Key clinical point: In real-world settings, dupilumab is safe and effective in children with moderate-to-severe atopic dermatitis (AD) who are age > 2 to < 12 years.

Major finding: Dupilumab led to significant improvements in the Eczema Area and Severity Index scores and Body Surface Area scores in children age > 2 to < 6 years (both P < .001) and ≥ 6 to < 12 years (both P < .001) but not in those age ≤ 2 years (P  =  .191 and P  =  .092, respectively). No serious adverse events were reported.

Study details: This multicenter retrospective study included 63 children with moderate-to-severe AD who were classified relative to age: ≤ 2 years (n = 4), > 2 to < 6 years (n = 25), and ≥ 6 to < 12 years (n = 34), with most having received prior systemic immunosuppressive therapies and all being treated with dupilumab.

Disclosures: This study did not disclose any funding source. Several authors declared receiving grants or honoraria from or serving as investigators, advisors, consultants, or speakers for various sources.

Source: Martinez-Cabriales S et al. Multicenter Canadian case series of pediatric patients less than 12 years of age with moderate-to-severe atopic dermatitis treated with dupilumab. Pediatr Dermatol. 2023 (Oct 31). doi: 10.1111/pde.15418

Key clinical point: In real-world settings, dupilumab is safe and effective in children with moderate-to-severe atopic dermatitis (AD) who are age > 2 to < 12 years.

Major finding: Dupilumab led to significant improvements in the Eczema Area and Severity Index scores and Body Surface Area scores in children age > 2 to < 6 years (both P < .001) and ≥ 6 to < 12 years (both P < .001) but not in those age ≤ 2 years (P  =  .191 and P  =  .092, respectively). No serious adverse events were reported.

Study details: This multicenter retrospective study included 63 children with moderate-to-severe AD who were classified relative to age: ≤ 2 years (n = 4), > 2 to < 6 years (n = 25), and ≥ 6 to < 12 years (n = 34), with most having received prior systemic immunosuppressive therapies and all being treated with dupilumab.

Disclosures: This study did not disclose any funding source. Several authors declared receiving grants or honoraria from or serving as investigators, advisors, consultants, or speakers for various sources.

Source: Martinez-Cabriales S et al. Multicenter Canadian case series of pediatric patients less than 12 years of age with moderate-to-severe atopic dermatitis treated with dupilumab. Pediatr Dermatol. 2023 (Oct 31). doi: 10.1111/pde.15418

Key clinical point: In real-world settings, dupilumab is safe and effective in children with moderate-to-severe atopic dermatitis (AD) who are age > 2 to < 12 years.

Major finding: Dupilumab led to significant improvements in the Eczema Area and Severity Index scores and Body Surface Area scores in children age > 2 to < 6 years (both P < .001) and ≥ 6 to < 12 years (both P < .001) but not in those age ≤ 2 years (P  =  .191 and P  =  .092, respectively). No serious adverse events were reported.

Study details: This multicenter retrospective study included 63 children with moderate-to-severe AD who were classified relative to age: ≤ 2 years (n = 4), > 2 to < 6 years (n = 25), and ≥ 6 to < 12 years (n = 34), with most having received prior systemic immunosuppressive therapies and all being treated with dupilumab.

Disclosures: This study did not disclose any funding source. Several authors declared receiving grants or honoraria from or serving as investigators, advisors, consultants, or speakers for various sources.

Source: Martinez-Cabriales S et al. Multicenter Canadian case series of pediatric patients less than 12 years of age with moderate-to-severe atopic dermatitis treated with dupilumab. Pediatr Dermatol. 2023 (Oct 31). doi: 10.1111/pde.15418

Key clinical point: Upadacitinib is effective and well-tolerated in patients with moderate-to-severe atopic dermatitis (AD) and prior failure to multiple systemic immunosuppressive and biologic therapies.

Major finding: At a median follow-up of 37.5 weeks, the median Investigator’s Global Assessment scores and Numerical Rating Scale itch scores reduced significantly from 3.00 to 1.50 and from 7.00 to 2.25, respectively (both P < .001). The adverse events reported were mostly mild in severity, with acne-like eruptions (25%) and nausea (13%) being the most common.

Study details: This prospective observational single-center study included 48 patients with moderate-to-severe AD receiving 15 mg or 30 mg upadacitinib daily, most of whom (n = 39) had failed other targeted therapies, including other Janus kinase inhibitors and biologics.

Disclosures: This study did not receive any funding. DJ Hijnen declared serving as an investigator and consultant for various sources. The other authors declared no conflicts of interest.

Source: Schlösser AR et al. Upadacitinib treatment in a real-world difficult-to-treat atopic dermatitis patient cohort. J Eur Acad Dermatol Venereol. 2023 (Oct 21). doi: 10.1111/jdv.19581

Key clinical point: Upadacitinib is effective and well-tolerated in patients with moderate-to-severe atopic dermatitis (AD) and prior failure to multiple systemic immunosuppressive and biologic therapies.

Major finding: At a median follow-up of 37.5 weeks, the median Investigator’s Global Assessment scores and Numerical Rating Scale itch scores reduced significantly from 3.00 to 1.50 and from 7.00 to 2.25, respectively (both P < .001). The adverse events reported were mostly mild in severity, with acne-like eruptions (25%) and nausea (13%) being the most common.

Study details: This prospective observational single-center study included 48 patients with moderate-to-severe AD receiving 15 mg or 30 mg upadacitinib daily, most of whom (n = 39) had failed other targeted therapies, including other Janus kinase inhibitors and biologics.

Disclosures: This study did not receive any funding. DJ Hijnen declared serving as an investigator and consultant for various sources. The other authors declared no conflicts of interest.

Source: Schlösser AR et al. Upadacitinib treatment in a real-world difficult-to-treat atopic dermatitis patient cohort. J Eur Acad Dermatol Venereol. 2023 (Oct 21). doi: 10.1111/jdv.19581

Key clinical point: Upadacitinib is effective and well-tolerated in patients with moderate-to-severe atopic dermatitis (AD) and prior failure to multiple systemic immunosuppressive and biologic therapies.

Major finding: At a median follow-up of 37.5 weeks, the median Investigator’s Global Assessment scores and Numerical Rating Scale itch scores reduced significantly from 3.00 to 1.50 and from 7.00 to 2.25, respectively (both P < .001). The adverse events reported were mostly mild in severity, with acne-like eruptions (25%) and nausea (13%) being the most common.

Study details: This prospective observational single-center study included 48 patients with moderate-to-severe AD receiving 15 mg or 30 mg upadacitinib daily, most of whom (n = 39) had failed other targeted therapies, including other Janus kinase inhibitors and biologics.

Disclosures: This study did not receive any funding. DJ Hijnen declared serving as an investigator and consultant for various sources. The other authors declared no conflicts of interest.

Source: Schlösser AR et al. Upadacitinib treatment in a real-world difficult-to-treat atopic dermatitis patient cohort. J Eur Acad Dermatol Venereol. 2023 (Oct 21). doi: 10.1111/jdv.19581

Since 1983, when I was a child and fled as a boat refugee from Vietnam with my mother, the international plight of displaced people has only worsened. From 1997 to 2022, the number of forcibly displaced people has more than tripled, growing from 34 million to more than 108 million.¹

Displaced people are designated as refugees only when they cross international borders and meet the United Nations High Commissioner for Refugees’ (UNHCR) definition as “persons outside their countries of origin who are in need of international protection because of a serious threat to their life, physical integrity, or freedom in their country of origin as a result of persecution, armed conflict, violence, or serious public disorder.”² There is a separate mandate by the United Nations for the aid of Palestinian refugees under the United Nations General Assembly’s United Nations Relief and Works Agency for Palestinian Refugees in the Near East (UNRWA).³ Of the displaced in 2022, more than 36 million were recognized as refugees under UNHCR and UNRWA mandates.¹ Of these, almost 50% were children, at 17.5 million.⁴ To make matters worse, worldwide children represent less than one-third of the population.⁴ Since 2022, the increase in refugeeism is mostly driven by Ukraine and Syria, though also significantly Afghanistan, Venezuela, Sudan, Myanmar, Congo, Somalia, and Central African Republic.⁴ Refugeeism is a growing problem that disproportionately impacts children through sheer number, and one suspects, given their greater overall vulnerabilities compared with adults, physical and mental health consequences.
 

Traumas of refugees compared with non-refugee immigrants

In terms of mental health, refugees are distinct from non-refugee immigrants in that they likely experience more severe psychosocial adversities from greater poverty, greater risk of family separation, and uncertainty of the asylum process.^5-8

From my own experience, this stems from the urgent nature of the refugee’s displacement, where they are often fleeing an immediate danger. My family had fled persecution from Communist forces and the social economic collapse that rendered Vietnam, for a time, one of the poorest in the world.⁹ Or, as my mother observed, “We had to leave because even doctors were starving.”

Refugees often have little preparation, have little legal protection since they are often criminalized, and are forced to endure dangerous conditions where they are vulnerable to smugglers and criminals who exploit their unprotected status. Once they arrive in their new country, they often do not have other family as social supports or resources. They themselves become the anchor for future legal and orderly immigration of their remaining family, given that they can extend their refugee status to those left behind.¹⁰ These non-refugee immigrants, unlike their refugee counterparts, are often flown to their new homes with more preparation, protecting them from dangerous conditions, and have the benefit of family who provide them with resources. As such, refugees tend to experience more traumatic life events than non-refugee immigrants. This was true in my family where those of us who initially escaped became the anchors to legally, and more safely, immigrate most of our family in Vietnam. We became their resources, likely making their acclimation smoother.
 

The mental health of refugee children and their caregivers

It is important to understand the stressors affecting the caregivers of children, since effective treatment of their mental health conditions can also benefit the children as well.¹¹ In fact, among the greatest protective factors for refugee children is the presence of an adult caregiver, suggesting that the child’s mental health is dependent on the caregivers.

Those children who are separated show much worse mental health sequalae.¹² As such, an understanding of the caregiver’s stressors is important. For example, when we were escaping Vietnam, my mom would protect me from our hardships by talking about our goals in America, minimizing our dangers by saying that we would be rewarded with things like a hamburger with its seemingly impossible amount of meat. Physically, my mother would always sleep with her arms around me and a knife hidden in order to ward off any attackers at night. When I was starving in the hull of a boat, having not eaten for days, my mother begged for food and gave me what she could get. And post-escape, my family focused on work and applied for aid for shelter and food, while encouraging us to invest in education, likely preventing involvement in criminal activities or gangs. Though overall, my family shielded me from the worst consequences, they also passed on their fears. One of my uncles had been killed by the police when he tried to escape, and so my family passed down a deep suspicion of authorities, whether they were the police or school principals. My mother had vivid memories of Communist re-education camps, which likely gave her a lasting fear that a Communist would find out our identities in America and re-capture us.
 

