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Two rheumatologists join MDedge Rheumatology editorial advisory board
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Dr. Oliver is an assistant professor of clinical pediatrics in the department of pediatric rheumatology at Indiana University and practices at Riley Hospital for Children, both in Indianapolis. She completed her training in pediatrics at New Jersey Medical School, Newark, and Pediatric Rheumatology at Stanford (Calif.) University.
Her research interests include improving patient outcomes in the juvenile spondyloarthropathy and chronic nonbacterial osteomyelitis populations. She is an active member of the Childhood Arthritis & Rheumatology Research Alliance.
Dr. Kwoh is director of the University of Arizona Arthritis Center, Tucson. He holds the Charles A.L. and Suzanne M. Stephens Endowed Chair in Rheumatology and is the chief of the division of rheumatology and professor of medicine and medical imaging at the university.
His current major research interests focus on the identification of biomarkers – most notably MRI imaging biomarkers for the development and/or progression of knee OA and the characterization of knee pain patterns in OA. He also has a major interest in the reduction and ultimately the elimination of disparities in the management of arthritis and musculoskeletal diseases.
.
Dr. Oliver is an assistant professor of clinical pediatrics in the department of pediatric rheumatology at Indiana University and practices at Riley Hospital for Children, both in Indianapolis. She completed her training in pediatrics at New Jersey Medical School, Newark, and Pediatric Rheumatology at Stanford (Calif.) University.
Her research interests include improving patient outcomes in the juvenile spondyloarthropathy and chronic nonbacterial osteomyelitis populations. She is an active member of the Childhood Arthritis & Rheumatology Research Alliance.
Dr. Kwoh is director of the University of Arizona Arthritis Center, Tucson. He holds the Charles A.L. and Suzanne M. Stephens Endowed Chair in Rheumatology and is the chief of the division of rheumatology and professor of medicine and medical imaging at the university.
His current major research interests focus on the identification of biomarkers – most notably MRI imaging biomarkers for the development and/or progression of knee OA and the characterization of knee pain patterns in OA. He also has a major interest in the reduction and ultimately the elimination of disparities in the management of arthritis and musculoskeletal diseases.
.
Dr. Oliver is an assistant professor of clinical pediatrics in the department of pediatric rheumatology at Indiana University and practices at Riley Hospital for Children, both in Indianapolis. She completed her training in pediatrics at New Jersey Medical School, Newark, and Pediatric Rheumatology at Stanford (Calif.) University.
Her research interests include improving patient outcomes in the juvenile spondyloarthropathy and chronic nonbacterial osteomyelitis populations. She is an active member of the Childhood Arthritis & Rheumatology Research Alliance.
Dr. Kwoh is director of the University of Arizona Arthritis Center, Tucson. He holds the Charles A.L. and Suzanne M. Stephens Endowed Chair in Rheumatology and is the chief of the division of rheumatology and professor of medicine and medical imaging at the university.
His current major research interests focus on the identification of biomarkers – most notably MRI imaging biomarkers for the development and/or progression of knee OA and the characterization of knee pain patterns in OA. He also has a major interest in the reduction and ultimately the elimination of disparities in the management of arthritis and musculoskeletal diseases.
Criminals in the psychiatric ED
Despite popular belief, the absence of a strong link between mental illness and violence has been well studied and established. In summary, in a small subset of patients, mental illness provides a minor increase in the risk of committing violence.1
In part as a result of this research, police departments across the country have established programs and protocols to divert patients with mental illness out of the legal system and into mental hospitals. Instead of accepting the common refrain that mental illness is the explanation and best predictor of all atrocious behaviors, police departments have correctly referred patients with mental illness to mental hospitals. We commend those initiatives and encourage their adoption in all locales. Yet, to safeguard such programs, we would like to warn of a potential pitfall and offer possible remedies.
Having worked in both correctional and clinical settings, we are saddened by the similar nature of the work with respect to the management of mental illness. It should defy logic to assume the need for mental health care in our jails is in any way comparable to the one in mental hospitals. However, we have grown accustomed to seeing large numbers of our most vulnerable patients with severe mental illness accumulating in our jails and correctional facilities, which often are the largest employers of mental health clinicians. The reasons correctional institutions have become so reliant on psychiatric clinicians are vast and complex. Incarceration is tremendously destabilizing and can lead to the onset or relapse of mental illness – even in the most resilient patients. In addition, mental illness is undertreated in our communities yet inescapable in the confined settings of our jails. Furthermore, our mass incarceration problems have resulted in the most disenfranchised populations, including our patients with mental illness, becoming the targets of policies criminalizing poverty.2
To prevent furthering the process by which our correctional facilities have become the new asylums,3 law enforcement agencies have enacted a vast array of initiatives. Some include the placement of mental health staff within emergency response teams. Some include training police officers in how to talk to patients with mental illness as well as how to deescalate mental health crises. Most of the initiatives have one common goal: diverting patients with mental illness who are better treated in mental hospitals from going to jail. However, herein lies the problem: If mental illness is an explanation for only a small subset of criminal behavior, why is there a large need to divert patients with mental illness from jails to mental hospitals?
Over the past few years, psychiatrists in emergency departments have noted a concerning trend: an increase in referrals to mental hospitals by law enforcement for what appears to be a crime with only a vague or obscure link to mental illness. Most psychiatrists who regularly work in emergency departments will witness many examples. Some might be fairly benign: “They were going to arrest me for trespassing; I was yelling at a coffee shop. But when I told them that I had run out of meds, they brought me here instead.”
However, some stories are more chilling, including the case of an older male who had made threats while shooting his gun in the air and was brought to the emergency department because, as the police officer told us, “I think that he is just depressed; you guys can keep him safe till he is better.”
We applaud society’s desire to reduce the criminalization of mental illness. We think that psychiatry should be deeply involved in the attempts to resolve this problem. Furthermore, we are cognizant that the number of patients with mental illness unnecessarily imprisoned as a result of prosecutorial zealousness is a larger problem than criminals inappropriately brought to mental hospitals. However, we also are aware of the limitation of psychiatric hospitals in solving nonpsychiatric problems.
Recent studies have demonstrated the need to examine criminogenic needs before psychiatric ones when attempting to reduce recidivism in all offenders, including those with mental illnesses.4 The emphasis on addressing psychiatric needs over criminogenic ones is misguided and not based on evidence. Yet, we appreciate the complexity of those questions and of individual cases.
Substance use disorders are emblematic of this problem. Psychiatry has now communicated the position that substance use disorders are mental illness and not a moral failing. However, are the crimes committed by individuals with substance use disorders, whether in a state of intoxication or driven by the cycles of addiction, the blameless result of mental illness? The legal system struggles with this question, trying to determine when addiction-related crimes should be referred to a diversion program or treated as a straightforward criminal prosecution. Those who favor diversion for addiction can point out that many criminal acts are associated with mitigating factors that are no less valid than is addiction.
However, those mitigating factors, such as poverty, childhood deprivation, or a violence-infused sociological milieu, cannot be found in the Diagnostic and Statistical Manual of Mental Disorders. As such, if those factors alone were considered, no diversion would be offered by the courts. There also can be unforeseen consequences to this bias for diversion or criminal prosecution. Violent outbursts are a recognized part of PTSD in veterans. Psychiatrists who work at Veterans Affairs can be faced with the diagnosis of PTSD being used as an excuse for violent behavior, which may, at some level be valid, but which can be dangerous in that labeling a patient with that diagnosis might lower the barriers to violent behavior by providing a ready-made explanation already internalized by the patient through unspoken, sociocultural norms.
With the awareness of the complex nature of the intersectionality of mental illness and criminality, we recommend improvements to current diversion programs. As diversion programs rightfully continue to expand across the country, we likely will see an increase in the number of referrals by police officers to our emergency departments. Some of the referrals will be considered “inappropriate” after thorough and thoughtful clinical evaluation by emergency psychiatrists. The inappropriateness might be secondary to an absence of active symptoms, an absence of correlation between the illness and the offense, or a more urgent criminogenic need.
When faced with someone who will not benefit from diversion to a psychiatric emergency department, psychiatrists should have the tools to revert the person back into the legal system. Those tools could come in many forms – law enforcement liaison, prosecution liaison, or simply the presence of officers who are mandated to wait for the approval of the clinician prior to dismissing legal charges. Whatever the solution might be for any particular locale, policy makers should not wait for adverse events to realize the potential pitfalls of the important work being done in developing our country’s diversion programs.
References
1. Swanson JW et al. Mental illness and reduction of gun violence and suicide: Bringing epidemiologic research to policy. Ann Epidemiol. 2015 May;25(5):366-76.
2. Ehrenreich B. “How America criminalized poverty.” The Guardian. 2011 Aug 10.
3. Roth A. “Prisons are the new asylums.” The Atlantic. 2018 April.
4. Latessa EJ et al. “What works (and doesn’t) in reducing recidivism.” New York: Routledge, 2015.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. Dr. Badre can be reached at his website, BadreMD.com. Dr. Lehman is an associate professor of psychiatry at the University of California, San Diego. He is codirector of all acute and intensive psychiatric treatment at the Veterans Affairs Medical Center in San Diego, where he practices clinical psychiatry. He also is the course director for the UCSD third-year medical student psychiatry clerkship.
Despite popular belief, the absence of a strong link between mental illness and violence has been well studied and established. In summary, in a small subset of patients, mental illness provides a minor increase in the risk of committing violence.1
In part as a result of this research, police departments across the country have established programs and protocols to divert patients with mental illness out of the legal system and into mental hospitals. Instead of accepting the common refrain that mental illness is the explanation and best predictor of all atrocious behaviors, police departments have correctly referred patients with mental illness to mental hospitals. We commend those initiatives and encourage their adoption in all locales. Yet, to safeguard such programs, we would like to warn of a potential pitfall and offer possible remedies.
Having worked in both correctional and clinical settings, we are saddened by the similar nature of the work with respect to the management of mental illness. It should defy logic to assume the need for mental health care in our jails is in any way comparable to the one in mental hospitals. However, we have grown accustomed to seeing large numbers of our most vulnerable patients with severe mental illness accumulating in our jails and correctional facilities, which often are the largest employers of mental health clinicians. The reasons correctional institutions have become so reliant on psychiatric clinicians are vast and complex. Incarceration is tremendously destabilizing and can lead to the onset or relapse of mental illness – even in the most resilient patients. In addition, mental illness is undertreated in our communities yet inescapable in the confined settings of our jails. Furthermore, our mass incarceration problems have resulted in the most disenfranchised populations, including our patients with mental illness, becoming the targets of policies criminalizing poverty.2
To prevent furthering the process by which our correctional facilities have become the new asylums,3 law enforcement agencies have enacted a vast array of initiatives. Some include the placement of mental health staff within emergency response teams. Some include training police officers in how to talk to patients with mental illness as well as how to deescalate mental health crises. Most of the initiatives have one common goal: diverting patients with mental illness who are better treated in mental hospitals from going to jail. However, herein lies the problem: If mental illness is an explanation for only a small subset of criminal behavior, why is there a large need to divert patients with mental illness from jails to mental hospitals?
Over the past few years, psychiatrists in emergency departments have noted a concerning trend: an increase in referrals to mental hospitals by law enforcement for what appears to be a crime with only a vague or obscure link to mental illness. Most psychiatrists who regularly work in emergency departments will witness many examples. Some might be fairly benign: “They were going to arrest me for trespassing; I was yelling at a coffee shop. But when I told them that I had run out of meds, they brought me here instead.”
However, some stories are more chilling, including the case of an older male who had made threats while shooting his gun in the air and was brought to the emergency department because, as the police officer told us, “I think that he is just depressed; you guys can keep him safe till he is better.”
