimilar matched the reference medication.

“The authors report no significant difference in their primary endpoint of cumulative number of active lesions as well as their secondary clinical endpoints of annualized relapse rate and changes from baseline Expanded Disability Status Scale scores,” said Dr. Rempe, who was not involved with the research.

The study also showed the reported adverse events were similar between the biosimilar and reference natalizumab, he noted.

However, although no cases of PML were uncovered during the study period, further research is needed to determine long-term safety in this area, Dr. Rempe said.

Finally, he agreed that the development of biosimilars such as this one addresses the issue of high annual costs for DMTs, an area of concern in the field of MS.

The study was funded by Polpharma Biologics. Dr. Hemmer has reported receiving personal fees from Polpharma and Sandoz during the conduct of the study and personal fees from Novartis, Biocom, and TG Therapeutics outside the submitted work. He has also received a patent for genetic determinants of antibodies against interferon-beta and a patent for KIR4.1 antibodies in MS; served on scientific advisory boards for Novartis; served as a data monitoring and safety committee member for AllergyCare, Polpharma Biologics, Sandoz, and TG Therapeutics; and received speaker honoraria from Desitin, grants from Regeneron for MS research, and funding from the Multiple MS EU consortium, the CLINSPECT-M consortium, and the German Research Foundation. Dr. Rempe has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An agent biologically similar to the humanized monoclonal antibody natalizumab is as effective and safe as the original reference drug for relapsing remitting multiple sclerosis (RRMS) – and has a similar level of immunogenicity, new research shows.

The investigators noted that these phase 3 trial findings are the final stage in the regulatory approval process.

“There will be a biosimilar that with respect to all parameters – efficacy, side effects, immunogenicity – doesn’t differ from the original drug and will probably be an option to consider to reduce treatment costs in MS,” said lead investigator Bernhard Hemmer, MD, a professor in the department of neurology, Technical University of Munich (Germany).

The findings were published online in JAMA Neurology.
 

Potential cost savings

Disease-modifying therapies (DMTs), particularly targeted biologics, have revolutionized the treatment of MS, including RRMS. Natalizumab, which was the first targeted biologic therapy approved for RRMS, is very effective and widely used, Dr. Hemmer said.

However, this and other DMTs are costly. Biosimilars, which are medicines clinically similar to an already marketed reference biologic medicine, can address this issue. In the areas of rheumatology and oncology, biosimilars have already demonstrated significant cost savings and improved treatment access.

The biosimilar natalizumab (biosim-NTZ), developed by Polpharma Biologics, is the first biosimilar monoclonal antibody therapy to be developed for MS.

Health authorities such as the Food and Drug Administration require comparative phase 3 studies to confirm there are no clinically relevant differences between a proposed biosimilar and its reference medicine.

The new multicenter, phase 3, double-blind, randomized trial – known as Antelope – included 264 adult patients with RRMS at 48 centers in seven Eastern European countries. Most study participants were women (61.4%), and their mean age was 36.7 years.

All study participants were randomly assigned to receive intravenous infusions every 4 weeks of 300 mg of biosim-NTZ or reference natalizumab (ref-NTZ) for a total of 12 infusions.

At week 24, 30 patients were switched from ref-NTZ to biosim-NTZ for the remainder of their infusions. Including such a population is required by regulatory agencies to ensure switching patients from a drug they’ve been taking to a new biosimilar does not introduce any concerns, said Dr. Hemmer.
 

Comparable efficacy, safety profile

The primary efficacy endpoint was the cumulative number of new active brain lesions on MRI.

At baseline, 48.1% of the biosimilar group and 45.9% of the reference drug group had at least one gadolinium-enhancing lesion. In addition, 96.9% of the biosimilar group had more than 15 T2 lesions, compared with 96.2% of the reference group.

At week 24, the mean difference between biosim-NTZ and ref-NTZ in the cumulative number of new active lesions was 0.17 (least square means, 0.34 vs. 0.45), with a 95% confidence interval of –0.61 to 0.94 and a point estimate within the prespecified margins of ± 2.1.

The annualized relapse rate for biosim-NTZ and ref-NTZ was similar at 24 weeks (0.21 vs. 0.15), as well as at 48 weeks (0.17 vs. 0.13). For Expanded Disability Status Scale scores, which were similar between treatment groups at baseline (mean, 3.4 vs. 3.2), change at 24 and 48 weeks was minimal and similar in both groups.

The safety profile was as expected for patients with RRMS receiving natalizumab. There were few adverse events of special interest, with similar proportions across all treatment groups.

The overall adverse-event profile for patients who switched from ref-NTZ to biosim-NTZ was similar to patients continuing ref-NTZ treatment and did not indicate any new or increased risks associated with switching.