The mental health risk of refugees

Given that refugees tend to experience greater amounts of traumatic life events and a vast array of stressors sustained across years and even decades before, during, and after migration, it is no wonder they have much higher rates of mental health conditions, most predominantly PTSD and affective disorders.^13,14 They are at particular risk of developing psychoses because they are more likely to experience a range of physical, psychological, and psychosocial problems associated with adversities such as violence, discrimination, economic stress, and social isolation.¹³ For example, the period leading up to my escape consisted of decades of prolonged war: the French-Indochina from 1945 to 1954, then the Vietnam War from 1955 to 1975) as well as the persecution and re-education camps afterward. What my family had to endure created a period of fear and loss into which I was born into in 1976. That year, my family had lost its fortune due to the Communist government seizing of our home and business, plunging us from a comfortable middle- to upper-class life to poverty. There was also widespread fear of systematic rape by the Communist victors. So my family endured great stress and the loss of a way of life leading up to our escape.

For the refugees, the escape itself is often a dangerous journey where, given its emergent nature, they are often exposed to the elements. We know about the current situation in Ukraine and Gaza, where children are fleeing from bombs and bullets. In my situation, we endured weeks of starvation crammed in the hull of boat as we forged through the Indian Ocean to the Philippines. One of my aunts, on a separate trip, perished because her boat had capsized, like so many others. Though impossible to verify, it has been estimated that up to 70% of Vietnamese refugees died during their escape.¹⁵ After the boat, my mother and I still had to brave Malaysian jungles and prisons, and then refugee camps for a year before we reached safety at an American Embassy in the Philippines. After we gained sponsorship to America, the traumas did not abate, but were only replaced by those of culture shock, poverty, and alienation. Taken by themselves, significant traumas exist in each phase of a refugee child’s escape, whether before, during, or after. These traumas are likely compounded since they are continuously layered and sustained across years, even decades. They affect not only the children, but their parents, and sometimes even a whole nation of people.
 

Summary

In recent decades, refugeeism has been a growing problem that disproportionately affects children. Refugee children and their families experience a variety of traumas, often sustained across years and even decades, because of armed conflict, persecution, or social upheavals. It is known that refugees are at greater risk for PTSD and affective and psychotic disorders, presumably due to increased traumatic life events before, during, and after their migration. The writer uses his own experience as a child refugee from Vietnam to elucidate the stressors evident in various phases of forced displacement.

Dr. Nguyen is a second year resident at UCSF Fresno Psychiatry Residency. He was a public high school English teacher for 15 years previously.

References

1. UNHCR. Global Trends. Forced displacement in 2016. Geneva, Switzerland: The UN Refugee Agency, 2022. https://www.unhcr.org/global-trends.

2. Office of the United Nations High Commissioner for Refugees. The refugee concept under international law. Global compact for safe, orderly and regular migration.  https://www.unhcr.org/sites/default/files/legacy-pdf/5aa290937.pdf. Published March 8, 2018.

3. United Nations. (2023, November 11). The Question of Palestine. Un.org. https://www.un.org/unispal/document/un-general-assembly-renews-unrwa-mandate-press-release/

4. UNICEF. (2023, November 11). Child displacement. Data.unicef.org. https://data.unicef.org/topic/child-migration-and-displacement/displacement

5. Kinzie JD. Immigrants and refugees: The psychiatric perspective. Transcult Psychiatry. 2006 Dec;43(4):577-91. doi: 10.1177/1363461506070782.

6. Eaton W and Harrison G. Ethnic disadvantage and schizophrenia. Acta Psychiatr Scand Suppl. 2000:(407):38-43. doi: 10.1034/j.1600-0447.2000.00007.x.

7. Gilliver SC et al. Recent research on the mental health of immigrants to Sweden: a literature review. Eur J Public Health. 2014 Aug:24 Suppl 1:72-9. doi: 10.1093/eurpub/cku101.

8. Rapp MA et al. When local poverty is more important than your income: Mental health in minorities in inner cities. World Psychiatry. 2015 Jun;14(2):249-50. doi: 10.1002/wps.20221.

9. Cima, Ronald, ed. Vietnam: A Country Study. Washington: GPO for the Library of Congress, 1987.

10. United States Citizenship & Immigration Services (2023, November 12). Refugees. Uscis.gov. https://www.uscis.gov/humanitarian/refugees-and-asylum/refugees

11. Fazel M and Betancourt TS. (2018). Preventive mental health interventions for refugee children and adolescents in high-income settings. Lancet Child Adolesc Health. 2018 Feb;2(2):121-32. doi: 10.1016/S2352-4642(17)30147-5.

12. Fazel M et al. Mental health of displaced and refugee children resettled in high-income countries: risk and protective factors. Lancet. 2012 Jan 21;379(9812):266-82. doi: 10.1016/S0140-6736(11)60051-2.

13. Dapunt J et al. Refugees and psychosis: A review of the literature. Transl Psychiatry. 2017 Jun 13;7(6):e1149. doi: 10.1038/tp.2017.119.

14. Fazel M et al. Prevalence of serious mental disorder in 7,000 refugees resettled in western countries: a systematic review. Lancet. 2005 Apr;365(9467):1309-14. doi: 10.1016/S0140-6736(05)61027-6.

15. Rummel R. Statistics of Vietnamese Democide, in his Statistics of Democide. 1997. Table 6.1B,lines 730, 749-51.

Since 1983, when I was a child and fled as a boat refugee from Vietnam with my mother, the international plight of displaced people has only worsened. From 1997 to 2022, the number of forcibly displaced people has more than tripled, growing from 34 million to more than 108 million.¹

Displaced people are designated as refugees only when they cross international borders and meet the United Nations High Commissioner for Refugees’ (UNHCR) definition as “persons outside their countries of origin who are in need of international protection because of a serious threat to their life, physical integrity, or freedom in their country of origin as a result of persecution, armed conflict, violence, or serious public disorder.”² There is a separate mandate by the United Nations for the aid of Palestinian refugees under the United Nations General Assembly’s United Nations Relief and Works Agency for Palestinian Refugees in the Near East (UNRWA).³ Of the displaced in 2022, more than 36 million were recognized as refugees under UNHCR and UNRWA mandates.¹ Of these, almost 50% were children, at 17.5 million.⁴ To make matters worse, worldwide children represent less than one-third of the population.⁴ Since 2022, the increase in refugeeism is mostly driven by Ukraine and Syria, though also significantly Afghanistan, Venezuela, Sudan, Myanmar, Congo, Somalia, and Central African Republic.⁴ Refugeeism is a growing problem that disproportionately impacts children through sheer number, and one suspects, given their greater overall vulnerabilities compared with adults, physical and mental health consequences.
 

Traumas of refugees compared with non-refugee immigrants

In terms of mental health, refugees are distinct from non-refugee immigrants in that they likely experience more severe psychosocial adversities from greater poverty, greater risk of family separation, and uncertainty of the asylum process.^5-8

From my own experience, this stems from the urgent nature of the refugee’s displacement, where they are often fleeing an immediate danger. My family had fled persecution from Communist forces and the social economic collapse that rendered Vietnam, for a time, one of the poorest in the world.⁹ Or, as my mother observed, “We had to leave because even doctors were starving.”

Refugees often have little preparation, have little legal protection since they are often criminalized, and are forced to endure dangerous conditions where they are vulnerable to smugglers and criminals who exploit their unprotected status. Once they arrive in their new country, they often do not have other family as social supports or resources. They themselves become the anchor for future legal and orderly immigration of their remaining family, given that they can extend their refugee status to those left behind.¹⁰ These non-refugee immigrants, unlike their refugee counterparts, are often flown to their new homes with more preparation, protecting them from dangerous conditions, and have the benefit of family who provide them with resources. As such, refugees tend to experience more traumatic life events than non-refugee immigrants. This was true in my family where those of us who initially escaped became the anchors to legally, and more safely, immigrate most of our family in Vietnam. We became their resources, likely making their acclimation smoother.
 

The mental health of refugee children and their caregivers

It is important to understand the stressors affecting the caregivers of children, since effective treatment of their mental health conditions can also benefit the children as well.¹¹ In fact, among the greatest protective factors for refugee children is the presence of an adult caregiver, suggesting that the child’s mental health is dependent on the caregivers.

Those children who are separated show much worse mental health sequalae.¹² As such, an understanding of the caregiver’s stressors is important. For example, when we were escaping Vietnam, my mom would protect me from our hardships by talking about our goals in America, minimizing our dangers by saying that we would be rewarded with things like a hamburger with its seemingly impossible amount of meat. Physically, my mother would always sleep with her arms around me and a knife hidden in order to ward off any attackers at night. When I was starving in the hull of a boat, having not eaten for days, my mother begged for food and gave me what she could get. And post-escape, my family focused on work and applied for aid for shelter and food, while encouraging us to invest in education, likely preventing involvement in criminal activities or gangs. Though overall, my family shielded me from the worst consequences, they also passed on their fears. One of my uncles had been killed by the police when he tried to escape, and so my family passed down a deep suspicion of authorities, whether they were the police or school principals. My mother had vivid memories of Communist re-education camps, which likely gave her a lasting fear that a Communist would find out our identities in America and re-capture us.
 

The mental health risk of refugees

Given that refugees tend to experience greater amounts of traumatic life events and a vast array of stressors sustained across years and even decades before, during, and after migration, it is no wonder they have much higher rates of mental health conditions, most predominantly PTSD and affective disorders.^13,14 They are at particular risk of developing psychoses because they are more likely to experience a range of physical, psychological, and psychosocial problems associated with adversities such as violence, discrimination, economic stress, and social isolation.¹³ For example, the period leading up to my escape consisted of decades of prolonged war: the French-Indochina from 1945 to 1954, then the Vietnam War from 1955 to 1975) as well as the persecution and re-education camps afterward. What my family had to endure created a period of fear and loss into which I was born into in 1976. That year, my family had lost its fortune due to the Communist government seizing of our home and business, plunging us from a comfortable middle- to upper-class life to poverty. There was also widespread fear of systematic rape by the Communist victors. So my family endured great stress and the loss of a way of life leading up to our escape.

For the refugees, the escape itself is often a dangerous journey where, given its emergent nature, they are often exposed to the elements. We know about the current situation in Ukraine and Gaza, where children are fleeing from bombs and bullets. In my situation, we endured weeks of starvation crammed in the hull of boat as we forged through the Indian Ocean to the Philippines. One of my aunts, on a separate trip, perished because her boat had capsized, like so many others. Though impossible to verify, it has been estimated that up to 70% of Vietnamese refugees died during their escape.¹⁵ After the boat, my mother and I still had to brave Malaysian jungles and prisons, and then refugee camps for a year before we reached safety at an American Embassy in the Philippines. After we gained sponsorship to America, the traumas did not abate, but were only replaced by those of culture shock, poverty, and alienation. Taken by themselves, significant traumas exist in each phase of a refugee child’s escape, whether before, during, or after. These traumas are likely compounded since they are continuously layered and sustained across years, even decades. They affect not only the children, but their parents, and sometimes even a whole nation of people.
 