We applaud society’s desire to reduce the criminalization of mental illness. We think that psychiatry should be deeply involved in the attempts to resolve this problem. Furthermore, we are cognizant that the number of patients with mental illness unnecessarily imprisoned as a result of prosecutorial zealousness is a larger problem than criminals inappropriately brought to mental hospitals. However, we also are aware of the limitation of psychiatric hospitals in solving nonpsychiatric problems.
Recent studies have demonstrated the need to examine criminogenic needs before psychiatric ones when attempting to reduce recidivism in all offenders, including those with mental illnesses.4 The emphasis on addressing psychiatric needs over criminogenic ones is misguided and not based on evidence. Yet, we appreciate the complexity of those questions and of individual cases.
Substance use disorders are emblematic of this problem. Psychiatry has now communicated the position that substance use disorders are mental illness and not a moral failing. However, are the crimes committed by individuals with substance use disorders, whether in a state of intoxication or driven by the cycles of addiction, the blameless result of mental illness? The legal system struggles with this question, trying to determine when addiction-related crimes should be referred to a diversion program or treated as a straightforward criminal prosecution. Those who favor diversion for addiction can point out that many criminal acts are associated with mitigating factors that are no less valid than is addiction.
However, those mitigating factors, such as poverty, childhood deprivation, or a violence-infused sociological milieu, cannot be found in the Diagnostic and Statistical Manual of Mental Disorders. As such, if those factors alone were considered, no diversion would be offered by the courts. There also can be unforeseen consequences to this bias for diversion or criminal prosecution. Violent outbursts are a recognized part of PTSD in veterans. Psychiatrists who work at Veterans Affairs can be faced with the diagnosis of PTSD being used as an excuse for violent behavior, which may, at some level be valid, but which can be dangerous in that labeling a patient with that diagnosis might lower the barriers to violent behavior by providing a ready-made explanation already internalized by the patient through unspoken, sociocultural norms.
With the awareness of the complex nature of the intersectionality of mental illness and criminality, we recommend improvements to current diversion programs. As diversion programs rightfully continue to expand across the country, we likely will see an increase in the number of referrals by police officers to our emergency departments. Some of the referrals will be considered “inappropriate” after thorough and thoughtful clinical evaluation by emergency psychiatrists. The inappropriateness might be secondary to an absence of active symptoms, an absence of correlation between the illness and the offense, or a more urgent criminogenic need.
When faced with someone who will not benefit from diversion to a psychiatric emergency department, psychiatrists should have the tools to revert the person back into the legal system. Those tools could come in many forms – law enforcement liaison, prosecution liaison, or simply the presence of officers who are mandated to wait for the approval of the clinician prior to dismissing legal charges. Whatever the solution might be for any particular locale, policy makers should not wait for adverse events to realize the potential pitfalls of the important work being done in developing our country’s diversion programs.
References
1. Swanson JW et al. Mental illness and reduction of gun violence and suicide: Bringing epidemiologic research to policy. Ann Epidemiol. 2015 May;25(5):366-76.
2. Ehrenreich B. “How America criminalized poverty.” The Guardian. 2011 Aug 10.
3. Roth A. “Prisons are the new asylums.” The Atlantic. 2018 April.
4. Latessa EJ et al. “What works (and doesn’t) in reducing recidivism.” New York: Routledge, 2015.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. Dr. Badre can be reached at his website, BadreMD.com. Dr. Lehman is an associate professor of psychiatry at the University of California, San Diego. He is codirector of all acute and intensive psychiatric treatment at the Veterans Affairs Medical Center in San Diego, where he practices clinical psychiatry. He also is the course director for the UCSD third-year medical student psychiatry clerkship.
Despite popular belief, the absence of a strong link between mental illness and violence has been well studied and established. In summary, in a small subset of patients, mental illness provides a minor increase in the risk of committing violence.1
In part as a result of this research, police departments across the country have established programs and protocols to divert patients with mental illness out of the legal system and into mental hospitals. Instead of accepting the common refrain that mental illness is the explanation and best predictor of all atrocious behaviors, police departments have correctly referred patients with mental illness to mental hospitals. We commend those initiatives and encourage their adoption in all locales. Yet, to safeguard such programs, we would like to warn of a potential pitfall and offer possible remedies.
Having worked in both correctional and clinical settings, we are saddened by the similar nature of the work with respect to the management of mental illness. It should defy logic to assume the need for mental health care in our jails is in any way comparable to the one in mental hospitals. However, we have grown accustomed to seeing large numbers of our most vulnerable patients with severe mental illness accumulating in our jails and correctional facilities, which often are the largest employers of mental health clinicians. The reasons correctional institutions have become so reliant on psychiatric clinicians are vast and complex. Incarceration is tremendously destabilizing and can lead to the onset or relapse of mental illness – even in the most resilient patients. In addition, mental illness is undertreated in our communities yet inescapable in the confined settings of our jails. Furthermore, our mass incarceration problems have resulted in the most disenfranchised populations, including our patients with mental illness, becoming the targets of policies criminalizing poverty.2
To prevent furthering the process by which our correctional facilities have become the new asylums,3 law enforcement agencies have enacted a vast array of initiatives. Some include the placement of mental health staff within emergency response teams. Some include training police officers in how to talk to patients with mental illness as well as how to deescalate mental health crises. Most of the initiatives have one common goal: diverting patients with mental illness who are better treated in mental hospitals from going to jail. However, herein lies the problem: If mental illness is an explanation for only a small subset of criminal behavior, why is there a large need to divert patients with mental illness from jails to mental hospitals?
Over the past few years, psychiatrists in emergency departments have noted a concerning trend: an increase in referrals to mental hospitals by law enforcement for what appears to be a crime with only a vague or obscure link to mental illness. Most psychiatrists who regularly work in emergency departments will witness many examples. Some might be fairly benign: “They were going to arrest me for trespassing; I was yelling at a coffee shop. But when I told them that I had run out of meds, they brought me here instead.”
However, some stories are more chilling, including the case of an older male who had made threats while shooting his gun in the air and was brought to the emergency department because, as the police officer told us, “I think that he is just depressed; you guys can keep him safe till he is better.”
We applaud society’s desire to reduce the criminalization of mental illness. We think that psychiatry should be deeply involved in the attempts to resolve this problem. Furthermore, we are cognizant that the number of patients with mental illness unnecessarily imprisoned as a result of prosecutorial zealousness is a larger problem than criminals inappropriately brought to mental hospitals. However, we also are aware of the limitation of psychiatric hospitals in solving nonpsychiatric problems.
Recent studies have demonstrated the need to examine criminogenic needs before psychiatric ones when attempting to reduce recidivism in all offenders, including those with mental illnesses.4 The emphasis on addressing psychiatric needs over criminogenic ones is misguided and not based on evidence. Yet, we appreciate the complexity of those questions and of individual cases.
Substance use disorders are emblematic of this problem. Psychiatry has now communicated the position that substance use disorders are mental illness and not a moral failing. However, are the crimes committed by individuals with substance use disorders, whether in a state of intoxication or driven by the cycles of addiction, the blameless result of mental illness? The legal system struggles with this question, trying to determine when addiction-related crimes should be referred to a diversion program or treated as a straightforward criminal prosecution. Those who favor diversion for addiction can point out that many criminal acts are associated with mitigating factors that are no less valid than is addiction.
However, those mitigating factors, such as poverty, childhood deprivation, or a violence-infused sociological milieu, cannot be found in the Diagnostic and Statistical Manual of Mental Disorders. As such, if those factors alone were considered, no diversion would be offered by the courts. There also can be unforeseen consequences to this bias for diversion or criminal prosecution. Violent outbursts are a recognized part of PTSD in veterans. Psychiatrists who work at Veterans Affairs can be faced with the diagnosis of PTSD being used as an excuse for violent behavior, which may, at some level be valid, but which can be dangerous in that labeling a patient with that diagnosis might lower the barriers to violent behavior by providing a ready-made explanation already internalized by the patient through unspoken, sociocultural norms.
With the awareness of the complex nature of the intersectionality of mental illness and criminality, we recommend improvements to current diversion programs. As diversion programs rightfully continue to expand across the country, we likely will see an increase in the number of referrals by police officers to our emergency departments. Some of the referrals will be considered “inappropriate” after thorough and thoughtful clinical evaluation by emergency psychiatrists. The inappropriateness might be secondary to an absence of active symptoms, an absence of correlation between the illness and the offense, or a more urgent criminogenic need.
When faced with someone who will not benefit from diversion to a psychiatric emergency department, psychiatrists should have the tools to revert the person back into the legal system. Those tools could come in many forms – law enforcement liaison, prosecution liaison, or simply the presence of officers who are mandated to wait for the approval of the clinician prior to dismissing legal charges. Whatever the solution might be for any particular locale, policy makers should not wait for adverse events to realize the potential pitfalls of the important work being done in developing our country’s diversion programs.
References
1. Swanson JW et al. Mental illness and reduction of gun violence and suicide: Bringing epidemiologic research to policy. Ann Epidemiol. 2015 May;25(5):366-76.
2. Ehrenreich B. “How America criminalized poverty.” The Guardian. 2011 Aug 10.
3. Roth A. “Prisons are the new asylums.” The Atlantic. 2018 April.
4. Latessa EJ et al. “What works (and doesn’t) in reducing recidivism.” New York: Routledge, 2015.
Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. Dr. Badre can be reached at his website, BadreMD.com. Dr. Lehman is an associate professor of psychiatry at the University of California, San Diego. He is codirector of all acute and intensive psychiatric treatment at the Veterans Affairs Medical Center in San Diego, where he practices clinical psychiatry. He also is the course director for the UCSD third-year medical student psychiatry clerkship.
False links between violence, mental illness fast-tracked report release
Stigmatizing language in the public domain that falsely links U.S. gun violence to mental illness led the National Council for Behavioral Health to move up release of a report analyzing causes, impacts, and solutions of mass violence, according to Jack Rozel, MD.
“We were planning to release it in October but released it early to push back,” Dr. Rozel, a member of the report’s expert panel and medical director of resolve Crisis Services, said on the Aug. 21 MDedge Psychcast.
The 82-page report examines behavior-based motives and solutions related to mass violence in the United States (Parks J et al. National Council for Behavioral Health. 2019 Aug 6. “Mass Violence in America: Causes, Impacts and Solutions”). It was created by the Medical Director Institute, which advises the National Council on current issues affecting clinical practice.
Policy makers and the public often leap to conclusions about the role of mental illness in the actions of individuals responsible for mass violence, wrote the panel convened by the institute. The panel included not only clinicians such as Dr. Rozel with expertise in treating mental illness, but also researchers, educators, law enforcement personnel, FBI members, judges, policy makers, and parents.
According to the report’s executive summary, perpetrators of mass violence share certain traits independent of cultural, demographic, socioeconomic, and occupational factors. The most common perpetrators of mass violence are “males, often hopeless and harboring grievances that are frequently related to work, school, finances, or interpersonal relationships; feeling victimized and sympathizing with others whom they perceive to be similarly mistreated; indifference to life; and often subsequently dying by suicide.”
, according to the report. In fact, many perpetrators do not suffer from any major psychiatric disorder, and most individuals who do suffer from mental illness are not violent.
“Lumping all mental illness together, and then assuming that acts that seem incomprehensible to the average person are due to mental illness, results in millions of harmless, nonviolent individuals recovering from treatable mental health conditions being subjected to stigma, rejection, discrimination and even unwarranted legal restrictions and social control,” the panel wrote. Recent episodes of mass violence in the United States can contribute to a generalized fear of individuals with mental illness, they added.
More research and strategies are needed to explore and address the root causes that contribute to acts of mass violence, including social problems and insufficient mental health care, the report said.