Rates of treatment-emergent adverse events (TEAEs) were similar, at 64.9% for biosim-NTZ, 68.9% for ref-NTZ, and 73.3% for the switch group. The most-reported TEAEs among all treatment groups were nervous system disorders and infections and infestations.

Progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal demyelinating disease of the central nervous system, is associated with some DMTs – notably ref-NTZ. It is caused by infection with the John Cunningham virus (JCV) (also referred to as human polyomavirus), the researchers noted.

As per the study protocol, no participant had a JCV-positive index of more than 1.5 at baseline. Proportions of patients positive for anti-JCV antibodies were similarly distributed between treatment groups throughout the study.
 

Similar immunogenicity

There was strong concordance regarding positivity for treatment-emergent antidrug antibodies between the biosim-NTZ and ref-NTZ groups (79.4% and 74.0%). This was also the case for antinatalizumab-neutralizing antibodies (69.0% and 66.2%).

“There was nothing that indicated immunogenicity is different” between the two agents, said Dr. Hemmer.

While this might change “when you look at longer time periods,” antibodies to natalizumab usually develop “very early on,” he added.

Dr. Hemmer noted that this comparison of the proposed biosimilar with the reference drug had no real surprises.

“If the immunogenicity is the same, the mode of action is the same, and the dose is the same, you would expect to have a similar clinical effect and also a similar side-effect profile, which is indeed the case,” he said.

Dr. Hemmer added that he has no insight as to when the drug might be approved but believes developers expect that to occur sometime this year.
 

Welcome results

Commenting on the study results, Torge Rempe, MD, assistant professor in the department of neurology, University of Florida, Gainesville, and the William T. And Janice M. Neely professor for research in MS, said he welcomes these new results showing the biosimilar matched the reference medication.

“The authors report no significant difference in their primary endpoint of cumulative number of active lesions as well as their secondary clinical endpoints of annualized relapse rate and changes from baseline Expanded Disability Status Scale scores,” said Dr. Rempe, who was not involved with the research.

The study also showed the reported adverse events were similar between the biosimilar and reference natalizumab, he noted.

However, although no cases of PML were uncovered during the study period, further research is needed to determine long-term safety in this area, Dr. Rempe said.

Finally, he agreed that the development of biosimilars such as this one addresses the issue of high annual costs for DMTs, an area of concern in the field of MS.

The study was funded by Polpharma Biologics. Dr. Hemmer has reported receiving personal fees from Polpharma and Sandoz during the conduct of the study and personal fees from Novartis, Biocom, and TG Therapeutics outside the submitted work. He has also received a patent for genetic determinants of antibodies against interferon-beta and a patent for KIR4.1 antibodies in MS; served on scientific advisory boards for Novartis; served as a data monitoring and safety committee member for AllergyCare, Polpharma Biologics, Sandoz, and TG Therapeutics; and received speaker honoraria from Desitin, grants from Regeneron for MS research, and funding from the Multiple MS EU consortium, the CLINSPECT-M consortium, and the German Research Foundation. Dr. Rempe has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An agent biologically similar to the humanized monoclonal antibody natalizumab is as effective and safe as the original reference drug for relapsing remitting multiple sclerosis (RRMS) – and has a similar level of immunogenicity, new research shows.

The investigators noted that these phase 3 trial findings are the final stage in the regulatory approval process.

“There will be a biosimilar that with respect to all parameters – efficacy, side effects, immunogenicity – doesn’t differ from the original drug and will probably be an option to consider to reduce treatment costs in MS,” said lead investigator Bernhard Hemmer, MD, a professor in the department of neurology, Technical University of Munich (Germany).

The findings were published online in JAMA Neurology.
 

Potential cost savings

Disease-modifying therapies (DMTs), particularly targeted biologics, have revolutionized the treatment of MS, including RRMS. Natalizumab, which was the first targeted biologic therapy approved for RRMS, is very effective and widely used, Dr. Hemmer said.

However, this and other DMTs are costly. Biosimilars, which are medicines clinically similar to an already marketed reference biologic medicine, can address this issue. In the areas of rheumatology and oncology, biosimilars have already demonstrated significant cost savings and improved treatment access.

The biosimilar natalizumab (biosim-NTZ), developed by Polpharma Biologics, is the first biosimilar monoclonal antibody therapy to be developed for MS.

Health authorities such as the Food and Drug Administration require comparative phase 3 studies to confirm there are no clinically relevant differences between a proposed biosimilar and its reference medicine.

The new multicenter, phase 3, double-blind, randomized trial – known as Antelope – included 264 adult patients with RRMS at 48 centers in seven Eastern European countries. Most study participants were women (61.4%), and their mean age was 36.7 years.