Summary

In recent decades, refugeeism has been a growing problem that disproportionately affects children. Refugee children and their families experience a variety of traumas, often sustained across years and even decades, because of armed conflict, persecution, or social upheavals. It is known that refugees are at greater risk for PTSD and affective and psychotic disorders, presumably due to increased traumatic life events before, during, and after their migration. The writer uses his own experience as a child refugee from Vietnam to elucidate the stressors evident in various phases of forced displacement.

Dr. Nguyen is a second year resident at UCSF Fresno Psychiatry Residency. He was a public high school English teacher for 15 years previously.

References

1. UNHCR. Global Trends. Forced displacement in 2016. Geneva, Switzerland: The UN Refugee Agency, 2022. https://www.unhcr.org/global-trends.

2. Office of the United Nations High Commissioner for Refugees. The refugee concept under international law. Global compact for safe, orderly and regular migration.  https://www.unhcr.org/sites/default/files/legacy-pdf/5aa290937.pdf. Published March 8, 2018.

3. United Nations. (2023, November 11). The Question of Palestine. Un.org. https://www.un.org/unispal/document/un-general-assembly-renews-unrwa-mandate-press-release/

4. UNICEF. (2023, November 11). Child displacement. Data.unicef.org. https://data.unicef.org/topic/child-migration-and-displacement/displacement

5. Kinzie JD. Immigrants and refugees: The psychiatric perspective. Transcult Psychiatry. 2006 Dec;43(4):577-91. doi: 10.1177/1363461506070782.

6. Eaton W and Harrison G. Ethnic disadvantage and schizophrenia. Acta Psychiatr Scand Suppl. 2000:(407):38-43. doi: 10.1034/j.1600-0447.2000.00007.x.

7. Gilliver SC et al. Recent research on the mental health of immigrants to Sweden: a literature review. Eur J Public Health. 2014 Aug:24 Suppl 1:72-9. doi: 10.1093/eurpub/cku101.

8. Rapp MA et al. When local poverty is more important than your income: Mental health in minorities in inner cities. World Psychiatry. 2015 Jun;14(2):249-50. doi: 10.1002/wps.20221.

9. Cima, Ronald, ed. Vietnam: A Country Study. Washington: GPO for the Library of Congress, 1987.

10. United States Citizenship & Immigration Services (2023, November 12). Refugees. Uscis.gov. https://www.uscis.gov/humanitarian/refugees-and-asylum/refugees

11. Fazel M and Betancourt TS. (2018). Preventive mental health interventions for refugee children and adolescents in high-income settings. Lancet Child Adolesc Health. 2018 Feb;2(2):121-32. doi: 10.1016/S2352-4642(17)30147-5.

12. Fazel M et al. Mental health of displaced and refugee children resettled in high-income countries: risk and protective factors. Lancet. 2012 Jan 21;379(9812):266-82. doi: 10.1016/S0140-6736(11)60051-2.

13. Dapunt J et al. Refugees and psychosis: A review of the literature. Transl Psychiatry. 2017 Jun 13;7(6):e1149. doi: 10.1038/tp.2017.119.

14. Fazel M et al. Prevalence of serious mental disorder in 7,000 refugees resettled in western countries: a systematic review. Lancet. 2005 Apr;365(9467):1309-14. doi: 10.1016/S0140-6736(05)61027-6.

15. Rummel R. Statistics of Vietnamese Democide, in his Statistics of Democide. 1997. Table 6.1B,lines 730, 749-51.

Since 1983, when I was a child and fled as a boat refugee from Vietnam with my mother, the international plight of displaced people has only worsened. From 1997 to 2022, the number of forcibly displaced people has more than tripled, growing from 34 million to more than 108 million.¹

Displaced people are designated as refugees only when they cross international borders and meet the United Nations High Commissioner for Refugees’ (UNHCR) definition as “persons outside their countries of origin who are in need of international protection because of a serious threat to their life, physical integrity, or freedom in their country of origin as a result of persecution, armed conflict, violence, or serious public disorder.”² There is a separate mandate by the United Nations for the aid of Palestinian refugees under the United Nations General Assembly’s United Nations Relief and Works Agency for Palestinian Refugees in the Near East (UNRWA).³ Of the displaced in 2022, more than 36 million were recognized as refugees under UNHCR and UNRWA mandates.¹ Of these, almost 50% were children, at 17.5 million.⁴ To make matters worse, worldwide children represent less than one-third of the population.⁴ Since 2022, the increase in refugeeism is mostly driven by Ukraine and Syria, though also significantly Afghanistan, Venezuela, Sudan, Myanmar, Congo, Somalia, and Central African Republic.⁴ Refugeeism is a growing problem that disproportionately impacts children through sheer number, and one suspects, given their greater overall vulnerabilities compared with adults, physical and mental health consequences.
 

Traumas of refugees compared with non-refugee immigrants

In terms of mental health, refugees are distinct from non-refugee immigrants in that they likely experience more severe psychosocial adversities from greater poverty, greater risk of family separation, and uncertainty of the asylum process.^5-8

From my own experience, this stems from the urgent nature of the refugee’s displacement, where they are often fleeing an immediate danger. My family had fled persecution from Communist forces and the social economic collapse that rendered Vietnam, for a time, one of the poorest in the world.⁹ Or, as my mother observed, “We had to leave because even doctors were starving.”

Refugees often have little preparation, have little legal protection since they are often criminalized, and are forced to endure dangerous conditions where they are vulnerable to smugglers and criminals who exploit their unprotected status. Once they arrive in their new country, they often do not have other family as social supports or resources. They themselves become the anchor for future legal and orderly immigration of their remaining family, given that they can extend their refugee status to those left behind.¹⁰ These non-refugee immigrants, unlike their refugee counterparts, are often flown to their new homes with more preparation, protecting them from dangerous conditions, and have the benefit of family who provide them with resources. As such, refugees tend to experience more traumatic life events than non-refugee immigrants. This was true in my family where those of us who initially escaped became the anchors to legally, and more safely, immigrate most of our family in Vietnam. We became their resources, likely making their acclimation smoother.
 

The mental health of refugee children and their caregivers

It is important to understand the stressors affecting the caregivers of children, since effective treatment of their mental health conditions can also benefit the children as well.¹¹ In fact, among the greatest protective factors for refugee children is the presence of an adult caregiver, suggesting that the child’s mental health is dependent on the caregivers.

Those children who are separated show much worse mental health sequalae.¹² As such, an understanding of the caregiver’s stressors is important. For example, when we were escaping Vietnam, my mom would protect me from our hardships by talking about our goals in America, minimizing our dangers by saying that we would be rewarded with things like a hamburger with its seemingly impossible amount of meat. Physically, my mother would always sleep with her arms around me and a knife hidden in order to ward off any attackers at night. When I was starving in the hull of a boat, having not eaten for days, my mother begged for food and gave me what she could get. And post-escape, my family focused on work and applied for aid for shelter and food, while encouraging us to invest in education, likely preventing involvement in criminal activities or gangs. Though overall, my family shielded me from the worst consequences, they also passed on their fears. One of my uncles had been killed by the police when he tried to escape, and so my family passed down a deep suspicion of authorities, whether they were the police or school principals. My mother had vivid memories of Communist re-education camps, which likely gave her a lasting fear that a Communist would find out our identities in America and re-capture us.
 

The mental health risk of refugees

Given that refugees tend to experience greater amounts of traumatic life events and a vast array of stressors sustained across years and even decades before, during, and after migration, it is no wonder they have much higher rates of mental health conditions, most predominantly PTSD and affective disorders.^13,14 They are at particular risk of developing psychoses because they are more likely to experience a range of physical, psychological, and psychosocial problems associated with adversities such as violence, discrimination, economic stress, and social isolation.¹³ For example, the period leading up to my escape consisted of decades of prolonged war: the French-Indochina from 1945 to 1954, then the Vietnam War from 1955 to 1975) as well as the persecution and re-education camps afterward. What my family had to endure created a period of fear and loss into which I was born into in 1976. That year, my family had lost its fortune due to the Communist government seizing of our home and business, plunging us from a comfortable middle- to upper-class life to poverty. There was also widespread fear of systematic rape by the Communist victors. So my family endured great stress and the loss of a way of life leading up to our escape.

For the refugees, the escape itself is often a dangerous journey where, given its emergent nature, they are often exposed to the elements. We know about the current situation in Ukraine and Gaza, where children are fleeing from bombs and bullets. In my situation, we endured weeks of starvation crammed in the hull of boat as we forged through the Indian Ocean to the Philippines. One of my aunts, on a separate trip, perished because her boat had capsized, like so many others. Though impossible to verify, it has been estimated that up to 70% of Vietnamese refugees died during their escape.¹⁵ After the boat, my mother and I still had to brave Malaysian jungles and prisons, and then refugee camps for a year before we reached safety at an American Embassy in the Philippines. After we gained sponsorship to America, the traumas did not abate, but were only replaced by those of culture shock, poverty, and alienation. Taken by themselves, significant traumas exist in each phase of a refugee child’s escape, whether before, during, or after. These traumas are likely compounded since they are continuously layered and sustained across years, even decades. They affect not only the children, but their parents, and sometimes even a whole nation of people.
 

Summary

In recent decades, refugeeism has been a growing problem that disproportionately affects children. Refugee children and their families experience a variety of traumas, often sustained across years and even decades, because of armed conflict, persecution, or social upheavals. It is known that refugees are at greater risk for PTSD and affective and psychotic disorders, presumably due to increased traumatic life events before, during, and after their migration. The writer uses his own experience as a child refugee from Vietnam to elucidate the stressors evident in various phases of forced displacement.

Dr. Nguyen is a second year resident at UCSF Fresno Psychiatry Residency. He was a public high school English teacher for 15 years previously.

References

1. UNHCR. Global Trends. Forced displacement in 2016. Geneva, Switzerland: The UN Refugee Agency, 2022. https://www.unhcr.org/global-trends.

2. Office of the United Nations High Commissioner for Refugees. The refugee concept under international law. Global compact for safe, orderly and regular migration.  https://www.unhcr.org/sites/default/files/legacy-pdf/5aa290937.pdf. Published March 8, 2018.

3. United Nations. (2023, November 11). The Question of Palestine. Un.org. https://www.un.org/unispal/document/un-general-assembly-renews-unrwa-mandate-press-release/

4. UNICEF. (2023, November 11). Child displacement. Data.unicef.org. https://data.unicef.org/topic/child-migration-and-displacement/displacement

5. Kinzie JD. Immigrants and refugees: The psychiatric perspective. Transcult Psychiatry. 2006 Dec;43(4):577-91. doi: 10.1177/1363461506070782.

6. Eaton W and Harrison G. Ethnic disadvantage and schizophrenia. Acta Psychiatr Scand Suppl. 2000:(407):38-43. doi: 10.1034/j.1600-0447.2000.00007.x.