The panelists also offered recommendations for stakeholders, including health care organizations, schools, law enforcement, and community groups.
Recommendations for health care organizations in particular include establishing multidisciplinary teams for threat assessment and management that include not only security personnel, but also human resources, legal, and law enforcement. In addition, the panel recommended that health care staff be trained in lethal means reduction. “This is a rational strategy for lethal violence reduction and very helpful in combating suicide,” they said. However, staff also should be prepared for compassion fatigue and vicarious trauma, and health care organizations should develop resources for self-care and staff support.
Other recommendations include enacting state red flag laws that would remove guns from high-risk individuals for the short term, and reassessing the value of school safety protocols, such as bulletproof glass, zero tolerance policies, and active shooter drills.
The panel also offered recommendations for additional research on mass violence, including studies on “the nature and factors that contribute to mass violence, including neurobiological, psychological and sociological factors,” as well as research on methods of intervention and prevention of mass violence and the creation of a standardized analysis for mass violence incidence led by the Department of Justice with a multidisciplinary team.
Working with the media is important for engaging and educating the public about mental illness and mass violence, the panel members wrote. They recommended that all stakeholders in mental health develop messages in advance and protocols about how to respond to media requests for information about behavioral health.
“Talk about the role of treatment in helping people at risk of violence. Highlight the fact that most people with mental illnesses will never become violent. Speak to untreated or undertreated mental illness in combination with other risk factors,” they said.
Finally, they emphasized the need to remind the public to be aware of risk factors for mass violence, and the value of the “see something, say something” message.
In the Psychcast interview, Dr. Rozel said he and several colleagues will be conducting talks and training on these issues over the next few months, including at the Institute on Psychiatric Services conference (IPS 2019) in October in New York; at the National Council’s preconference (NatCon20) in April in Austin, Tex.; and at the American College of Emergency Physicians (ACEP 2019) meeting in October in Denver.
The National Council’s expert panel was led by Joe Parks, MD, medical director of the National Council; Donald W. Bechtold, MD, of the Colorado-based Jefferson Center for Mental Health; Sara Coffey, DO, of Oklahoma State University, Tulsa; Jeffrey A. Lieberman, MD, of Columbia University, New York; and Frank Shelp, MD, MPH, of Envolve Health, Atlanta.
Stigmatizing language in the public domain that falsely links U.S. gun violence to mental illness led the National Council for Behavioral Health to move up release of a report analyzing causes, impacts, and solutions of mass violence, according to Jack Rozel, MD.
“We were planning to release it in October but released it early to push back,” Dr. Rozel, a member of the report’s expert panel and medical director of resolve Crisis Services, said on the Aug. 21 MDedge Psychcast.
The 82-page report examines behavior-based motives and solutions related to mass violence in the United States (Parks J et al. National Council for Behavioral Health. 2019 Aug 6. “Mass Violence in America: Causes, Impacts and Solutions”). It was created by the Medical Director Institute, which advises the National Council on current issues affecting clinical practice.
Policy makers and the public often leap to conclusions about the role of mental illness in the actions of individuals responsible for mass violence, wrote the panel convened by the institute. The panel included not only clinicians such as Dr. Rozel with expertise in treating mental illness, but also researchers, educators, law enforcement personnel, FBI members, judges, policy makers, and parents.
According to the report’s executive summary, perpetrators of mass violence share certain traits independent of cultural, demographic, socioeconomic, and occupational factors. The most common perpetrators of mass violence are “males, often hopeless and harboring grievances that are frequently related to work, school, finances, or interpersonal relationships; feeling victimized and sympathizing with others whom they perceive to be similarly mistreated; indifference to life; and often subsequently dying by suicide.”
, according to the report. In fact, many perpetrators do not suffer from any major psychiatric disorder, and most individuals who do suffer from mental illness are not violent.
“Lumping all mental illness together, and then assuming that acts that seem incomprehensible to the average person are due to mental illness, results in millions of harmless, nonviolent individuals recovering from treatable mental health conditions being subjected to stigma, rejection, discrimination and even unwarranted legal restrictions and social control,” the panel wrote. Recent episodes of mass violence in the United States can contribute to a generalized fear of individuals with mental illness, they added.
More research and strategies are needed to explore and address the root causes that contribute to acts of mass violence, including social problems and insufficient mental health care, the report said.
The panelists also offered recommendations for stakeholders, including health care organizations, schools, law enforcement, and community groups.
Recommendations for health care organizations in particular include establishing multidisciplinary teams for threat assessment and management that include not only security personnel, but also human resources, legal, and law enforcement. In addition, the panel recommended that health care staff be trained in lethal means reduction. “This is a rational strategy for lethal violence reduction and very helpful in combating suicide,” they said. However, staff also should be prepared for compassion fatigue and vicarious trauma, and health care organizations should develop resources for self-care and staff support.
Other recommendations include enacting state red flag laws that would remove guns from high-risk individuals for the short term, and reassessing the value of school safety protocols, such as bulletproof glass, zero tolerance policies, and active shooter drills.
The panel also offered recommendations for additional research on mass violence, including studies on “the nature and factors that contribute to mass violence, including neurobiological, psychological and sociological factors,” as well as research on methods of intervention and prevention of mass violence and the creation of a standardized analysis for mass violence incidence led by the Department of Justice with a multidisciplinary team.
Working with the media is important for engaging and educating the public about mental illness and mass violence, the panel members wrote. They recommended that all stakeholders in mental health develop messages in advance and protocols about how to respond to media requests for information about behavioral health.
“Talk about the role of treatment in helping people at risk of violence. Highlight the fact that most people with mental illnesses will never become violent. Speak to untreated or undertreated mental illness in combination with other risk factors,” they said.
Finally, they emphasized the need to remind the public to be aware of risk factors for mass violence, and the value of the “see something, say something” message.
In the Psychcast interview, Dr. Rozel said he and several colleagues will be conducting talks and training on these issues over the next few months, including at the Institute on Psychiatric Services conference (IPS 2019) in October in New York; at the National Council’s preconference (NatCon20) in April in Austin, Tex.; and at the American College of Emergency Physicians (ACEP 2019) meeting in October in Denver.
The National Council’s expert panel was led by Joe Parks, MD, medical director of the National Council; Donald W. Bechtold, MD, of the Colorado-based Jefferson Center for Mental Health; Sara Coffey, DO, of Oklahoma State University, Tulsa; Jeffrey A. Lieberman, MD, of Columbia University, New York; and Frank Shelp, MD, MPH, of Envolve Health, Atlanta.
Stigmatizing language in the public domain that falsely links U.S. gun violence to mental illness led the National Council for Behavioral Health to move up release of a report analyzing causes, impacts, and solutions of mass violence, according to Jack Rozel, MD.
“We were planning to release it in October but released it early to push back,” Dr. Rozel, a member of the report’s expert panel and medical director of resolve Crisis Services, said on the Aug. 21 MDedge Psychcast.
The 82-page report examines behavior-based motives and solutions related to mass violence in the United States (Parks J et al. National Council for Behavioral Health. 2019 Aug 6. “Mass Violence in America: Causes, Impacts and Solutions”). It was created by the Medical Director Institute, which advises the National Council on current issues affecting clinical practice.
Policy makers and the public often leap to conclusions about the role of mental illness in the actions of individuals responsible for mass violence, wrote the panel convened by the institute. The panel included not only clinicians such as Dr. Rozel with expertise in treating mental illness, but also researchers, educators, law enforcement personnel, FBI members, judges, policy makers, and parents.
According to the report’s executive summary, perpetrators of mass violence share certain traits independent of cultural, demographic, socioeconomic, and occupational factors. The most common perpetrators of mass violence are “males, often hopeless and harboring grievances that are frequently related to work, school, finances, or interpersonal relationships; feeling victimized and sympathizing with others whom they perceive to be similarly mistreated; indifference to life; and often subsequently dying by suicide.”
, according to the report. In fact, many perpetrators do not suffer from any major psychiatric disorder, and most individuals who do suffer from mental illness are not violent.
“Lumping all mental illness together, and then assuming that acts that seem incomprehensible to the average person are due to mental illness, results in millions of harmless, nonviolent individuals recovering from treatable mental health conditions being subjected to stigma, rejection, discrimination and even unwarranted legal restrictions and social control,” the panel wrote. Recent episodes of mass violence in the United States can contribute to a generalized fear of individuals with mental illness, they added.
More research and strategies are needed to explore and address the root causes that contribute to acts of mass violence, including social problems and insufficient mental health care, the report said.
The panelists also offered recommendations for stakeholders, including health care organizations, schools, law enforcement, and community groups.
Recommendations for health care organizations in particular include establishing multidisciplinary teams for threat assessment and management that include not only security personnel, but also human resources, legal, and law enforcement. In addition, the panel recommended that health care staff be trained in lethal means reduction. “This is a rational strategy for lethal violence reduction and very helpful in combating suicide,” they said. However, staff also should be prepared for compassion fatigue and vicarious trauma, and health care organizations should develop resources for self-care and staff support.
Other recommendations include enacting state red flag laws that would remove guns from high-risk individuals for the short term, and reassessing the value of school safety protocols, such as bulletproof glass, zero tolerance policies, and active shooter drills.
The panel also offered recommendations for additional research on mass violence, including studies on “the nature and factors that contribute to mass violence, including neurobiological, psychological and sociological factors,” as well as research on methods of intervention and prevention of mass violence and the creation of a standardized analysis for mass violence incidence led by the Department of Justice with a multidisciplinary team.
Working with the media is important for engaging and educating the public about mental illness and mass violence, the panel members wrote. They recommended that all stakeholders in mental health develop messages in advance and protocols about how to respond to media requests for information about behavioral health.
“Talk about the role of treatment in helping people at risk of violence. Highlight the fact that most people with mental illnesses will never become violent. Speak to untreated or undertreated mental illness in combination with other risk factors,” they said.
Finally, they emphasized the need to remind the public to be aware of risk factors for mass violence, and the value of the “see something, say something” message.
In the Psychcast interview, Dr. Rozel said he and several colleagues will be conducting talks and training on these issues over the next few months, including at the Institute on Psychiatric Services conference (IPS 2019) in October in New York; at the National Council’s preconference (NatCon20) in April in Austin, Tex.; and at the American College of Emergency Physicians (ACEP 2019) meeting in October in Denver.
The National Council’s expert panel was led by Joe Parks, MD, medical director of the National Council; Donald W. Bechtold, MD, of the Colorado-based Jefferson Center for Mental Health; Sara Coffey, DO, of Oklahoma State University, Tulsa; Jeffrey A. Lieberman, MD, of Columbia University, New York; and Frank Shelp, MD, MPH, of Envolve Health, Atlanta.
Immune Checkpoint Inhibitors for Urothelial Cancer: An Update on New Therapies (FULL)
An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.
Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.3 This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.3
Immune Biology
CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.4
Immunotherapy Treatments in Cisplatin-Ineligible Patients
Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).
In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.5At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.5 The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.5
Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.6 Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.3
Immunotherapy Treatments After Progression With Cisplatin
Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.7 Immunotherapy provides an effective and a much-needed option in this scenario.
Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).3 In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).7 Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).7 In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.8 The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.8
It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.9 In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.12
Future Directions
Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.
Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.
Conclusion
Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.
1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
2. Morales A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol Immunother. 1980;9 (1-2):69-72.
3. US Food and drug administration. FDA approved drug products. www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed July 5, 2018.
4. Farina MS, Lundgren KT, Bellmunt J. Immunotherapy in urothelial cancer: recent results and future perspectives. Drugs. 2017;77(10):1077-1089.
5. Balar AV, Castellano DE, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
6. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
7. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
8. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.
9. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.
10. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64.
11. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411.
12. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768.
An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.
Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.3 This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.3
Immune Biology
CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.4
Immunotherapy Treatments in Cisplatin-Ineligible Patients
Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).
In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.5At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.5 The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.5
Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.6 Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.3
Immunotherapy Treatments After Progression With Cisplatin
Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.7 Immunotherapy provides an effective and a much-needed option in this scenario.
Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).3 In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).7 Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).7 In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.8 The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.8
It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.9 In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.12
Future Directions
Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.
Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.
Conclusion
Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.
An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.
Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.3 This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.3
Immune Biology
CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.4
Immunotherapy Treatments in Cisplatin-Ineligible Patients
Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).
In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.5At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.5 The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.5
Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.6 Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.3
Immunotherapy Treatments After Progression With Cisplatin
Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.7 Immunotherapy provides an effective and a much-needed option in this scenario.
Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).3 In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).7 Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).7 In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.8 The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.8
It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.9 In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.12
Future Directions
Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.
Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.
Conclusion
Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.
1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
2. Morales A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol Immunother. 1980;9 (1-2):69-72.
3. US Food and drug administration. FDA approved drug products. www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed July 5, 2018.
4. Farina MS, Lundgren KT, Bellmunt J. Immunotherapy in urothelial cancer: recent results and future perspectives. Drugs. 2017;77(10):1077-1089.
5. Balar AV, Castellano DE, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
6. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
7. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
8. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.
9. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.
10. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64.
11. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411.
12. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768.
1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
2. Morales A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol Immunother. 1980;9 (1-2):69-72.
3. US Food and drug administration. FDA approved drug products. www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed July 5, 2018.
4. Farina MS, Lundgren KT, Bellmunt J. Immunotherapy in urothelial cancer: recent results and future perspectives. Drugs. 2017;77(10):1077-1089.
5. Balar AV, Castellano DE, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
6. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
7. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
8. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.
9. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.
10. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64.
11. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411.
12. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768.
To be, or not to be ... on backup?
A staffing backup system is essential
It was late 2011. We were a practice of around 20 physicians, and just starting to integrate advanced practice providers into our practice. Our average daily census was about 100 patients and slightly more than 50% of our services were resident services.
My boss, colleague, friend, and mentor – Charles “Chuck” Sargent, MD, and I were on service together early one Saturday morning; Chuck gets a phone call that one of our colleagues was ill. With just 10 physicians working and 10 off, it was an ordeal for Chuck to call all 10 colleagues. Unlike most times, no one could come to moonlight that day. In the end Chuck and I took care of our colleague’s patients.
Yes, it was an exhausting few days, but illness and family needs do not come announced. Now, close to a decade later, we are a practice of 70 physicians and 16 advanced practice providers, our average daily census is about 270 patients, and we have two backup physicians every day – known as Jeopardy-1 and Jeopardy-2. Paternity leave, maternity leave, minor illness, minor trauma, surgery, and family needs are common for our practice. We considered it a good year when we utilized our Jeopardy-1 and Jeopardy-2 for 10% and 1% respectively; and for the past year with a lot of needs, we employed Jeopardy-1 and Jeopardy-2 for 25% and 10%, respectively.
A staffing backup system is a necessary tool for almost every practice. Not having a formal backup system doesn’t mean you don’t need one or you don’t have one – it is just called “no formal backup system.” The Society of Hospital Medicine’s State of Hospital Medicine Reports (SoHM) have been providing data about staffing backup systems every other year. Backup systems come in three flavors. The first system is no formal backup, which means the leaders of the program scramble for coverage every time there is a need. The second is a voluntary backup system in which clinicians volunteer to be on a backup schedule, and the third is a mandatory system in which all or most clinicians are required to be on the backup schedule.
The cumulative data reported in the 2014, 2016, and 2018 SoHM for hospital medicine groups serving adults only, children only, and both adults and children (weighted for number of groups reporting), suggests that 48.3% of respondent practices had no formal backup system, 31.7% had a voluntary system, and 20% had a mandatory backup system.
When we look at different populations served, the trend of “no formal backup system” responses is in decline. The 2014, 2016, and 2018 SoHM reports for hospital medicine groups serving adults, children, and both adults and children, reinforce such trends. The SoHM 2018 report shows 65.6% of hospital medicine groups serving children, 41.6% of groups serving adults, and only 25% of groups serving both adults and children have “no formal backup system.” Our medicine-pediatrics colleagues seem to be leading the trend and have already deduced that, for a solid practice, a backup system is a necessity.
It is also important to see the trend of “no formal backup system” based on geographic area, employer type, academic status, or total number of full-time employees. As we would have predicted, the larger the group the more likely they are to have a backup system. For academic practices a similar trend was seen; they had a higher percentage of some type of backup system year after year.
When it comes to compensation for backup work, four patterns were explored by the SoHM over the years. The most common type of arrangement was “no additional compensation for being on the backup schedule, but additional compensation was provided when called into work.” This kind of arrangement would be easiest to negotiate when the hospitalist and the employer sit across a table. There is nothing at risk for the employer when there isn’t a need, or when there is a need to fill a shift.
The least common method was “additional compensation for being on the backup schedule, but no additional compensation if called into work.” From employers’ perspectives, this is an extra expense and is not ideal for the hospitalist either. In the middle of the pack were “no additional compensation associated with the backup plan” (the second most common model), while the third most common model was “additional compensation for being on the backup schedule, as well as additional compensation if called into work.”
Once you have seen one hospital medicine practice, you have seen one hospital medicine practice. There are different needs for every group, and the backup system – as well its compensation model – has to be designed for it. Thankfully, the SoHM reports reveal the patterns and trends so that we don’t have to reinvent the wheel. For our practice, we decreased a week of clinical service for 2 weeks a year of backup. Every time we activate our backup system, the person coming in receives extra compensation or a similar shift off. In the long run, our backup system didn’t kill us, but rather made us stronger as a group.
Dr. Chadha is interim division chief in the division of hospital medicine at the University of Kentucky HealthCare in Lexington. He actively leads efforts of recruiting, scheduling, practice analysis, and operation of the group. He is a first-time member of the SHM Practice Analysis Committee. Ms. Babb is administrative support associate in the division of hospital medicine at University of Kentucky HealthCare.
A staffing backup system is essential
A staffing backup system is essential
It was late 2011. We were a practice of around 20 physicians, and just starting to integrate advanced practice providers into our practice. Our average daily census was about 100 patients and slightly more than 50% of our services were resident services.
My boss, colleague, friend, and mentor – Charles “Chuck” Sargent, MD, and I were on service together early one Saturday morning; Chuck gets a phone call that one of our colleagues was ill. With just 10 physicians working and 10 off, it was an ordeal for Chuck to call all 10 colleagues. Unlike most times, no one could come to moonlight that day. In the end Chuck and I took care of our colleague’s patients.
Yes, it was an exhausting few days, but illness and family needs do not come announced. Now, close to a decade later, we are a practice of 70 physicians and 16 advanced practice providers, our average daily census is about 270 patients, and we have two backup physicians every day – known as Jeopardy-1 and Jeopardy-2. Paternity leave, maternity leave, minor illness, minor trauma, surgery, and family needs are common for our practice. We considered it a good year when we utilized our Jeopardy-1 and Jeopardy-2 for 10% and 1% respectively; and for the past year with a lot of needs, we employed Jeopardy-1 and Jeopardy-2 for 25% and 10%, respectively.
A staffing backup system is a necessary tool for almost every practice. Not having a formal backup system doesn’t mean you don’t need one or you don’t have one – it is just called “no formal backup system.” The Society of Hospital Medicine’s State of Hospital Medicine Reports (SoHM) have been providing data about staffing backup systems every other year. Backup systems come in three flavors. The first system is no formal backup, which means the leaders of the program scramble for coverage every time there is a need. The second is a voluntary backup system in which clinicians volunteer to be on a backup schedule, and the third is a mandatory system in which all or most clinicians are required to be on the backup schedule.
The cumulative data reported in the 2014, 2016, and 2018 SoHM for hospital medicine groups serving adults only, children only, and both adults and children (weighted for number of groups reporting), suggests that 48.3% of respondent practices had no formal backup system, 31.7% had a voluntary system, and 20% had a mandatory backup system.
When we look at different populations served, the trend of “no formal backup system” responses is in decline. The 2014, 2016, and 2018 SoHM reports for hospital medicine groups serving adults, children, and both adults and children, reinforce such trends. The SoHM 2018 report shows 65.6% of hospital medicine groups serving children, 41.6% of groups serving adults, and only 25% of groups serving both adults and children have “no formal backup system.” Our medicine-pediatrics colleagues seem to be leading the trend and have already deduced that, for a solid practice, a backup system is a necessity.
It is also important to see the trend of “no formal backup system” based on geographic area, employer type, academic status, or total number of full-time employees. As we would have predicted, the larger the group the more likely they are to have a backup system. For academic practices a similar trend was seen; they had a higher percentage of some type of backup system year after year.
When it comes to compensation for backup work, four patterns were explored by the SoHM over the years. The most common type of arrangement was “no additional compensation for being on the backup schedule, but additional compensation was provided when called into work.” This kind of arrangement would be easiest to negotiate when the hospitalist and the employer sit across a table. There is nothing at risk for the employer when there isn’t a need, or when there is a need to fill a shift.
The least common method was “additional compensation for being on the backup schedule, but no additional compensation if called into work.” From employers’ perspectives, this is an extra expense and is not ideal for the hospitalist either. In the middle of the pack were “no additional compensation associated with the backup plan” (the second most common model), while the third most common model was “additional compensation for being on the backup schedule, as well as additional compensation if called into work.”
Once you have seen one hospital medicine practice, you have seen one hospital medicine practice. There are different needs for every group, and the backup system – as well its compensation model – has to be designed for it. Thankfully, the SoHM reports reveal the patterns and trends so that we don’t have to reinvent the wheel. For our practice, we decreased a week of clinical service for 2 weeks a year of backup. Every time we activate our backup system, the person coming in receives extra compensation or a similar shift off. In the long run, our backup system didn’t kill us, but rather made us stronger as a group.
Dr. Chadha is interim division chief in the division of hospital medicine at the University of Kentucky HealthCare in Lexington. He actively leads efforts of recruiting, scheduling, practice analysis, and operation of the group. He is a first-time member of the SHM Practice Analysis Committee. Ms. Babb is administrative support associate in the division of hospital medicine at University of Kentucky HealthCare.
It was late 2011. We were a practice of around 20 physicians, and just starting to integrate advanced practice providers into our practice. Our average daily census was about 100 patients and slightly more than 50% of our services were resident services.
My boss, colleague, friend, and mentor – Charles “Chuck” Sargent, MD, and I were on service together early one Saturday morning; Chuck gets a phone call that one of our colleagues was ill. With just 10 physicians working and 10 off, it was an ordeal for Chuck to call all 10 colleagues. Unlike most times, no one could come to moonlight that day. In the end Chuck and I took care of our colleague’s patients.
Yes, it was an exhausting few days, but illness and family needs do not come announced. Now, close to a decade later, we are a practice of 70 physicians and 16 advanced practice providers, our average daily census is about 270 patients, and we have two backup physicians every day – known as Jeopardy-1 and Jeopardy-2. Paternity leave, maternity leave, minor illness, minor trauma, surgery, and family needs are common for our practice. We considered it a good year when we utilized our Jeopardy-1 and Jeopardy-2 for 10% and 1% respectively; and for the past year with a lot of needs, we employed Jeopardy-1 and Jeopardy-2 for 25% and 10%, respectively.
A staffing backup system is a necessary tool for almost every practice. Not having a formal backup system doesn’t mean you don’t need one or you don’t have one – it is just called “no formal backup system.” The Society of Hospital Medicine’s State of Hospital Medicine Reports (SoHM) have been providing data about staffing backup systems every other year. Backup systems come in three flavors. The first system is no formal backup, which means the leaders of the program scramble for coverage every time there is a need. The second is a voluntary backup system in which clinicians volunteer to be on a backup schedule, and the third is a mandatory system in which all or most clinicians are required to be on the backup schedule.