All study participants were randomly assigned to receive intravenous infusions every 4 weeks of 300 mg of biosim-NTZ or reference natalizumab (ref-NTZ) for a total of 12 infusions.

At week 24, 30 patients were switched from ref-NTZ to biosim-NTZ for the remainder of their infusions. Including such a population is required by regulatory agencies to ensure switching patients from a drug they’ve been taking to a new biosimilar does not introduce any concerns, said Dr. Hemmer.
 

Comparable efficacy, safety profile

The primary efficacy endpoint was the cumulative number of new active brain lesions on MRI.

At baseline, 48.1% of the biosimilar group and 45.9% of the reference drug group had at least one gadolinium-enhancing lesion. In addition, 96.9% of the biosimilar group had more than 15 T2 lesions, compared with 96.2% of the reference group.

At week 24, the mean difference between biosim-NTZ and ref-NTZ in the cumulative number of new active lesions was 0.17 (least square means, 0.34 vs. 0.45), with a 95% confidence interval of –0.61 to 0.94 and a point estimate within the prespecified margins of ± 2.1.

The annualized relapse rate for biosim-NTZ and ref-NTZ was similar at 24 weeks (0.21 vs. 0.15), as well as at 48 weeks (0.17 vs. 0.13). For Expanded Disability Status Scale scores, which were similar between treatment groups at baseline (mean, 3.4 vs. 3.2), change at 24 and 48 weeks was minimal and similar in both groups.

The safety profile was as expected for patients with RRMS receiving natalizumab. There were few adverse events of special interest, with similar proportions across all treatment groups.

The overall adverse-event profile for patients who switched from ref-NTZ to biosim-NTZ was similar to patients continuing ref-NTZ treatment and did not indicate any new or increased risks associated with switching.

Rates of treatment-emergent adverse events (TEAEs) were similar, at 64.9% for biosim-NTZ, 68.9% for ref-NTZ, and 73.3% for the switch group. The most-reported TEAEs among all treatment groups were nervous system disorders and infections and infestations.

Progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal demyelinating disease of the central nervous system, is associated with some DMTs – notably ref-NTZ. It is caused by infection with the John Cunningham virus (JCV) (also referred to as human polyomavirus), the researchers noted.

As per the study protocol, no participant had a JCV-positive index of more than 1.5 at baseline. Proportions of patients positive for anti-JCV antibodies were similarly distributed between treatment groups throughout the study.
 

Similar immunogenicity

There was strong concordance regarding positivity for treatment-emergent antidrug antibodies between the biosim-NTZ and ref-NTZ groups (79.4% and 74.0%). This was also the case for antinatalizumab-neutralizing antibodies (69.0% and 66.2%).

“There was nothing that indicated immunogenicity is different” between the two agents, said Dr. Hemmer.

While this might change “when you look at longer time periods,” antibodies to natalizumab usually develop “very early on,” he added.

Dr. Hemmer noted that this comparison of the proposed biosimilar with the reference drug had no real surprises.

“If the immunogenicity is the same, the mode of action is the same, and the dose is the same, you would expect to have a similar clinical effect and also a similar side-effect profile, which is indeed the case,” he said.

Dr. Hemmer added that he has no insight as to when the drug might be approved but believes developers expect that to occur sometime this year.
 

Welcome results

Commenting on the study results, Torge Rempe, MD, assistant professor in the department of neurology, University of Florida, Gainesville, and the William T. And Janice M. Neely professor for research in MS, said he welcomes these new results showing the biosimilar matched the reference medication.

“The authors report no significant difference in their primary endpoint of cumulative number of active lesions as well as their secondary clinical endpoints of annualized relapse rate and changes from baseline Expanded Disability Status Scale scores,” said Dr. Rempe, who was not involved with the research.

The study also showed the reported adverse events were similar between the biosimilar and reference natalizumab, he noted.

However, although no cases of PML were uncovered during the study period, further research is needed to determine long-term safety in this area, Dr. Rempe said.

Finally, he agreed that the development of biosimilars such as this one addresses the issue of high annual costs for DMTs, an area of concern in the field of MS.

The study was funded by Polpharma Biologics. Dr. Hemmer has reported receiving personal fees from Polpharma and Sandoz during the conduct of the study and personal fees from Novartis, Biocom, and TG Therapeutics outside the submitted work. He has also received a patent for genetic determinants of antibodies against interferon-beta and a patent for KIR4.1 antibodies in MS; served on scientific advisory boards for Novartis; served as a data monitoring and safety committee member for AllergyCare, Polpharma Biologics, Sandoz, and TG Therapeutics; and received speaker honoraria from Desitin, grants from Regeneron for MS research, and funding from the Multiple MS EU consortium, the CLINSPECT-M consortium, and the German Research Foundation. Dr. Rempe has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.