7. Gilliver SC et al. Recent research on the mental health of immigrants to Sweden: a literature review. Eur J Public Health. 2014 Aug:24 Suppl 1:72-9. doi: 10.1093/eurpub/cku101.

8. Rapp MA et al. When local poverty is more important than your income: Mental health in minorities in inner cities. World Psychiatry. 2015 Jun;14(2):249-50. doi: 10.1002/wps.20221.

9. Cima, Ronald, ed. Vietnam: A Country Study. Washington: GPO for the Library of Congress, 1987.

10. United States Citizenship & Immigration Services (2023, November 12). Refugees. Uscis.gov. https://www.uscis.gov/humanitarian/refugees-and-asylum/refugees

11. Fazel M and Betancourt TS. (2018). Preventive mental health interventions for refugee children and adolescents in high-income settings. Lancet Child Adolesc Health. 2018 Feb;2(2):121-32. doi: 10.1016/S2352-4642(17)30147-5.

12. Fazel M et al. Mental health of displaced and refugee children resettled in high-income countries: risk and protective factors. Lancet. 2012 Jan 21;379(9812):266-82. doi: 10.1016/S0140-6736(11)60051-2.

13. Dapunt J et al. Refugees and psychosis: A review of the literature. Transl Psychiatry. 2017 Jun 13;7(6):e1149. doi: 10.1038/tp.2017.119.

14. Fazel M et al. Prevalence of serious mental disorder in 7,000 refugees resettled in western countries: a systematic review. Lancet. 2005 Apr;365(9467):1309-14. doi: 10.1016/S0140-6736(05)61027-6.

15. Rummel R. Statistics of Vietnamese Democide, in his Statistics of Democide. 1997. Table 6.1B,lines 730, 749-51.

Key clinical point: Lebrikizumab monotherapy for 16 weeks significantly reduced itch and itch-associated sleep loss in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: At 16 weeks, a significantly higher number of patients from the ADvocate1 and ADvocate2 trials treated with lebrikizumab vs placebo achieved a ≥ 3-point improvement in the Pruritus Numeric Rating Scale scores (ADvocate1 54.6% vs 19.2%; ADvocate2 49.4% vs 14.0%; both P < .001) and ≥ 1-point improvement in Sleep-Loss Scale scores (ADvocate1 64.1% vs 27.2%; ADvocate2 58.1% vs 21.7%; both P < .001).

Study details: Findings are from a study including patients from the ADvocate1 (n = 424) and ADvocate2 (n = 427) trials who had moderate-to-severe AD and were randomized to receive subcutaneous lebrikizumab or placebo every 2 weeks.

Disclosures: This study was sponsored by Dermira, a wholly owned subsidiary of Eli Lilly and Company. Several authors declared receiving research grants or honoraria from, serving as employees and shareholders of, or having other ties with various sources, including Eli Lilly and Dermira.

Source: Yosipovitch G et al. Lebrikizumab improved itch and reduced the extent of itch interference on sleep in patients with moderate-to-severe atopic dermatitis: Two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2023 (Nov 6). doi: 10.1093/bjd/ljad435

Key clinical point: Lebrikizumab monotherapy for 16 weeks significantly reduced itch and itch-associated sleep loss in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: At 16 weeks, a significantly higher number of patients from the ADvocate1 and ADvocate2 trials treated with lebrikizumab vs placebo achieved a ≥ 3-point improvement in the Pruritus Numeric Rating Scale scores (ADvocate1 54.6% vs 19.2%; ADvocate2 49.4% vs 14.0%; both P < .001) and ≥ 1-point improvement in Sleep-Loss Scale scores (ADvocate1 64.1% vs 27.2%; ADvocate2 58.1% vs 21.7%; both P < .001).

Study details: Findings are from a study including patients from the ADvocate1 (n = 424) and ADvocate2 (n = 427) trials who had moderate-to-severe AD and were randomized to receive subcutaneous lebrikizumab or placebo every 2 weeks.

Disclosures: This study was sponsored by Dermira, a wholly owned subsidiary of Eli Lilly and Company. Several authors declared receiving research grants or honoraria from, serving as employees and shareholders of, or having other ties with various sources, including Eli Lilly and Dermira.

Source: Yosipovitch G et al. Lebrikizumab improved itch and reduced the extent of itch interference on sleep in patients with moderate-to-severe atopic dermatitis: Two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2023 (Nov 6). doi: 10.1093/bjd/ljad435

Key clinical point: Lebrikizumab monotherapy for 16 weeks significantly reduced itch and itch-associated sleep loss in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: At 16 weeks, a significantly higher number of patients from the ADvocate1 and ADvocate2 trials treated with lebrikizumab vs placebo achieved a ≥ 3-point improvement in the Pruritus Numeric Rating Scale scores (ADvocate1 54.6% vs 19.2%; ADvocate2 49.4% vs 14.0%; both P < .001) and ≥ 1-point improvement in Sleep-Loss Scale scores (ADvocate1 64.1% vs 27.2%; ADvocate2 58.1% vs 21.7%; both P < .001).

Study details: Findings are from a study including patients from the ADvocate1 (n = 424) and ADvocate2 (n = 427) trials who had moderate-to-severe AD and were randomized to receive subcutaneous lebrikizumab or placebo every 2 weeks.

Disclosures: This study was sponsored by Dermira, a wholly owned subsidiary of Eli Lilly and Company. Several authors declared receiving research grants or honoraria from, serving as employees and shareholders of, or having other ties with various sources, including Eli Lilly and Dermira.

Source: Yosipovitch G et al. Lebrikizumab improved itch and reduced the extent of itch interference on sleep in patients with moderate-to-severe atopic dermatitis: Two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2023 (Nov 6). doi: 10.1093/bjd/ljad435

Patients often come to us with questions about vitamin and mineral supplements. Sometimes they come to us with bags full of the things they are taking. The Internet is full of the wonders these nutritional supplements can do, from turmeric curing cancer to vitamin D curing COVID. It is hard to keep up with medicine itself without learning a whole new field of nutritional supplements.

However, for cardiovascular disease (CVD) and cancer prevention, the answer is pretty easy according to USPSTF (United States Preventative Services Task Force) guidelines. They evaluated 17,459 unique citations as well as 379 full-text articles that included randomized clinical trials and observational cohort studies. The conclusions of their research showed that there was little to no benefit in taking vitamin or mineral supplements to prevent CVD, cancer, or death. In fact, beta-carotene supplementation was associated with increased risk of lung cancer and other adverse outcomes in patients at increased risk of lung cancer.

Although they are often marketed like drugs, nutritional supplements are regulated as foods, with less stringent standards.* Our current medical culture pushes us to practice evidence-based medicine. Without evidence, we simply cannot counsel patients about supplements because there is little evidence to support their use.

Additionally, many patients assume that they are safe. While this may be true for many of them, some of them can be harmful in several ways. They can interact with medications the patient may be taking for medical conditions. Some of them have been shown to cause liver and other organ damage. When they are used to replace traditional medicine, they can also lead to harm by delaying appropriate medical care. For example, a patient who believes a supplement can treat cancer when it does nothing is delaying care that might save their life. By the time they realize it is not working, the cancer may have advanced too far to be treatable.

While there may be a few studies that do show some efficacy for vitamins and minerals in certain diseases, these guidelines are looking only at use in terms of preventing cancer and CVD. As primary care physicians, we all know the screening guidelines for cancer prevention. We are better off recommending screening mammograms and colon cancer screening tests. And we all know the risk factors for CVD and how to mitigate these risks.

What can we do when patients come to us with false claims regarding supplements?

• Hear what they are saying. They don’t know who to trust. We will never become their trusted source of medical information if we don’t listen to their concerns.
• Answer their questions, no matter how ridiculous they may seem to us. Many people who sell supplements sound convincing. That is how they sell their products. Our advice may seem just as ridiculous to them. We need to explain the facts clearly and be sure the patient understands.
• Give the patient resources. Know what websites to direct them to so that they can get accurate information.
• Know what’s out there. I was once surprised when a patient told me she was going to try turmeric as a treatment for uterine cancer. We cannot combat misinformation when we don’t know what’s being said.
• Become a voice for medical information. There is so much misinformation being spread. We need more doctors to speak up about the right medical information.

Currently, patients often look for medical information online. We do them a disservice when we brush aside their questions regarding supplements, no matter how trivial they seem. We need to take a firm stand and tell them the evidence regarding these supplements: They are neither FDA approved nor studied for safety and efficacy. Anyone can sell a supplement and make any claim regarding it that they want. It is much better to eat a healthy, balanced diet to get the vitamins and minerals that you need. Not only do we need to show them the evidence, we need to convince them that it is true.

*Correction, 12/4: An earlier version of this article misstated the regulatory requirements for nutritional supplements.

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. She was paid by Pfizer as a consultant on Paxlovid and is the editor in chief of Physician’s Weekly.

Patients often come to us with questions about vitamin and mineral supplements. Sometimes they come to us with bags full of the things they are taking. The Internet is full of the wonders these nutritional supplements can do, from turmeric curing cancer to vitamin D curing COVID. It is hard to keep up with medicine itself without learning a whole new field of nutritional supplements.

However, for cardiovascular disease (CVD) and cancer prevention, the answer is pretty easy according to USPSTF (United States Preventative Services Task Force) guidelines. They evaluated 17,459 unique citations as well as 379 full-text articles that included randomized clinical trials and observational cohort studies. The conclusions of their research showed that there was little to no benefit in taking vitamin or mineral supplements to prevent CVD, cancer, or death. In fact, beta-carotene supplementation was associated with increased risk of lung cancer and other adverse outcomes in patients at increased risk of lung cancer.

Although they are often marketed like drugs, nutritional supplements are regulated as foods, with less stringent standards.* Our current medical culture pushes us to practice evidence-based medicine. Without evidence, we simply cannot counsel patients about supplements because there is little evidence to support their use.

Additionally, many patients assume that they are safe. While this may be true for many of them, some of them can be harmful in several ways. They can interact with medications the patient may be taking for medical conditions. Some of them have been shown to cause liver and other organ damage. When they are used to replace traditional medicine, they can also lead to harm by delaying appropriate medical care. For example, a patient who believes a supplement can treat cancer when it does nothing is delaying care that might save their life. By the time they realize it is not working, the cancer may have advanced too far to be treatable.

While there may be a few studies that do show some efficacy for vitamins and minerals in certain diseases, these guidelines are looking only at use in terms of preventing cancer and CVD. As primary care physicians, we all know the screening guidelines for cancer prevention. We are better off recommending screening mammograms and colon cancer screening tests. And we all know the risk factors for CVD and how to mitigate these risks.

What can we do when patients come to us with false claims regarding supplements?