The cumulative data reported in the 2014, 2016, and 2018 SoHM for hospital medicine groups serving adults only, children only, and both adults and children (weighted for number of groups reporting), suggests that 48.3% of respondent practices had no formal backup system, 31.7% had a voluntary system, and 20% had a mandatory backup system.
When we look at different populations served, the trend of “no formal backup system” responses is in decline. The 2014, 2016, and 2018 SoHM reports for hospital medicine groups serving adults, children, and both adults and children, reinforce such trends. The SoHM 2018 report shows 65.6% of hospital medicine groups serving children, 41.6% of groups serving adults, and only 25% of groups serving both adults and children have “no formal backup system.” Our medicine-pediatrics colleagues seem to be leading the trend and have already deduced that, for a solid practice, a backup system is a necessity.
It is also important to see the trend of “no formal backup system” based on geographic area, employer type, academic status, or total number of full-time employees. As we would have predicted, the larger the group the more likely they are to have a backup system. For academic practices a similar trend was seen; they had a higher percentage of some type of backup system year after year.
When it comes to compensation for backup work, four patterns were explored by the SoHM over the years. The most common type of arrangement was “no additional compensation for being on the backup schedule, but additional compensation was provided when called into work.” This kind of arrangement would be easiest to negotiate when the hospitalist and the employer sit across a table. There is nothing at risk for the employer when there isn’t a need, or when there is a need to fill a shift.
The least common method was “additional compensation for being on the backup schedule, but no additional compensation if called into work.” From employers’ perspectives, this is an extra expense and is not ideal for the hospitalist either. In the middle of the pack were “no additional compensation associated with the backup plan” (the second most common model), while the third most common model was “additional compensation for being on the backup schedule, as well as additional compensation if called into work.”
Once you have seen one hospital medicine practice, you have seen one hospital medicine practice. There are different needs for every group, and the backup system – as well its compensation model – has to be designed for it. Thankfully, the SoHM reports reveal the patterns and trends so that we don’t have to reinvent the wheel. For our practice, we decreased a week of clinical service for 2 weeks a year of backup. Every time we activate our backup system, the person coming in receives extra compensation or a similar shift off. In the long run, our backup system didn’t kill us, but rather made us stronger as a group.
Dr. Chadha is interim division chief in the division of hospital medicine at the University of Kentucky HealthCare in Lexington. He actively leads efforts of recruiting, scheduling, practice analysis, and operation of the group. He is a first-time member of the SHM Practice Analysis Committee. Ms. Babb is administrative support associate in the division of hospital medicine at University of Kentucky HealthCare.
Lamotrigine-Induced Cutaneous Pseudolymphoma
To the Editor:
An 8-year-old girl presented with new lesions on the scalp that were mildly painful to palpation and had been increasing in size and number over the last 2 months. Her medical history was remarkable for seizures, keratosis pilaris, and seborrheic dermatitis. The seizures had been well controlled on oxcarbazepine; however, she was switched to lamotrigine 6 months prior to presentation under the care of her neurologist. The patient was not taking other oral medications, and she denied any trauma/insect bites to the affected area or systemic symptoms such as fever, fatigue, weight loss, nausea, swollen lymph nodes, or night sweats. Physical examination revealed 3 well-circumscribed, pink, slightly scaly, indurated nodules on the frontal and vertex scalp (Figure 1). She reported pain on palpation of the lesions. Treatment with ketoconazole shampoo and high-potency topical corticosteroids was ineffective.
Over a period of 2 months after the initial presentation, the patient developed a total of 9 scalp lesions. Testing was performed 4 months after presentation of lesions. Bacterial and fungal cultures of the lesional skin of the scalp were negative. Two biopsies of lesions on the scalp were performed, the first of which showed a nonspecific lymphohistiocytic infiltrate. The second biopsy revealed a dense, nodular, atypical dermal lymphoid infiltrate composed primarily of round regular lymphocytes intermixed with some larger, more irregular lymphocytes and few scattered mitoses (Figure 2).
Immunohistochemical studies revealed small B-cell lymphoma 2–positive lymphocytes with a 2:1 mixture of CD3+ T cells and CD20+CD79a+ B cells. The T cells expressed CD2, CD5, and CD43, and a subset showed a loss of CD7. The CD4:CD8 ratio was 10 to 1. No follicular dendritic networks were noted with CD21 and CD23. Rare, scattered, medium-sized CD30 cells were noted. Staining for CD10, B-cell lymphoma 6, anaplastic lymphoma kinase, Epstein-Barr virus–encoded RNA 1, IgD, and IgM were negative. The plasma cells had a κ/λ free light chain ratio of 2 to 1. Ki-67 was positive in 15% of lymphoid cells. Polymerase chain reaction analysis of T-cell receptor gene rearrangement revealed a peak at 228 bp in a predominantly polyclonal background. A thorough systemic workup including complete blood cell count, immunoglobulin assay, bone marrow transplant panel, comprehensive metabolic panel, lactate dehydrogenase test, inflammatory markers, and viral testing failed to reveal any evidence of underlying malignancy.
After conferring with the patient’s neurologist, lamotrigine was discontinued. Within a few weeks of cessation, the scalp lesions resolved without recurrence at 9-month follow-up. In addition to the lack of clinical, histological, or immunohistochemical evidence of underlying malignancy, the temporal association of the development of lesions after starting lamotrigine and rapid resolution upon its discontinuation suggested a diagnosis of lamotrigine-induced cutaneous pseudolymphoma.
Cutaneous pseudolymphoma is a term used to describe a heterogenous group of benign reactive T-cell, B-cell, or mixed-cell lymphoproliferative processes that resemble cutaneous lymphomas clinically and/or histopathologically.1 Historically, these types of proliferations have been classified under many alternative names that originally served to describe only B-cell–type proliferations. With advances in immunohistochemistry allowing for more specific cell marker identification, cutaneous pseudolymphomas often are found to contain a mixture of T-cell and B-cell populations, which also led to identifying and describing T-cell–type pseudolymphomas.2
The clinical appearance of cutaneous pseudolymphoma is variable, ranging from discrete nodules or papules to even confluent erythroderma in certain cases.2 The high clinical variability further complicates diagnosis. Although our patient presented with 9 individual nodular lesions, this finding alone is not sufficient to have high suspicion for cutaneous pseudolymphoma without including a much broader differential diagnosis. In our case, the differential diagnosis also included cutaneous lymphoma, arthropod bite reaction, lymphomatoid papulosis, tumid lupus, follicular mucinosis, lymphocytic infiltrate of Jessner, and leukemia cutis.
The primary concern regarding diagnosis of cutaneous pseudolymphoma is the clinician’s ability to effectively differentiate this entity from a true malignant lymphoma. Immunostaining has some value by identification of heterogeneous cell–type populations with a mixed T-cell and B-cell infiltrate that is more characteristic of a benign reactive process. Subsequent polymerase chain reaction analysis can detect the presence or absence of monoclonal T-cell receptor gene rearrangement or immunoglobulin heavy chain rearrangement.3 If these monoclonal rearrangements are absent, a benign diagnosis is favored; however, these rearrangements also have been shown to exist in a case of cutaneous pseudolymphoma that earned the final diagnosis when removal of the offending agent led to spontaneous lesion regression, similar to our case.4
Many different entities have been described as causative factors for the development of cutaneous pseudolymphoma. Of those that have been considered causative, simple categories have emerged, including endogenous, exogenous, and iatrogenic causes. One potential endogenous etiology of cutaneous pseudolymphoma is IgG4-related disease.5 A multitude of exogenous causes have been reported, including several cases of cutaneous pseudolymphoma developing in a prior tattoo site.6 Viruses, specifically molluscum contagiosum, also have been implicated as exogenous causes, and a report of cutaneous pseudolymphoma development at a prior site of herpes zoster lesions has been described.7 Development of cutaneous pseudolymphoma in vaccination sites also has been reported,8 as well as more obscure inciting events such as Leishmania donovani infection and medicinal leech therapy.9
A considerable number of reported cases of cutaneous pseudolymphoma have been attributed to drugs, including monoclonal antibodies,10 herbal supplements,11 and a multitude of other medications.1 As a class, anticonvulsants are considered more likely to cause lymph node pseudolymphomas than strictly cutaneous pseudolymphomas12; however, many drugs in this class of medications have been described in the development of cutaneous pseudolymphoma.3 A review of the literature by Ploysangam et al1 revealed reports of the development of cutaneous pseudolymphomas after administration of phenytoin, carbamazepine, mephenytoin, trimethadione, phenobarbital, primidone, butabarbital, methsuximide, phensuximide, and valproic acid.
Our patient represents a rare case of strictly cutaneous pseudolymphoma caused by administration of lamotrigine. Our case demonstrated a clear temporal relation between the cessation of lamotrigine and rapid and spontaneous disappearance of cutaneous lesions. We found another case of pseudolymphoma in which lamotrigine was deemed causative, but only lymph node involvement was observed.12
Proper diagnosis of cutaneous pseudolymphoma is important not only with regard to the initial differentiation from true malignant lymphoma but in allowing for appropriate follow-up and vigilant surveillance. Cases of progression from cutaneous pseudolymphoma to true lymphoma have been reported.1,2 It is recommended that watchful follow-up for these patients be carried out until at least 5 years after the diagnosis of cutaneous pseudolymphoma is made to rule out the possibility of malignant transformation, particularly in idiopathic cases.13
- Ploysangam T, Breneman D, Mutasim D. Cutaneous pseudolymphomas. J Am Acad Dermatol. 1998;38:877-898.
- Bergman R. Pseudolymphoma and cutaneous lymphoma: facts and controversies. Clin Dermatol. 2010;28:568-574.
- Braddock S, Harrington D, Vose J. Generalized nodular cutaneous pseudolymphoma associated with phenytoin therapy. J Am Acad Dermatol. 1992;27:337-340.
- Cogrel O, Beylot-Barry M, Vergier B, et al. Sodium valproate-induced cutaneous pseudolymphoma followed by recurrence with carbamazepine. Br J Dermatol. 2001;144:1235-1238.
- Cheuk W, Lee K, Chong L, et al. IgG4-related sclerosing disease: a potential new etiology of cutaneous pseudolymphoma. Am J Surg Pathol. 2009;33:1713-1719.
- Marchesi A, Parodi P, Brioschi M, et al. Tattoo ink-related cutaneous pseudolymphomas: a rare but significant complication. case report and review of the literature. Aesthetic Plast Surg. 2014;38:471-478.
- Gonzalez J, Sanz A, Martin T, et al. Cutaneous pseudolymphoma associated with molluscum contagiosum: a case report. Int J Dermatol. 2008;47:502-504.
- Maubec E, Pinquier L, Viguier M, et al. Vaccination-induced cutaneous pseudolymphoma. J Am Acad Dermatol. 2005;52:623-629.
- Altamura D, Calonje E, Liau J, et al. Diffuse cutaneous pseudolymphoma due to therapy with medicinal leeches. JAMA Dermatol. 2014;150:783-784.
- Imafuku S, Ito K, Nakayama J. Cutaneous pseudolymphoma induced by adalimumab and reproduced by infliximab in a patient with arthopathic psoriasis. Br J Dermatol. 2011;166:675-678.
- Meyer S, Vogt T, Obermann EC, et al. Cutaneous pseudolymphoma induced by Cimicifuga racemosa. Dermatology. 2007;214:94-96.
- Pathak P, McLachlan R. Drug-induced pseudolymphoma secondary to lamotrigine. Neurology. 1998;50:1509-1510.