• Hear what they are saying. They don’t know who to trust. We will never become their trusted source of medical information if we don’t listen to their concerns.
• Answer their questions, no matter how ridiculous they may seem to us. Many people who sell supplements sound convincing. That is how they sell their products. Our advice may seem just as ridiculous to them. We need to explain the facts clearly and be sure the patient understands.
• Give the patient resources. Know what websites to direct them to so that they can get accurate information.
• Know what’s out there. I was once surprised when a patient told me she was going to try turmeric as a treatment for uterine cancer. We cannot combat misinformation when we don’t know what’s being said.
• Become a voice for medical information. There is so much misinformation being spread. We need more doctors to speak up about the right medical information.

Currently, patients often look for medical information online. We do them a disservice when we brush aside their questions regarding supplements, no matter how trivial they seem. We need to take a firm stand and tell them the evidence regarding these supplements: They are neither FDA approved nor studied for safety and efficacy. Anyone can sell a supplement and make any claim regarding it that they want. It is much better to eat a healthy, balanced diet to get the vitamins and minerals that you need. Not only do we need to show them the evidence, we need to convince them that it is true.

*Correction, 12/4: An earlier version of this article misstated the regulatory requirements for nutritional supplements.

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. She was paid by Pfizer as a consultant on Paxlovid and is the editor in chief of Physician’s Weekly.

Patients often come to us with questions about vitamin and mineral supplements. Sometimes they come to us with bags full of the things they are taking. The Internet is full of the wonders these nutritional supplements can do, from turmeric curing cancer to vitamin D curing COVID. It is hard to keep up with medicine itself without learning a whole new field of nutritional supplements.

However, for cardiovascular disease (CVD) and cancer prevention, the answer is pretty easy according to USPSTF (United States Preventative Services Task Force) guidelines. They evaluated 17,459 unique citations as well as 379 full-text articles that included randomized clinical trials and observational cohort studies. The conclusions of their research showed that there was little to no benefit in taking vitamin or mineral supplements to prevent CVD, cancer, or death. In fact, beta-carotene supplementation was associated with increased risk of lung cancer and other adverse outcomes in patients at increased risk of lung cancer.

Although they are often marketed like drugs, nutritional supplements are regulated as foods, with less stringent standards.* Our current medical culture pushes us to practice evidence-based medicine. Without evidence, we simply cannot counsel patients about supplements because there is little evidence to support their use.

Additionally, many patients assume that they are safe. While this may be true for many of them, some of them can be harmful in several ways. They can interact with medications the patient may be taking for medical conditions. Some of them have been shown to cause liver and other organ damage. When they are used to replace traditional medicine, they can also lead to harm by delaying appropriate medical care. For example, a patient who believes a supplement can treat cancer when it does nothing is delaying care that might save their life. By the time they realize it is not working, the cancer may have advanced too far to be treatable.

While there may be a few studies that do show some efficacy for vitamins and minerals in certain diseases, these guidelines are looking only at use in terms of preventing cancer and CVD. As primary care physicians, we all know the screening guidelines for cancer prevention. We are better off recommending screening mammograms and colon cancer screening tests. And we all know the risk factors for CVD and how to mitigate these risks.

What can we do when patients come to us with false claims regarding supplements?

• Hear what they are saying. They don’t know who to trust. We will never become their trusted source of medical information if we don’t listen to their concerns.
• Answer their questions, no matter how ridiculous they may seem to us. Many people who sell supplements sound convincing. That is how they sell their products. Our advice may seem just as ridiculous to them. We need to explain the facts clearly and be sure the patient understands.
• Give the patient resources. Know what websites to direct them to so that they can get accurate information.
• Know what’s out there. I was once surprised when a patient told me she was going to try turmeric as a treatment for uterine cancer. We cannot combat misinformation when we don’t know what’s being said.
• Become a voice for medical information. There is so much misinformation being spread. We need more doctors to speak up about the right medical information.

Currently, patients often look for medical information online. We do them a disservice when we brush aside their questions regarding supplements, no matter how trivial they seem. We need to take a firm stand and tell them the evidence regarding these supplements: They are neither FDA approved nor studied for safety and efficacy. Anyone can sell a supplement and make any claim regarding it that they want. It is much better to eat a healthy, balanced diet to get the vitamins and minerals that you need. Not only do we need to show them the evidence, we need to convince them that it is true.

*Correction, 12/4: An earlier version of this article misstated the regulatory requirements for nutritional supplements.

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. She was paid by Pfizer as a consultant on Paxlovid and is the editor in chief of Physician’s Weekly.

SAN DIEGO – The Food and Drug Administration has launched Project Optimus to dramatically overhaul how oncology therapies are developed in clinical trials, with investigational blood cancer drugs taking center stage in this effort.

The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.

Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”

The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.

In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
 

Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?

Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.

Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?

Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.

Q: What is FDA’s goal for Project Optimus?

Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.

Q: What kind of resistance is the FDA getting from drug companies?

Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.

Q: How will all this affect drug development?

Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.

Q: Could this reduce the number of investigational drugs?

Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.

Q: What do you think the future holds?

Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.

SAN DIEGO – The Food and Drug Administration has launched Project Optimus to dramatically overhaul how oncology therapies are developed in clinical trials, with investigational blood cancer drugs taking center stage in this effort.

The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.

Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”

The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.

In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
 

Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?

Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.

Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?

Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.

Q: What is FDA’s goal for Project Optimus?

Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.

Q: What kind of resistance is the FDA getting from drug companies?

Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.

Q: How will all this affect drug development?

Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.

Q: Could this reduce the number of investigational drugs?

Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.

Q: What do you think the future holds?

Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.

SAN DIEGO – The Food and Drug Administration has launched Project Optimus to dramatically overhaul how oncology therapies are developed in clinical trials, with investigational blood cancer drugs taking center stage in this effort.

The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.

Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”

The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.

In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
 

Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?

Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.

Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?

Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.

Q: What is FDA’s goal for Project Optimus?

Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.

Q: What kind of resistance is the FDA getting from drug companies?

Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.

Q: How will all this affect drug development?

Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.

Q: Could this reduce the number of investigational drugs?

Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.

Q: What do you think the future holds?

Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

REVIEW

By James Greenberg, MD

Chief of Gynecology

Associate Professor, Harvard Medical School

Boston, Massachusetts
 

Guardenia: A “really great solution” for contained tissue extraction

The Guardenia Contained Extraction System, developed by Advanced Surgical Concepts (Wicklow, Ireland), offers a comprehensive approach to contained tissue extraction.

Background. Contained tissue extraction has been an integral part of laparoscopic procedures from at least the late 1980s and early 1990s. Bags of one sort or another are routinely used to remove from the abdomen all sorts of human tissues, including but not limited to ovaries, ectopic pregnancies, gallbladders, kidneys, spleens, and the list goes on. However, after the April 17, 2014, FDA Safety Communication discouraging the use of power morcellators with myomectomy or hysterectomy, the need for more robust contained tissue extraction systems has been ongoing, and there has yet to be a really good solution despite some innovative attempts.

Design/Functionality. Advanced Surgical Concepts’ Guardenia System is the latest attempt to provide a “really great solution” for surgeons to address my 3 “musts” for any system to gain traction in this niche.

1. Must #1. An easy method for getting the device into the abdomen.
2. Must #2. An easy method for getting the tissue into the bag.
3. Must #3. An easy method for getting the tissue out of the body while still containing the cells within the system.

In my opinion based on my usage, Guardenia does a pretty good job addressing all my “musts.”

The Guardenia System is a sterile, single-use device with 3 main components—an introducer with a plunger that will fit through any standard 12-mm trocar, a polyurethane film bag supported by a nitinol ring, and an opening ring with expandable semi-rigid polyethylene “Guard Petals.” When I used it in the operating room to manually morcellate a 10-cm myoma through the umbilicus, I thought it was pretty spot on. Getting the bag into the abdomen is 100% intuitive but even has a nifty up-arrow built onto the tip to make sure the bag is opened in the proper direction. The bag material and the nitinol ring, in combination with the 17.5-cm opening ring, make the process of getting the specimen into the bag and exteriorized easier than any other system I have ever used. And, the opening ring with the Guard Petals yields a very large retraction area for the incision size while providing excellent protection to the surrounding tissues. Overall, Guardenia worked better than anything else I have previously used.

Innovation. Guardenia does not really introduce any fundamentally novel ideas, but it does combine a lot of standard technologies into a product whose sum is much larger than its parts. I would like to see it combined with an occlusive top piece to allow the retractor to be used for single-port laparoscopy as well, but that would just be the cherry on top.

Summary. I have been working on inventing a really good contained tissue extraction system for a long time, and I am a bit chagrined to see someone else outsmart me (low bar), but Advanced Surgical Concepts did, and I really like Guardenia. For pathology that is appropriate for contained morcellation, this device is definitely worth a try, and I suspect many surgeons will switch to it from whatever they are currently using.

FOR MORE INFORMATION, VISIT https://advancedsurgical.ie/guardenia-contained-extraction-system/

The views of the author are personal opinions and do not necessarily represent the views of OBG Management.Dr. Greenberg personally trials all the products he reviews. Dr. Greenberg has no conflicts of interest with this product or the company that produces it. ●

REVIEW

By James Greenberg, MD

Chief of Gynecology

Associate Professor, Harvard Medical School

Boston, Massachusetts
 

Guardenia: A “really great solution” for contained tissue extraction

The Guardenia Contained Extraction System, developed by Advanced Surgical Concepts (Wicklow, Ireland), offers a comprehensive approach to contained tissue extraction.

Background. Contained tissue extraction has been an integral part of laparoscopic procedures from at least the late 1980s and early 1990s. Bags of one sort or another are routinely used to remove from the abdomen all sorts of human tissues, including but not limited to ovaries, ectopic pregnancies, gallbladders, kidneys, spleens, and the list goes on. However, after the April 17, 2014, FDA Safety Communication discouraging the use of power morcellators with myomectomy or hysterectomy, the need for more robust contained tissue extraction systems has been ongoing, and there has yet to be a really good solution despite some innovative attempts.

Design/Functionality. Advanced Surgical Concepts’ Guardenia System is the latest attempt to provide a “really great solution” for surgeons to address my 3 “musts” for any system to gain traction in this niche.

1. Must #1. An easy method for getting the device into the abdomen.
2. Must #2. An easy method for getting the tissue into the bag.
3. Must #3. An easy method for getting the tissue out of the body while still containing the cells within the system.

In my opinion based on my usage, Guardenia does a pretty good job addressing all my “musts.”

The Guardenia System is a sterile, single-use device with 3 main components—an introducer with a plunger that will fit through any standard 12-mm trocar, a polyurethane film bag supported by a nitinol ring, and an opening ring with expandable semi-rigid polyethylene “Guard Petals.” When I used it in the operating room to manually morcellate a 10-cm myoma through the umbilicus, I thought it was pretty spot on. Getting the bag into the abdomen is 100% intuitive but even has a nifty up-arrow built onto the tip to make sure the bag is opened in the proper direction. The bag material and the nitinol ring, in combination with the 17.5-cm opening ring, make the process of getting the specimen into the bag and exteriorized easier than any other system I have ever used. And, the opening ring with the Guard Petals yields a very large retraction area for the incision size while providing excellent protection to the surrounding tissues. Overall, Guardenia worked better than anything else I have previously used.