- Prabu V, Shivani A, Pawar V. Idiopathic cutaneous pseudolymphoma: an enigma. Indian Dermatol Online J. 2014;5:224-226.
To the Editor:
An 8-year-old girl presented with new lesions on the scalp that were mildly painful to palpation and had been increasing in size and number over the last 2 months. Her medical history was remarkable for seizures, keratosis pilaris, and seborrheic dermatitis. The seizures had been well controlled on oxcarbazepine; however, she was switched to lamotrigine 6 months prior to presentation under the care of her neurologist. The patient was not taking other oral medications, and she denied any trauma/insect bites to the affected area or systemic symptoms such as fever, fatigue, weight loss, nausea, swollen lymph nodes, or night sweats. Physical examination revealed 3 well-circumscribed, pink, slightly scaly, indurated nodules on the frontal and vertex scalp (Figure 1). She reported pain on palpation of the lesions. Treatment with ketoconazole shampoo and high-potency topical corticosteroids was ineffective.
Over a period of 2 months after the initial presentation, the patient developed a total of 9 scalp lesions. Testing was performed 4 months after presentation of lesions. Bacterial and fungal cultures of the lesional skin of the scalp were negative. Two biopsies of lesions on the scalp were performed, the first of which showed a nonspecific lymphohistiocytic infiltrate. The second biopsy revealed a dense, nodular, atypical dermal lymphoid infiltrate composed primarily of round regular lymphocytes intermixed with some larger, more irregular lymphocytes and few scattered mitoses (Figure 2).
Immunohistochemical studies revealed small B-cell lymphoma 2–positive lymphocytes with a 2:1 mixture of CD3+ T cells and CD20+CD79a+ B cells. The T cells expressed CD2, CD5, and CD43, and a subset showed a loss of CD7. The CD4:CD8 ratio was 10 to 1. No follicular dendritic networks were noted with CD21 and CD23. Rare, scattered, medium-sized CD30 cells were noted. Staining for CD10, B-cell lymphoma 6, anaplastic lymphoma kinase, Epstein-Barr virus–encoded RNA 1, IgD, and IgM were negative. The plasma cells had a κ/λ free light chain ratio of 2 to 1. Ki-67 was positive in 15% of lymphoid cells. Polymerase chain reaction analysis of T-cell receptor gene rearrangement revealed a peak at 228 bp in a predominantly polyclonal background. A thorough systemic workup including complete blood cell count, immunoglobulin assay, bone marrow transplant panel, comprehensive metabolic panel, lactate dehydrogenase test, inflammatory markers, and viral testing failed to reveal any evidence of underlying malignancy.
After conferring with the patient’s neurologist, lamotrigine was discontinued. Within a few weeks of cessation, the scalp lesions resolved without recurrence at 9-month follow-up. In addition to the lack of clinical, histological, or immunohistochemical evidence of underlying malignancy, the temporal association of the development of lesions after starting lamotrigine and rapid resolution upon its discontinuation suggested a diagnosis of lamotrigine-induced cutaneous pseudolymphoma.
Cutaneous pseudolymphoma is a term used to describe a heterogenous group of benign reactive T-cell, B-cell, or mixed-cell lymphoproliferative processes that resemble cutaneous lymphomas clinically and/or histopathologically.1 Historically, these types of proliferations have been classified under many alternative names that originally served to describe only B-cell–type proliferations. With advances in immunohistochemistry allowing for more specific cell marker identification, cutaneous pseudolymphomas often are found to contain a mixture of T-cell and B-cell populations, which also led to identifying and describing T-cell–type pseudolymphomas.2
The clinical appearance of cutaneous pseudolymphoma is variable, ranging from discrete nodules or papules to even confluent erythroderma in certain cases.2 The high clinical variability further complicates diagnosis. Although our patient presented with 9 individual nodular lesions, this finding alone is not sufficient to have high suspicion for cutaneous pseudolymphoma without including a much broader differential diagnosis. In our case, the differential diagnosis also included cutaneous lymphoma, arthropod bite reaction, lymphomatoid papulosis, tumid lupus, follicular mucinosis, lymphocytic infiltrate of Jessner, and leukemia cutis.
The primary concern regarding diagnosis of cutaneous pseudolymphoma is the clinician’s ability to effectively differentiate this entity from a true malignant lymphoma. Immunostaining has some value by identification of heterogeneous cell–type populations with a mixed T-cell and B-cell infiltrate that is more characteristic of a benign reactive process. Subsequent polymerase chain reaction analysis can detect the presence or absence of monoclonal T-cell receptor gene rearrangement or immunoglobulin heavy chain rearrangement.3 If these monoclonal rearrangements are absent, a benign diagnosis is favored; however, these rearrangements also have been shown to exist in a case of cutaneous pseudolymphoma that earned the final diagnosis when removal of the offending agent led to spontaneous lesion regression, similar to our case.4
Many different entities have been described as causative factors for the development of cutaneous pseudolymphoma. Of those that have been considered causative, simple categories have emerged, including endogenous, exogenous, and iatrogenic causes. One potential endogenous etiology of cutaneous pseudolymphoma is IgG4-related disease.5 A multitude of exogenous causes have been reported, including several cases of cutaneous pseudolymphoma developing in a prior tattoo site.6 Viruses, specifically molluscum contagiosum, also have been implicated as exogenous causes, and a report of cutaneous pseudolymphoma development at a prior site of herpes zoster lesions has been described.7 Development of cutaneous pseudolymphoma in vaccination sites also has been reported,8 as well as more obscure inciting events such as Leishmania donovani infection and medicinal leech therapy.9
A considerable number of reported cases of cutaneous pseudolymphoma have been attributed to drugs, including monoclonal antibodies,10 herbal supplements,11 and a multitude of other medications.1 As a class, anticonvulsants are considered more likely to cause lymph node pseudolymphomas than strictly cutaneous pseudolymphomas12; however, many drugs in this class of medications have been described in the development of cutaneous pseudolymphoma.3 A review of the literature by Ploysangam et al1 revealed reports of the development of cutaneous pseudolymphomas after administration of phenytoin, carbamazepine, mephenytoin, trimethadione, phenobarbital, primidone, butabarbital, methsuximide, phensuximide, and valproic acid.
Our patient represents a rare case of strictly cutaneous pseudolymphoma caused by administration of lamotrigine. Our case demonstrated a clear temporal relation between the cessation of lamotrigine and rapid and spontaneous disappearance of cutaneous lesions. We found another case of pseudolymphoma in which lamotrigine was deemed causative, but only lymph node involvement was observed.12
Proper diagnosis of cutaneous pseudolymphoma is important not only with regard to the initial differentiation from true malignant lymphoma but in allowing for appropriate follow-up and vigilant surveillance. Cases of progression from cutaneous pseudolymphoma to true lymphoma have been reported.1,2 It is recommended that watchful follow-up for these patients be carried out until at least 5 years after the diagnosis of cutaneous pseudolymphoma is made to rule out the possibility of malignant transformation, particularly in idiopathic cases.13
To the Editor:
An 8-year-old girl presented with new lesions on the scalp that were mildly painful to palpation and had been increasing in size and number over the last 2 months. Her medical history was remarkable for seizures, keratosis pilaris, and seborrheic dermatitis. The seizures had been well controlled on oxcarbazepine; however, she was switched to lamotrigine 6 months prior to presentation under the care of her neurologist. The patient was not taking other oral medications, and she denied any trauma/insect bites to the affected area or systemic symptoms such as fever, fatigue, weight loss, nausea, swollen lymph nodes, or night sweats. Physical examination revealed 3 well-circumscribed, pink, slightly scaly, indurated nodules on the frontal and vertex scalp (Figure 1). She reported pain on palpation of the lesions. Treatment with ketoconazole shampoo and high-potency topical corticosteroids was ineffective.
Over a period of 2 months after the initial presentation, the patient developed a total of 9 scalp lesions. Testing was performed 4 months after presentation of lesions. Bacterial and fungal cultures of the lesional skin of the scalp were negative. Two biopsies of lesions on the scalp were performed, the first of which showed a nonspecific lymphohistiocytic infiltrate. The second biopsy revealed a dense, nodular, atypical dermal lymphoid infiltrate composed primarily of round regular lymphocytes intermixed with some larger, more irregular lymphocytes and few scattered mitoses (Figure 2).
Immunohistochemical studies revealed small B-cell lymphoma 2–positive lymphocytes with a 2:1 mixture of CD3+ T cells and CD20+CD79a+ B cells. The T cells expressed CD2, CD5, and CD43, and a subset showed a loss of CD7. The CD4:CD8 ratio was 10 to 1. No follicular dendritic networks were noted with CD21 and CD23. Rare, scattered, medium-sized CD30 cells were noted. Staining for CD10, B-cell lymphoma 6, anaplastic lymphoma kinase, Epstein-Barr virus–encoded RNA 1, IgD, and IgM were negative. The plasma cells had a κ/λ free light chain ratio of 2 to 1. Ki-67 was positive in 15% of lymphoid cells. Polymerase chain reaction analysis of T-cell receptor gene rearrangement revealed a peak at 228 bp in a predominantly polyclonal background. A thorough systemic workup including complete blood cell count, immunoglobulin assay, bone marrow transplant panel, comprehensive metabolic panel, lactate dehydrogenase test, inflammatory markers, and viral testing failed to reveal any evidence of underlying malignancy.
After conferring with the patient’s neurologist, lamotrigine was discontinued. Within a few weeks of cessation, the scalp lesions resolved without recurrence at 9-month follow-up. In addition to the lack of clinical, histological, or immunohistochemical evidence of underlying malignancy, the temporal association of the development of lesions after starting lamotrigine and rapid resolution upon its discontinuation suggested a diagnosis of lamotrigine-induced cutaneous pseudolymphoma.
Cutaneous pseudolymphoma is a term used to describe a heterogenous group of benign reactive T-cell, B-cell, or mixed-cell lymphoproliferative processes that resemble cutaneous lymphomas clinically and/or histopathologically.1 Historically, these types of proliferations have been classified under many alternative names that originally served to describe only B-cell–type proliferations. With advances in immunohistochemistry allowing for more specific cell marker identification, cutaneous pseudolymphomas often are found to contain a mixture of T-cell and B-cell populations, which also led to identifying and describing T-cell–type pseudolymphomas.2
The clinical appearance of cutaneous pseudolymphoma is variable, ranging from discrete nodules or papules to even confluent erythroderma in certain cases.2 The high clinical variability further complicates diagnosis. Although our patient presented with 9 individual nodular lesions, this finding alone is not sufficient to have high suspicion for cutaneous pseudolymphoma without including a much broader differential diagnosis. In our case, the differential diagnosis also included cutaneous lymphoma, arthropod bite reaction, lymphomatoid papulosis, tumid lupus, follicular mucinosis, lymphocytic infiltrate of Jessner, and leukemia cutis.