Innovation. Guardenia does not really introduce any fundamentally novel ideas, but it does combine a lot of standard technologies into a product whose sum is much larger than its parts. I would like to see it combined with an occlusive top piece to allow the retractor to be used for single-port laparoscopy as well, but that would just be the cherry on top.

Summary. I have been working on inventing a really good contained tissue extraction system for a long time, and I am a bit chagrined to see someone else outsmart me (low bar), but Advanced Surgical Concepts did, and I really like Guardenia. For pathology that is appropriate for contained morcellation, this device is definitely worth a try, and I suspect many surgeons will switch to it from whatever they are currently using.

FOR MORE INFORMATION, VISIT https://advancedsurgical.ie/guardenia-contained-extraction-system/

The views of the author are personal opinions and do not necessarily represent the views of OBG Management.Dr. Greenberg personally trials all the products he reviews. Dr. Greenberg has no conflicts of interest with this product or the company that produces it. ●

REVIEW

By James Greenberg, MD

Chief of Gynecology

Associate Professor, Harvard Medical School

Boston, Massachusetts
 

Guardenia: A “really great solution” for contained tissue extraction

The Guardenia Contained Extraction System, developed by Advanced Surgical Concepts (Wicklow, Ireland), offers a comprehensive approach to contained tissue extraction.

Background. Contained tissue extraction has been an integral part of laparoscopic procedures from at least the late 1980s and early 1990s. Bags of one sort or another are routinely used to remove from the abdomen all sorts of human tissues, including but not limited to ovaries, ectopic pregnancies, gallbladders, kidneys, spleens, and the list goes on. However, after the April 17, 2014, FDA Safety Communication discouraging the use of power morcellators with myomectomy or hysterectomy, the need for more robust contained tissue extraction systems has been ongoing, and there has yet to be a really good solution despite some innovative attempts.

Design/Functionality. Advanced Surgical Concepts’ Guardenia System is the latest attempt to provide a “really great solution” for surgeons to address my 3 “musts” for any system to gain traction in this niche.

1. Must #1. An easy method for getting the device into the abdomen.
2. Must #2. An easy method for getting the tissue into the bag.
3. Must #3. An easy method for getting the tissue out of the body while still containing the cells within the system.

In my opinion based on my usage, Guardenia does a pretty good job addressing all my “musts.”

The Guardenia System is a sterile, single-use device with 3 main components—an introducer with a plunger that will fit through any standard 12-mm trocar, a polyurethane film bag supported by a nitinol ring, and an opening ring with expandable semi-rigid polyethylene “Guard Petals.” When I used it in the operating room to manually morcellate a 10-cm myoma through the umbilicus, I thought it was pretty spot on. Getting the bag into the abdomen is 100% intuitive but even has a nifty up-arrow built onto the tip to make sure the bag is opened in the proper direction. The bag material and the nitinol ring, in combination with the 17.5-cm opening ring, make the process of getting the specimen into the bag and exteriorized easier than any other system I have ever used. And, the opening ring with the Guard Petals yields a very large retraction area for the incision size while providing excellent protection to the surrounding tissues. Overall, Guardenia worked better than anything else I have previously used.

Innovation. Guardenia does not really introduce any fundamentally novel ideas, but it does combine a lot of standard technologies into a product whose sum is much larger than its parts. I would like to see it combined with an occlusive top piece to allow the retractor to be used for single-port laparoscopy as well, but that would just be the cherry on top.

Summary. I have been working on inventing a really good contained tissue extraction system for a long time, and I am a bit chagrined to see someone else outsmart me (low bar), but Advanced Surgical Concepts did, and I really like Guardenia. For pathology that is appropriate for contained morcellation, this device is definitely worth a try, and I suspect many surgeons will switch to it from whatever they are currently using.

FOR MORE INFORMATION, VISIT https://advancedsurgical.ie/guardenia-contained-extraction-system/

The views of the author are personal opinions and do not necessarily represent the views of OBG Management.Dr. Greenberg personally trials all the products he reviews. Dr. Greenberg has no conflicts of interest with this product or the company that produces it. ●

SAN DIEGO – Continuing a tumor necrosis factor inhibitor (TNFi) during pregnancy does not increase risk of worse fetal or obstetric outcomes, according to new research presented at the annual meeting of the American College of Rheumatology.

Patients who continued a TNFi also had fewer severe infections requiring hospitalization, compared with those who stopped taking the medication during their pregnancy.

Lucy Hicks/Medscape Medical News

“The main message is that patients continuing were not doing worse than the patients stopping. It’s an important clinical message for rheumatologists who are not really confident in dealing with these drugs during pregnancy,” said Anna Moltó, MD, PhD, a rheumatologist at Cochin Hospital, Paris, who led the research. “It adds to the data that it seems to be safe,” she added in an interview.

Previous research, largely from pregnant patients with inflammatory bowel disease, suggests that taking a TNFi during pregnancy is safe, and 2020 ACR guidelines conditionally recommend continuing therapy prior to and during pregnancy; however, many people still stop taking the drugs during pregnancy for fear of potentially harming the fetus.

To better understand how TNFi use affected pregnancy outcomes, Dr. Moltó and colleagues analyzed data from a French nationwide health insurance database to identify adult women with chronic rheumatic inflammatory disease. All women included in the cohort had a singleton pregnancy between 2008 and 2017 and were taking a TNFi upon pregnancy diagnosis.

Patients who restarted TNFi after initially pausing because of pregnancy were included in the continuation group.

Researchers identified more than 2,000 pregnancies, including 1,503 in individuals with spondyloarthritis and 579 individuals with rheumatoid arthritis. Patients were, on average, 31 years old and were diagnosed with a rheumatic disease 4 years prior to their pregnancy.

About 72% (n = 1,497) discontinued TNFi after learning they were pregnant, and 584 individuals continued treatment. Dr. Moltó noted that data from more recent years might have captured lower discontinuation rates among pregnant individuals, but those data were not available for the study.

There was no difference in unfavorable obstetrical or infant outcomes, including spontaneous abortion, preeclampsia, gestational diabetes, major congenital malformation, and severe infection of the infant requiring hospitalization. Somewhat surprisingly, the data showed that women who discontinued a TNFi were more likely to be hospitalized for infection either during their pregnancy or up to 6 weeks after delivery, compared with those who continued therapy (1.3% vs. 0.2%, respectively).

Dr. Moltó is currently looking into what could be behind this counterintuitive result, but she hypothesizes that patients who had stopped TNFi may have been taking more glucocorticoids.

“At our institution, there is generally a comfort level with continuing TNF inhibitors during pregnancy, at least until about 36 weeks,” said Sara K. Tedeschi, MD, MPH, a rheumatologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. Sometimes, there is concern for risk of infection to the infant, depending on the type of TNFi being used, she added during a press conference.

“I think that these are really informative and supportive data to let women know that they probably have a really good chance of doing very well during the pregnancy if they continue” their TNFi, said Dr. Tedeschi, who was not involved with the study.
 

TNF discontinuation on the decline

In a related study, researchers at McGill University, Montreal, found that TNFi discontinuation prior to pregnancy had decreased over time in individuals with chronic inflammatory diseases.

Using a database of U.S. insurance claims, they identified 3,372 women with RA, ankylosing spondylitis (AS), psoriasis/psoriatic arthritis (PsA), and/or inflammatory bowel disease (IBD) who previously used a TNFi and gave birth between 2011 and 2019. A patient was considered to have used a TNFi if she had filled a prescription or had an infusion procedure insurance claim within 12 weeks before the gestational period or anytime during pregnancy. Researchers did not have time-specific data to account for women who stopped treatment at pregnancy diagnosis.

Nearly half (47%) of all identified pregnancies were in individuals with IBD, and the rest included patients with RA (24%), psoriasis or PsA (16%), AS (3%), or more than one diagnosis (10%).

In total, 14% of women discontinued TNFi use in the 12 weeks before becoming pregnant and did not restart. From 2011 to 2013, 19% of patients stopped their TNFi, but this proportion decreased overtime, with 10% of patients stopping therapy from 2017 to 2019 (P < .0001).

Lucy Hicks/Medscape Medical News

This decline “possibly reflects the increase in real-world evidence about the safety of TNFi in pregnancy. That research, in turn, led to new guidelines recommending the continuation of TNFi during pregnancy,” first author Leah Flatman, a PhD candidate in epidemiology at McGill, said in an interview. “I think we can see this potentially as good news.”

More patients with RA, psoriasis/PsA, and AS discontinued TNFi therapy prior to conception (23%-25%), compared with those with IBD (5%).

Ms. Flatman noted that her study and Moltó’s study complement each other by providing data on individuals stopping TNFi prior to conception versus those stopping treatment after pregnancy diagnosis.

“These findings demonstrate that continuing TNFi during pregnancy appears not to be associated with an increase in adverse obstetrical or infant outcomes,” Ms. Flatman said of Dr. Moltó’s study. “As guidelines currently recommend continuing TNFi, studies like this help demonstrate that the guideline changes do not appear to be associated with an increase in adverse events.”

Dr. Moltó and Ms. Flatman disclosed no relevant financial relationships. Dr. Tedeschi has worked as a consultant for Novartis.

A version of this article appeared on Medscape.com.

SAN DIEGO – Continuing a tumor necrosis factor inhibitor (TNFi) during pregnancy does not increase risk of worse fetal or obstetric outcomes, according to new research presented at the annual meeting of the American College of Rheumatology.

Patients who continued a TNFi also had fewer severe infections requiring hospitalization, compared with those who stopped taking the medication during their pregnancy.

Lucy Hicks/Medscape Medical News

“The main message is that patients continuing were not doing worse than the patients stopping. It’s an important clinical message for rheumatologists who are not really confident in dealing with these drugs during pregnancy,” said Anna Moltó, MD, PhD, a rheumatologist at Cochin Hospital, Paris, who led the research. “It adds to the data that it seems to be safe,” she added in an interview.

Previous research, largely from pregnant patients with inflammatory bowel disease, suggests that taking a TNFi during pregnancy is safe, and 2020 ACR guidelines conditionally recommend continuing therapy prior to and during pregnancy; however, many people still stop taking the drugs during pregnancy for fear of potentially harming the fetus.

To better understand how TNFi use affected pregnancy outcomes, Dr. Moltó and colleagues analyzed data from a French nationwide health insurance database to identify adult women with chronic rheumatic inflammatory disease. All women included in the cohort had a singleton pregnancy between 2008 and 2017 and were taking a TNFi upon pregnancy diagnosis.

Patients who restarted TNFi after initially pausing because of pregnancy were included in the continuation group.

Researchers identified more than 2,000 pregnancies, including 1,503 in individuals with spondyloarthritis and 579 individuals with rheumatoid arthritis. Patients were, on average, 31 years old and were diagnosed with a rheumatic disease 4 years prior to their pregnancy.