The primary concern regarding diagnosis of cutaneous pseudolymphoma is the clinician’s ability to effectively differentiate this entity from a true malignant lymphoma. Immunostaining has some value by identification of heterogeneous cell–type populations with a mixed T-cell and B-cell infiltrate that is more characteristic of a benign reactive process. Subsequent polymerase chain reaction analysis can detect the presence or absence of monoclonal T-cell receptor gene rearrangement or immunoglobulin heavy chain rearrangement.3 If these monoclonal rearrangements are absent, a benign diagnosis is favored; however, these rearrangements also have been shown to exist in a case of cutaneous pseudolymphoma that earned the final diagnosis when removal of the offending agent led to spontaneous lesion regression, similar to our case.4
Many different entities have been described as causative factors for the development of cutaneous pseudolymphoma. Of those that have been considered causative, simple categories have emerged, including endogenous, exogenous, and iatrogenic causes. One potential endogenous etiology of cutaneous pseudolymphoma is IgG4-related disease.5 A multitude of exogenous causes have been reported, including several cases of cutaneous pseudolymphoma developing in a prior tattoo site.6 Viruses, specifically molluscum contagiosum, also have been implicated as exogenous causes, and a report of cutaneous pseudolymphoma development at a prior site of herpes zoster lesions has been described.7 Development of cutaneous pseudolymphoma in vaccination sites also has been reported,8 as well as more obscure inciting events such as Leishmania donovani infection and medicinal leech therapy.9
A considerable number of reported cases of cutaneous pseudolymphoma have been attributed to drugs, including monoclonal antibodies,10 herbal supplements,11 and a multitude of other medications.1 As a class, anticonvulsants are considered more likely to cause lymph node pseudolymphomas than strictly cutaneous pseudolymphomas12; however, many drugs in this class of medications have been described in the development of cutaneous pseudolymphoma.3 A review of the literature by Ploysangam et al1 revealed reports of the development of cutaneous pseudolymphomas after administration of phenytoin, carbamazepine, mephenytoin, trimethadione, phenobarbital, primidone, butabarbital, methsuximide, phensuximide, and valproic acid.
Our patient represents a rare case of strictly cutaneous pseudolymphoma caused by administration of lamotrigine. Our case demonstrated a clear temporal relation between the cessation of lamotrigine and rapid and spontaneous disappearance of cutaneous lesions. We found another case of pseudolymphoma in which lamotrigine was deemed causative, but only lymph node involvement was observed.12
Proper diagnosis of cutaneous pseudolymphoma is important not only with regard to the initial differentiation from true malignant lymphoma but in allowing for appropriate follow-up and vigilant surveillance. Cases of progression from cutaneous pseudolymphoma to true lymphoma have been reported.1,2 It is recommended that watchful follow-up for these patients be carried out until at least 5 years after the diagnosis of cutaneous pseudolymphoma is made to rule out the possibility of malignant transformation, particularly in idiopathic cases.13
- Ploysangam T, Breneman D, Mutasim D. Cutaneous pseudolymphomas. J Am Acad Dermatol. 1998;38:877-898.
- Bergman R. Pseudolymphoma and cutaneous lymphoma: facts and controversies. Clin Dermatol. 2010;28:568-574.
- Braddock S, Harrington D, Vose J. Generalized nodular cutaneous pseudolymphoma associated with phenytoin therapy. J Am Acad Dermatol. 1992;27:337-340.
- Cogrel O, Beylot-Barry M, Vergier B, et al. Sodium valproate-induced cutaneous pseudolymphoma followed by recurrence with carbamazepine. Br J Dermatol. 2001;144:1235-1238.
- Cheuk W, Lee K, Chong L, et al. IgG4-related sclerosing disease: a potential new etiology of cutaneous pseudolymphoma. Am J Surg Pathol. 2009;33:1713-1719.
- Marchesi A, Parodi P, Brioschi M, et al. Tattoo ink-related cutaneous pseudolymphomas: a rare but significant complication. case report and review of the literature. Aesthetic Plast Surg. 2014;38:471-478.
- Gonzalez J, Sanz A, Martin T, et al. Cutaneous pseudolymphoma associated with molluscum contagiosum: a case report. Int J Dermatol. 2008;47:502-504.
- Maubec E, Pinquier L, Viguier M, et al. Vaccination-induced cutaneous pseudolymphoma. J Am Acad Dermatol. 2005;52:623-629.
- Altamura D, Calonje E, Liau J, et al. Diffuse cutaneous pseudolymphoma due to therapy with medicinal leeches. JAMA Dermatol. 2014;150:783-784.
- Imafuku S, Ito K, Nakayama J. Cutaneous pseudolymphoma induced by adalimumab and reproduced by infliximab in a patient with arthopathic psoriasis. Br J Dermatol. 2011;166:675-678.
- Meyer S, Vogt T, Obermann EC, et al. Cutaneous pseudolymphoma induced by Cimicifuga racemosa. Dermatology. 2007;214:94-96.
- Pathak P, McLachlan R. Drug-induced pseudolymphoma secondary to lamotrigine. Neurology. 1998;50:1509-1510.
- Prabu V, Shivani A, Pawar V. Idiopathic cutaneous pseudolymphoma: an enigma. Indian Dermatol Online J. 2014;5:224-226.
- Ploysangam T, Breneman D, Mutasim D. Cutaneous pseudolymphomas. J Am Acad Dermatol. 1998;38:877-898.
- Bergman R. Pseudolymphoma and cutaneous lymphoma: facts and controversies. Clin Dermatol. 2010;28:568-574.
- Braddock S, Harrington D, Vose J. Generalized nodular cutaneous pseudolymphoma associated with phenytoin therapy. J Am Acad Dermatol. 1992;27:337-340.
- Cogrel O, Beylot-Barry M, Vergier B, et al. Sodium valproate-induced cutaneous pseudolymphoma followed by recurrence with carbamazepine. Br J Dermatol. 2001;144:1235-1238.
- Cheuk W, Lee K, Chong L, et al. IgG4-related sclerosing disease: a potential new etiology of cutaneous pseudolymphoma. Am J Surg Pathol. 2009;33:1713-1719.
- Marchesi A, Parodi P, Brioschi M, et al. Tattoo ink-related cutaneous pseudolymphomas: a rare but significant complication. case report and review of the literature. Aesthetic Plast Surg. 2014;38:471-478.
- Gonzalez J, Sanz A, Martin T, et al. Cutaneous pseudolymphoma associated with molluscum contagiosum: a case report. Int J Dermatol. 2008;47:502-504.
- Maubec E, Pinquier L, Viguier M, et al. Vaccination-induced cutaneous pseudolymphoma. J Am Acad Dermatol. 2005;52:623-629.
- Altamura D, Calonje E, Liau J, et al. Diffuse cutaneous pseudolymphoma due to therapy with medicinal leeches. JAMA Dermatol. 2014;150:783-784.
- Imafuku S, Ito K, Nakayama J. Cutaneous pseudolymphoma induced by adalimumab and reproduced by infliximab in a patient with arthopathic psoriasis. Br J Dermatol. 2011;166:675-678.
- Meyer S, Vogt T, Obermann EC, et al. Cutaneous pseudolymphoma induced by Cimicifuga racemosa. Dermatology. 2007;214:94-96.
- Pathak P, McLachlan R. Drug-induced pseudolymphoma secondary to lamotrigine. Neurology. 1998;50:1509-1510.
- Prabu V, Shivani A, Pawar V. Idiopathic cutaneous pseudolymphoma: an enigma. Indian Dermatol Online J. 2014;5:224-226.
Practice Points
- Cutaneous pseudolymphomas are a heterogenous group of benign T-cell, B-cell, or mixed-cell lymphoproliferative processes that resemble cutaneous lymphomas clinically and/or histopathologically.
- Cutaneous pseudolymphomas have many causative factors, including medications, infections, tattoo ink, vaccinations, and insect bites.
- Lamotrigine is a potential inciting factor of cutaneous pseudolymphoma.
CDC updates recommendation for serologic Lyme disease detection
, according to CDC investigators.
At the 1994 Second National Conference on Serologic Diagnosis of Lyme Disease, several groups and organizations convened, recommending a two-test methodology for Lyme disease detection. First, an enzyme immunoassay (EIA) or immunofluorescence assay should be used, followed by a western immunoblot assay for specimens yielding positive or equivocal results. The guideline advised that all future tests should be evaluated against a challenge panel, and that new assays should only move forward if their specificity, sensitivity, and precision equaled or surpassed the performance of tests used in the recommended two-test procedure.
On July 29, 2019, the Food and Drug Administration approved several Lyme disease serologic assays with new indications for use based on a modified two-test methodology, with a second EIA replacing the western immunoblot assay.
“Clearance by FDA of the new Lyme disease assays indicates that test performance has been evaluated and is ‘substantially equivalent to or better than’ a legally marketed predicate test,” the CDC investigators noted (MMWR Morb Mortal Wkly Rep. 2019 Aug 15;68(32):703).
The recommendation advises that FDA-cleared “serologic assays that utilize EIA rather than western immunoblot assay in a two-test format are acceptable alternatives for the laboratory diagnosis of Lyme disease.”
, according to CDC investigators.
At the 1994 Second National Conference on Serologic Diagnosis of Lyme Disease, several groups and organizations convened, recommending a two-test methodology for Lyme disease detection. First, an enzyme immunoassay (EIA) or immunofluorescence assay should be used, followed by a western immunoblot assay for specimens yielding positive or equivocal results. The guideline advised that all future tests should be evaluated against a challenge panel, and that new assays should only move forward if their specificity, sensitivity, and precision equaled or surpassed the performance of tests used in the recommended two-test procedure.
On July 29, 2019, the Food and Drug Administration approved several Lyme disease serologic assays with new indications for use based on a modified two-test methodology, with a second EIA replacing the western immunoblot assay.
“Clearance by FDA of the new Lyme disease assays indicates that test performance has been evaluated and is ‘substantially equivalent to or better than’ a legally marketed predicate test,” the CDC investigators noted (MMWR Morb Mortal Wkly Rep. 2019 Aug 15;68(32):703).
The recommendation advises that FDA-cleared “serologic assays that utilize EIA rather than western immunoblot assay in a two-test format are acceptable alternatives for the laboratory diagnosis of Lyme disease.”
, according to CDC investigators.
At the 1994 Second National Conference on Serologic Diagnosis of Lyme Disease, several groups and organizations convened, recommending a two-test methodology for Lyme disease detection. First, an enzyme immunoassay (EIA) or immunofluorescence assay should be used, followed by a western immunoblot assay for specimens yielding positive or equivocal results. The guideline advised that all future tests should be evaluated against a challenge panel, and that new assays should only move forward if their specificity, sensitivity, and precision equaled or surpassed the performance of tests used in the recommended two-test procedure.
On July 29, 2019, the Food and Drug Administration approved several Lyme disease serologic assays with new indications for use based on a modified two-test methodology, with a second EIA replacing the western immunoblot assay.
“Clearance by FDA of the new Lyme disease assays indicates that test performance has been evaluated and is ‘substantially equivalent to or better than’ a legally marketed predicate test,” the CDC investigators noted (MMWR Morb Mortal Wkly Rep. 2019 Aug 15;68(32):703).
The recommendation advises that FDA-cleared “serologic assays that utilize EIA rather than western immunoblot assay in a two-test format are acceptable alternatives for the laboratory diagnosis of Lyme disease.”
FROM THE MMWR
Heart of the Matter
During the last year, the field of psoriasis has continued to expand, with new therapies, new guidelines, and further understanding of the impact of treatment on associated comorbidities.
One of the most exciting prospects of the treatment of psoriasis with biologics is the potential for the reduction in major adverse cardiovascular events (MACEs). It has been well established that psoriasis is associated with increased cardiovascular risk.1,2 Ahlehoff et al1 conducted a cohort study of the entire Danish population 18 years and older followed from 1997 to 2006 by individual-level linkage of nationwide registers. They concluded that psoriasis is associated with increased risk for adverse cardiovascular events and all-cause mortality. Young age, severe skin affection, and/or psoriatic arthritis (PsA) carry the most risk. They suggested that patients with psoriasis may be candidates for early cardiovascular risk factor modification.1
Ogdie et al2 endeavored to quantify the risk for MACE among patients with PsA, rheumatoid arthritis (RA), and psoriasis without known PsA compared to the general population after adjusting for traditional cardiovascular risk factors. Patients with PsA (N=8706), RA (N=41,752), psoriasis (N=138,424), and unexposed controls (N=81,573) were identified. After adjustment for traditional risk factors, the risk for MACE was higher in patients with PsA not prescribed a disease-modifying antirheumatic drug (DMARD)(hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.49), patients with RA (no DMARD: HR, 1.39; 95% CI, 1.28-1.50; DMARD: HR, 1.58; 95% CI, 1.46-1.70), patients with psoriasis not prescribed a DMARD (HR, 1.08; 95% CI, 1.02-1.15), and patients with severe psoriasis (DMARD: HR, 1.42; 95% CI, 1.17-1.73).2 These data are one aspect of our increasing insight into the management of psoriasis.