About 72% (n = 1,497) discontinued TNFi after learning they were pregnant, and 584 individuals continued treatment. Dr. Moltó noted that data from more recent years might have captured lower discontinuation rates among pregnant individuals, but those data were not available for the study.

There was no difference in unfavorable obstetrical or infant outcomes, including spontaneous abortion, preeclampsia, gestational diabetes, major congenital malformation, and severe infection of the infant requiring hospitalization. Somewhat surprisingly, the data showed that women who discontinued a TNFi were more likely to be hospitalized for infection either during their pregnancy or up to 6 weeks after delivery, compared with those who continued therapy (1.3% vs. 0.2%, respectively).

Dr. Moltó is currently looking into what could be behind this counterintuitive result, but she hypothesizes that patients who had stopped TNFi may have been taking more glucocorticoids.

“At our institution, there is generally a comfort level with continuing TNF inhibitors during pregnancy, at least until about 36 weeks,” said Sara K. Tedeschi, MD, MPH, a rheumatologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. Sometimes, there is concern for risk of infection to the infant, depending on the type of TNFi being used, she added during a press conference.

“I think that these are really informative and supportive data to let women know that they probably have a really good chance of doing very well during the pregnancy if they continue” their TNFi, said Dr. Tedeschi, who was not involved with the study.
 

TNF discontinuation on the decline

In a related study, researchers at McGill University, Montreal, found that TNFi discontinuation prior to pregnancy had decreased over time in individuals with chronic inflammatory diseases.

Using a database of U.S. insurance claims, they identified 3,372 women with RA, ankylosing spondylitis (AS), psoriasis/psoriatic arthritis (PsA), and/or inflammatory bowel disease (IBD) who previously used a TNFi and gave birth between 2011 and 2019. A patient was considered to have used a TNFi if she had filled a prescription or had an infusion procedure insurance claim within 12 weeks before the gestational period or anytime during pregnancy. Researchers did not have time-specific data to account for women who stopped treatment at pregnancy diagnosis.

Nearly half (47%) of all identified pregnancies were in individuals with IBD, and the rest included patients with RA (24%), psoriasis or PsA (16%), AS (3%), or more than one diagnosis (10%).

In total, 14% of women discontinued TNFi use in the 12 weeks before becoming pregnant and did not restart. From 2011 to 2013, 19% of patients stopped their TNFi, but this proportion decreased overtime, with 10% of patients stopping therapy from 2017 to 2019 (P < .0001).

Lucy Hicks/Medscape Medical News

This decline “possibly reflects the increase in real-world evidence about the safety of TNFi in pregnancy. That research, in turn, led to new guidelines recommending the continuation of TNFi during pregnancy,” first author Leah Flatman, a PhD candidate in epidemiology at McGill, said in an interview. “I think we can see this potentially as good news.”

More patients with RA, psoriasis/PsA, and AS discontinued TNFi therapy prior to conception (23%-25%), compared with those with IBD (5%).

Ms. Flatman noted that her study and Moltó’s study complement each other by providing data on individuals stopping TNFi prior to conception versus those stopping treatment after pregnancy diagnosis.

“These findings demonstrate that continuing TNFi during pregnancy appears not to be associated with an increase in adverse obstetrical or infant outcomes,” Ms. Flatman said of Dr. Moltó’s study. “As guidelines currently recommend continuing TNFi, studies like this help demonstrate that the guideline changes do not appear to be associated with an increase in adverse events.”

Dr. Moltó and Ms. Flatman disclosed no relevant financial relationships. Dr. Tedeschi has worked as a consultant for Novartis.

A version of this article appeared on Medscape.com.

SAN DIEGO – Continuing a tumor necrosis factor inhibitor (TNFi) during pregnancy does not increase risk of worse fetal or obstetric outcomes, according to new research presented at the annual meeting of the American College of Rheumatology.

Patients who continued a TNFi also had fewer severe infections requiring hospitalization, compared with those who stopped taking the medication during their pregnancy.

Lucy Hicks/Medscape Medical News

“The main message is that patients continuing were not doing worse than the patients stopping. It’s an important clinical message for rheumatologists who are not really confident in dealing with these drugs during pregnancy,” said Anna Moltó, MD, PhD, a rheumatologist at Cochin Hospital, Paris, who led the research. “It adds to the data that it seems to be safe,” she added in an interview.

Previous research, largely from pregnant patients with inflammatory bowel disease, suggests that taking a TNFi during pregnancy is safe, and 2020 ACR guidelines conditionally recommend continuing therapy prior to and during pregnancy; however, many people still stop taking the drugs during pregnancy for fear of potentially harming the fetus.

To better understand how TNFi use affected pregnancy outcomes, Dr. Moltó and colleagues analyzed data from a French nationwide health insurance database to identify adult women with chronic rheumatic inflammatory disease. All women included in the cohort had a singleton pregnancy between 2008 and 2017 and were taking a TNFi upon pregnancy diagnosis.

Patients who restarted TNFi after initially pausing because of pregnancy were included in the continuation group.

Researchers identified more than 2,000 pregnancies, including 1,503 in individuals with spondyloarthritis and 579 individuals with rheumatoid arthritis. Patients were, on average, 31 years old and were diagnosed with a rheumatic disease 4 years prior to their pregnancy.

About 72% (n = 1,497) discontinued TNFi after learning they were pregnant, and 584 individuals continued treatment. Dr. Moltó noted that data from more recent years might have captured lower discontinuation rates among pregnant individuals, but those data were not available for the study.

There was no difference in unfavorable obstetrical or infant outcomes, including spontaneous abortion, preeclampsia, gestational diabetes, major congenital malformation, and severe infection of the infant requiring hospitalization. Somewhat surprisingly, the data showed that women who discontinued a TNFi were more likely to be hospitalized for infection either during their pregnancy or up to 6 weeks after delivery, compared with those who continued therapy (1.3% vs. 0.2%, respectively).

Dr. Moltó is currently looking into what could be behind this counterintuitive result, but she hypothesizes that patients who had stopped TNFi may have been taking more glucocorticoids.

“At our institution, there is generally a comfort level with continuing TNF inhibitors during pregnancy, at least until about 36 weeks,” said Sara K. Tedeschi, MD, MPH, a rheumatologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. Sometimes, there is concern for risk of infection to the infant, depending on the type of TNFi being used, she added during a press conference.

“I think that these are really informative and supportive data to let women know that they probably have a really good chance of doing very well during the pregnancy if they continue” their TNFi, said Dr. Tedeschi, who was not involved with the study.
 

TNF discontinuation on the decline

In a related study, researchers at McGill University, Montreal, found that TNFi discontinuation prior to pregnancy had decreased over time in individuals with chronic inflammatory diseases.

Using a database of U.S. insurance claims, they identified 3,372 women with RA, ankylosing spondylitis (AS), psoriasis/psoriatic arthritis (PsA), and/or inflammatory bowel disease (IBD) who previously used a TNFi and gave birth between 2011 and 2019. A patient was considered to have used a TNFi if she had filled a prescription or had an infusion procedure insurance claim within 12 weeks before the gestational period or anytime during pregnancy. Researchers did not have time-specific data to account for women who stopped treatment at pregnancy diagnosis.

Nearly half (47%) of all identified pregnancies were in individuals with IBD, and the rest included patients with RA (24%), psoriasis or PsA (16%), AS (3%), or more than one diagnosis (10%).

In total, 14% of women discontinued TNFi use in the 12 weeks before becoming pregnant and did not restart. From 2011 to 2013, 19% of patients stopped their TNFi, but this proportion decreased overtime, with 10% of patients stopping therapy from 2017 to 2019 (P < .0001).

Lucy Hicks/Medscape Medical News

This decline “possibly reflects the increase in real-world evidence about the safety of TNFi in pregnancy. That research, in turn, led to new guidelines recommending the continuation of TNFi during pregnancy,” first author Leah Flatman, a PhD candidate in epidemiology at McGill, said in an interview. “I think we can see this potentially as good news.”

More patients with RA, psoriasis/PsA, and AS discontinued TNFi therapy prior to conception (23%-25%), compared with those with IBD (5%).

Ms. Flatman noted that her study and Moltó’s study complement each other by providing data on individuals stopping TNFi prior to conception versus those stopping treatment after pregnancy diagnosis.

“These findings demonstrate that continuing TNFi during pregnancy appears not to be associated with an increase in adverse obstetrical or infant outcomes,” Ms. Flatman said of Dr. Moltó’s study. “As guidelines currently recommend continuing TNFi, studies like this help demonstrate that the guideline changes do not appear to be associated with an increase in adverse events.”

Dr. Moltó and Ms. Flatman disclosed no relevant financial relationships. Dr. Tedeschi has worked as a consultant for Novartis.

A version of this article appeared on Medscape.com.

SAN DIEGO – A real-world analysis linked the PEXIVAS reduced-dose glucocorticoid (GC) regimen to a higher likelihood of a group of poor outcomes such as death in patients with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).

The retrospective observational study, presented at the annual meeting of the American College of Rheumatology, aimed to see whether results from the landmark PEXIVAS trial would hold up in a real-world analysis given some important limitations of the PEXIVAS’s primary outcome and its relative lack of balance in choice of induction agents.

First author of the new study, Sophie Nagle, MD, of Cochin Hospital in Paris, and colleagues in the French Vasculitis Study Group noted that PEXIVAS “demonstrated noninferiority of reduced-dose GC regimen compared to standard dose for the incidence of death or end-stage kidney disease (ESKD), with a significant reduction in serious infections at 1 year. However, the primary endpoint did not include disease progression or relapse, the majority of patients received cyclophosphamide as induction therapy, and subgroup analysis showed a trend towards an increased risk of death or ESKD in [rituximab]-treated patients.”

The new findings “give us pause about using low-dose glucocorticoid regimens” and suggest that rheumatologists might be a little more conservative about their use than randomized controlled trials such as PEXIVAS might suggest, said Vanderbilt University vasculitis specialist Kevin W. Byram, MD, who’s familiar with the findings but did not take part in the study.

Dr. Nagle reported that among 234 patients with either GPA or MPA, 33.3% of 126 who received a reduced-dose GC regimen experienced one of the 12-month composite primary outcome’s events of death, disease relapse, ESKD, or disease progression before remission that required treatment modification, compared with 18.5% of 108 who received the standard GC regimen (P = .016).

In a propensity score analysis, the higher risk of poor outcomes in the reduced-dose group remained (hazard ratio, 1.57; 95% confidence interval, 0.93-2.64). A multivariate analysis also identified a higher risk for the composite primary outcome in the reduced-dose group (HR, 1.72; 95% CI, 1.08-2.74), although there was no association with an increased risk of death or ESKD.

The PEXIVAS study, published in 2020, supported lower GC doses in antineutrophil cytoplasmic antibody–associated vasculitis, potentially revolutionizing treatment. “Historically, we have used high doses of glucocorticoids on slower tapers to treat this disease, which itself is a strategy that leads to potential complications,” Dr. Byram said. “PEXIVAS suggested we could potentially use less glucocorticoids in these patients.”

For the retrospective, multicenter study, researchers tracked patients from 2018 to 2022, all aged 15 and above. They included 93 with MPA and 141 with GPA. Nearly half were female, and they had a mean age of 61 years. The patients had severe flare-ups treated with rituximab or cyclophosphamide induction and reduced-dose or standard GC regimen.

The standard care and reduced-dose groups were similar, Dr. Nagle said, although the standard group had significantly more patients with GPA (71% vs. 29% with MPA) than did the low-dose group (51% with GPA, 49% with MPA).

The researchers reported that in a reduced-dose subgroup, patients with creatinine levels above 300 micromol/L were more likely to meet the primary endpoint (relative risk, 2.14; 95% CI, 1.14-4.03). Those treated with the reduced-dose GC regimen were also more likely to reach the primary endpoint (HR, 1.61; 95% CI, 0.94-2.77) and die or develop ESKD (HR, 2.42; 95% CI, 1.04-5.66).

However, adverse events at 12 months were similar in both groups: The authors noted that those who received the reduced-dose GC regimen didn’t have higher risk of death, ESKD, or severe infections.

The authors highlighted that “increased vigilance is required when using the reduced-dose GC regimen especially in two subgroups of patients due to the risk of failure: Patients receiving rituximab as induction therapy [and] patients with severe initial kidney disease (serum creatinine > 300 micromol/L).”

The study authors note several limitations: The study is retrospective, and the standard dose group is heterogeneous.

“This study raises the idea that we need to be careful in using low-dose glucocorticoid regimens, but not avoid them all together,” Dr. Byram said. “The finding that those with worse kidney function fared worse lines up with my clinical experiences. There are clearly populations with this disease that could benefit from more steroid, and it tends to be the ones that are sicker at presentation, particularly those requiring ICU-level care.”

He advised colleagues to “not be dogmatic and use strict low-dose regimens ‘just because.’ ”

No study funding was reported. Dr. Nagle reported having no relevant financial relationships, and disclosures for other authors were not reported. Dr. Byram reports serving on the Vasculitis Foundation board of directors.

SAN DIEGO – A real-world analysis linked the PEXIVAS reduced-dose glucocorticoid (GC) regimen to a higher likelihood of a group of poor outcomes such as death in patients with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).

The retrospective observational study, presented at the annual meeting of the American College of Rheumatology, aimed to see whether results from the landmark PEXIVAS trial would hold up in a real-world analysis given some important limitations of the PEXIVAS’s primary outcome and its relative lack of balance in choice of induction agents.

First author of the new study, Sophie Nagle, MD, of Cochin Hospital in Paris, and colleagues in the French Vasculitis Study Group noted that PEXIVAS “demonstrated noninferiority of reduced-dose GC regimen compared to standard dose for the incidence of death or end-stage kidney disease (ESKD), with a significant reduction in serious infections at 1 year. However, the primary endpoint did not include disease progression or relapse, the majority of patients received cyclophosphamide as induction therapy, and subgroup analysis showed a trend towards an increased risk of death or ESKD in [rituximab]-treated patients.”

The new findings “give us pause about using low-dose glucocorticoid regimens” and suggest that rheumatologists might be a little more conservative about their use than randomized controlled trials such as PEXIVAS might suggest, said Vanderbilt University vasculitis specialist Kevin W. Byram, MD, who’s familiar with the findings but did not take part in the study.

Dr. Nagle reported that among 234 patients with either GPA or MPA, 33.3% of 126 who received a reduced-dose GC regimen experienced one of the 12-month composite primary outcome’s events of death, disease relapse, ESKD, or disease progression before remission that required treatment modification, compared with 18.5% of 108 who received the standard GC regimen (P = .016).

In a propensity score analysis, the higher risk of poor outcomes in the reduced-dose group remained (hazard ratio, 1.57; 95% confidence interval, 0.93-2.64). A multivariate analysis also identified a higher risk for the composite primary outcome in the reduced-dose group (HR, 1.72; 95% CI, 1.08-2.74), although there was no association with an increased risk of death or ESKD.

The PEXIVAS study, published in 2020, supported lower GC doses in antineutrophil cytoplasmic antibody–associated vasculitis, potentially revolutionizing treatment. “Historically, we have used high doses of glucocorticoids on slower tapers to treat this disease, which itself is a strategy that leads to potential complications,” Dr. Byram said. “PEXIVAS suggested we could potentially use less glucocorticoids in these patients.”

For the retrospective, multicenter study, researchers tracked patients from 2018 to 2022, all aged 15 and above. They included 93 with MPA and 141 with GPA. Nearly half were female, and they had a mean age of 61 years. The patients had severe flare-ups treated with rituximab or cyclophosphamide induction and reduced-dose or standard GC regimen.

The standard care and reduced-dose groups were similar, Dr. Nagle said, although the standard group had significantly more patients with GPA (71% vs. 29% with MPA) than did the low-dose group (51% with GPA, 49% with MPA).

The researchers reported that in a reduced-dose subgroup, patients with creatinine levels above 300 micromol/L were more likely to meet the primary endpoint (relative risk, 2.14; 95% CI, 1.14-4.03). Those treated with the reduced-dose GC regimen were also more likely to reach the primary endpoint (HR, 1.61; 95% CI, 0.94-2.77) and die or develop ESKD (HR, 2.42; 95% CI, 1.04-5.66).

However, adverse events at 12 months were similar in both groups: The authors noted that those who received the reduced-dose GC regimen didn’t have higher risk of death, ESKD, or severe infections.

The authors highlighted that “increased vigilance is required when using the reduced-dose GC regimen especially in two subgroups of patients due to the risk of failure: Patients receiving rituximab as induction therapy [and] patients with severe initial kidney disease (serum creatinine > 300 micromol/L).”

The study authors note several limitations: The study is retrospective, and the standard dose group is heterogeneous.

“This study raises the idea that we need to be careful in using low-dose glucocorticoid regimens, but not avoid them all together,” Dr. Byram said. “The finding that those with worse kidney function fared worse lines up with my clinical experiences. There are clearly populations with this disease that could benefit from more steroid, and it tends to be the ones that are sicker at presentation, particularly those requiring ICU-level care.”

He advised colleagues to “not be dogmatic and use strict low-dose regimens ‘just because.’ ”

No study funding was reported. Dr. Nagle reported having no relevant financial relationships, and disclosures for other authors were not reported. Dr. Byram reports serving on the Vasculitis Foundation board of directors.

SAN DIEGO – A real-world analysis linked the PEXIVAS reduced-dose glucocorticoid (GC) regimen to a higher likelihood of a group of poor outcomes such as death in patients with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).

The retrospective observational study, presented at the annual meeting of the American College of Rheumatology, aimed to see whether results from the landmark PEXIVAS trial would hold up in a real-world analysis given some important limitations of the PEXIVAS’s primary outcome and its relative lack of balance in choice of induction agents.

First author of the new study, Sophie Nagle, MD, of Cochin Hospital in Paris, and colleagues in the French Vasculitis Study Group noted that PEXIVAS “demonstrated noninferiority of reduced-dose GC regimen compared to standard dose for the incidence of death or end-stage kidney disease (ESKD), with a significant reduction in serious infections at 1 year. However, the primary endpoint did not include disease progression or relapse, the majority of patients received cyclophosphamide as induction therapy, and subgroup analysis showed a trend towards an increased risk of death or ESKD in [rituximab]-treated patients.”

The new findings “give us pause about using low-dose glucocorticoid regimens” and suggest that rheumatologists might be a little more conservative about their use than randomized controlled trials such as PEXIVAS might suggest, said Vanderbilt University vasculitis specialist Kevin W. Byram, MD, who’s familiar with the findings but did not take part in the study.

Dr. Nagle reported that among 234 patients with either GPA or MPA, 33.3% of 126 who received a reduced-dose GC regimen experienced one of the 12-month composite primary outcome’s events of death, disease relapse, ESKD, or disease progression before remission that required treatment modification, compared with 18.5% of 108 who received the standard GC regimen (P = .016).

In a propensity score analysis, the higher risk of poor outcomes in the reduced-dose group remained (hazard ratio, 1.57; 95% confidence interval, 0.93-2.64). A multivariate analysis also identified a higher risk for the composite primary outcome in the reduced-dose group (HR, 1.72; 95% CI, 1.08-2.74), although there was no association with an increased risk of death or ESKD.

The PEXIVAS study, published in 2020, supported lower GC doses in antineutrophil cytoplasmic antibody–associated vasculitis, potentially revolutionizing treatment. “Historically, we have used high doses of glucocorticoids on slower tapers to treat this disease, which itself is a strategy that leads to potential complications,” Dr. Byram said. “PEXIVAS suggested we could potentially use less glucocorticoids in these patients.”

For the retrospective, multicenter study, researchers tracked patients from 2018 to 2022, all aged 15 and above. They included 93 with MPA and 141 with GPA. Nearly half were female, and they had a mean age of 61 years. The patients had severe flare-ups treated with rituximab or cyclophosphamide induction and reduced-dose or standard GC regimen.

The standard care and reduced-dose groups were similar, Dr. Nagle said, although the standard group had significantly more patients with GPA (71% vs. 29% with MPA) than did the low-dose group (51% with GPA, 49% with MPA).

The researchers reported that in a reduced-dose subgroup, patients with creatinine levels above 300 micromol/L were more likely to meet the primary endpoint (relative risk, 2.14; 95% CI, 1.14-4.03). Those treated with the reduced-dose GC regimen were also more likely to reach the primary endpoint (HR, 1.61; 95% CI, 0.94-2.77) and die or develop ESKD (HR, 2.42; 95% CI, 1.04-5.66).

However, adverse events at 12 months were similar in both groups: The authors noted that those who received the reduced-dose GC regimen didn’t have higher risk of death, ESKD, or severe infections.

The authors highlighted that “increased vigilance is required when using the reduced-dose GC regimen especially in two subgroups of patients due to the risk of failure: Patients receiving rituximab as induction therapy [and] patients with severe initial kidney disease (serum creatinine > 300 micromol/L).”

The study authors note several limitations: The study is retrospective, and the standard dose group is heterogeneous.

“This study raises the idea that we need to be careful in using low-dose glucocorticoid regimens, but not avoid them all together,” Dr. Byram said. “The finding that those with worse kidney function fared worse lines up with my clinical experiences. There are clearly populations with this disease that could benefit from more steroid, and it tends to be the ones that are sicker at presentation, particularly those requiring ICU-level care.”

He advised colleagues to “not be dogmatic and use strict low-dose regimens ‘just because.’ ”

No study funding was reported. Dr. Nagle reported having no relevant financial relationships, and disclosures for other authors were not reported. Dr. Byram reports serving on the Vasculitis Foundation board of directors.