To expand on the new guidelines and new therapies presented in 2019, this issue includes review articles looking at these facets. Wu and Weinberg3 review the impact of diet on psoriasis. Pithadia et al4 explain the American Academy of Dermatology and National Psoriasis Foundation guidelines of care for the management of psoriasis with biologics for the prescribing dermatologist, with an emphasis on the most clinically significant considerations during each step of treatment with biologic therapies (ie, choosing a biologic, initiating therapy, assessing treatment response, switching biologics). Havnaer et al5 provide an update on the newly approved and pipeline systemic agents for psoriasis.
We hope that you find this issue enjoyable and informative.
- Ahlehoff O, Gislason GH, Charlot M, et al. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med. 2011;270:147-157.
- Ogdie A, Yu Y, Haynes K, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis. 2015;74:326-332.
- Wu AG, Weinberg JM. The impact of diet on psoriasis. Cutis. 2019;104(suppl 2):7-10.
- Pithadia DJ, Reynolds KA, Lee EB, et al. Translating the 2019 AAD-NPF guidelines of care for the management of psoriasis with biologics to clinical practice. Cutis. 2019;104(suppl 2):12-16, 20.
- Havnaer A, Weinberg JM, Han G. Systemic therapies in psoriasis: an update on newly approved and pipeline biologics and oral treatments. Cutis. 2019;104(suppl 2):17-20.
During the last year, the field of psoriasis has continued to expand, with new therapies, new guidelines, and further understanding of the impact of treatment on associated comorbidities.
One of the most exciting prospects of the treatment of psoriasis with biologics is the potential for the reduction in major adverse cardiovascular events (MACEs). It has been well established that psoriasis is associated with increased cardiovascular risk.1,2 Ahlehoff et al1 conducted a cohort study of the entire Danish population 18 years and older followed from 1997 to 2006 by individual-level linkage of nationwide registers. They concluded that psoriasis is associated with increased risk for adverse cardiovascular events and all-cause mortality. Young age, severe skin affection, and/or psoriatic arthritis (PsA) carry the most risk. They suggested that patients with psoriasis may be candidates for early cardiovascular risk factor modification.1
Ogdie et al2 endeavored to quantify the risk for MACE among patients with PsA, rheumatoid arthritis (RA), and psoriasis without known PsA compared to the general population after adjusting for traditional cardiovascular risk factors. Patients with PsA (N=8706), RA (N=41,752), psoriasis (N=138,424), and unexposed controls (N=81,573) were identified. After adjustment for traditional risk factors, the risk for MACE was higher in patients with PsA not prescribed a disease-modifying antirheumatic drug (DMARD)(hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.49), patients with RA (no DMARD: HR, 1.39; 95% CI, 1.28-1.50; DMARD: HR, 1.58; 95% CI, 1.46-1.70), patients with psoriasis not prescribed a DMARD (HR, 1.08; 95% CI, 1.02-1.15), and patients with severe psoriasis (DMARD: HR, 1.42; 95% CI, 1.17-1.73).2 These data are one aspect of our increasing insight into the management of psoriasis.
To expand on the new guidelines and new therapies presented in 2019, this issue includes review articles looking at these facets. Wu and Weinberg3 review the impact of diet on psoriasis. Pithadia et al4 explain the American Academy of Dermatology and National Psoriasis Foundation guidelines of care for the management of psoriasis with biologics for the prescribing dermatologist, with an emphasis on the most clinically significant considerations during each step of treatment with biologic therapies (ie, choosing a biologic, initiating therapy, assessing treatment response, switching biologics). Havnaer et al5 provide an update on the newly approved and pipeline systemic agents for psoriasis.
We hope that you find this issue enjoyable and informative.
During the last year, the field of psoriasis has continued to expand, with new therapies, new guidelines, and further understanding of the impact of treatment on associated comorbidities.
One of the most exciting prospects of the treatment of psoriasis with biologics is the potential for the reduction in major adverse cardiovascular events (MACEs). It has been well established that psoriasis is associated with increased cardiovascular risk.1,2 Ahlehoff et al1 conducted a cohort study of the entire Danish population 18 years and older followed from 1997 to 2006 by individual-level linkage of nationwide registers. They concluded that psoriasis is associated with increased risk for adverse cardiovascular events and all-cause mortality. Young age, severe skin affection, and/or psoriatic arthritis (PsA) carry the most risk. They suggested that patients with psoriasis may be candidates for early cardiovascular risk factor modification.1
Ogdie et al2 endeavored to quantify the risk for MACE among patients with PsA, rheumatoid arthritis (RA), and psoriasis without known PsA compared to the general population after adjusting for traditional cardiovascular risk factors. Patients with PsA (N=8706), RA (N=41,752), psoriasis (N=138,424), and unexposed controls (N=81,573) were identified. After adjustment for traditional risk factors, the risk for MACE was higher in patients with PsA not prescribed a disease-modifying antirheumatic drug (DMARD)(hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.49), patients with RA (no DMARD: HR, 1.39; 95% CI, 1.28-1.50; DMARD: HR, 1.58; 95% CI, 1.46-1.70), patients with psoriasis not prescribed a DMARD (HR, 1.08; 95% CI, 1.02-1.15), and patients with severe psoriasis (DMARD: HR, 1.42; 95% CI, 1.17-1.73).2 These data are one aspect of our increasing insight into the management of psoriasis.
To expand on the new guidelines and new therapies presented in 2019, this issue includes review articles looking at these facets. Wu and Weinberg3 review the impact of diet on psoriasis. Pithadia et al4 explain the American Academy of Dermatology and National Psoriasis Foundation guidelines of care for the management of psoriasis with biologics for the prescribing dermatologist, with an emphasis on the most clinically significant considerations during each step of treatment with biologic therapies (ie, choosing a biologic, initiating therapy, assessing treatment response, switching biologics). Havnaer et al5 provide an update on the newly approved and pipeline systemic agents for psoriasis.
We hope that you find this issue enjoyable and informative.
- Ahlehoff O, Gislason GH, Charlot M, et al. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med. 2011;270:147-157.
- Ogdie A, Yu Y, Haynes K, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis. 2015;74:326-332.
- Wu AG, Weinberg JM. The impact of diet on psoriasis. Cutis. 2019;104(suppl 2):7-10.
- Pithadia DJ, Reynolds KA, Lee EB, et al. Translating the 2019 AAD-NPF guidelines of care for the management of psoriasis with biologics to clinical practice. Cutis. 2019;104(suppl 2):12-16, 20.
- Havnaer A, Weinberg JM, Han G. Systemic therapies in psoriasis: an update on newly approved and pipeline biologics and oral treatments. Cutis. 2019;104(suppl 2):17-20.
- Ahlehoff O, Gislason GH, Charlot M, et al. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med. 2011;270:147-157.
- Ogdie A, Yu Y, Haynes K, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis. 2015;74:326-332.
- Wu AG, Weinberg JM. The impact of diet on psoriasis. Cutis. 2019;104(suppl 2):7-10.
- Pithadia DJ, Reynolds KA, Lee EB, et al. Translating the 2019 AAD-NPF guidelines of care for the management of psoriasis with biologics to clinical practice. Cutis. 2019;104(suppl 2):12-16, 20.
- Havnaer A, Weinberg JM, Han G. Systemic therapies in psoriasis: an update on newly approved and pipeline biologics and oral treatments. Cutis. 2019;104(suppl 2):17-20.
The Impact of Diet on Psoriasis
Psoriasis is a chronic cutaneous disease associated with immune-mediated inflammation. The disease has a complex etiology, with factors such as genetics, smoking, alcohol use, diet, and stress all believed to be implicated in its appearance and severity. Specific factors, including increased body mass index and weight gain, have been associated with a higher prevalence of psoriasis and are risk factors for the disease. Because psoriasis varies in severity and incidence, patients often can experience a substantial negative impact on their quality of life, with increased incidences of anxiety and depression.1 Because diet is an accessible and controllable variable, many patients choose to alter their diets to help relieve symptoms of the disease. This article aims to review and summarize the existing literature for possible relationships and correlations between diet and psoriasis.
Because diet is a factor contributing to psoriasis, it is a lifestyle change that patients often make. In a 2017 survey of 1206 patients with psoriasis, 86% reported modifying their diets.2 Furthermore, when patients were compared with control individuals of the same sex and of similar age, it was shown that those with psoriasis consumed statistically significant lower amounts of sugar, whole-grain fiber, dairy products, and calcium (P<.001). The survey also found that patient diets included significantly more fruits, vegetables, and legumes (P<.01). Although no single diet was adhered to by patients, 40% did report attempting a specialized diet to improve their psoriasis. The most common diets were gluten free (35.6%), low carbohydrate/high protein (16.6%), and Paleolithic (11.6%). In addition to these diets, the Mediterranean diet and a vegetarian diet were both among those reported to improve psoriatic symptoms. Finally, certain foods stood out as more frequently reported to affect symptoms, particularly fish oil, fruits, vegetables, and water, which were all reported by at least 10% of respondents to positively affect their psoriasis. Reductions in consumption of alcohol, gluten, nightshades, and junk foods were associated with skin improvements in at least 50% of patients.2 These baseline differences in diet informed our search of the literature and showed that dietary changes can serve as an important adjunct to treatment for many patients.
Mediterranean Diet
The Mediterranean diet consists of a high amount of fruits, vegetables, nuts and legumes, cereals, and olive oil, while restricting consumption of red meats, dairy products, and alcohol (besides red wine) at meals.3 Adherence to the diet has been associated with a reduced risk for cardiovascular diseases,4 rheumatoid arthritis, and Crohn disease,3 among others, possibly because the diet contains a high proportion and variety of foods that contain antioxidants and anti-inflammatory compounds, including the monounsaturated fatty acids (MUFAs) in olive oil and the polyphenols in fruits and vegetables. Consumption of both MUFAs and highly anti-inflammatory nutrients has been associated with reduced prevalence of risk factors for chronic inflammatory diseases, and consumption levels of MUFAs in particular have been reported to be a predictive factor in psoriasis severity.3
Recent studies have tried to quantify an association between consumption of the Mediterranean diet and psoriasis. One cross-sectional study in 2015 evaluated 62 patients with psoriasis for their adherence to the Mediterranean diet and psoriasis severity.4 Utilizing a 14-question evaluation, the study found that patients with a higher severity of psoriasis, as evaluated by a psoriasis area and severity index (PASI) score and C-reactive protein levels, had a lower adherence to the diet. Notably, consumption of extra-virgin olive oil was found to be an independent predictor of PASI score, and consumption of fish was an independent predictor of C-reactive protein levels.4
A second cross-sectional questionnaire study found similar results in a larger population of 3557 patients. The same association between patients with severe psoriasis and low levels of adherence to the Mediterranean diet was reported.3 Although neither study showed a causal relationship between the diet and psoriasis severity, both did report the potential impacts of proinflammatory and anti-inflammatory foods. General foods and nutrients listed by the studies as having anti-inflammatory properties include MUFAs; fish; vitamins A, C, D, and E; and omega-3 fatty acids.3 Because of the large number of confounding factors in dietary studies that rely on questionnaires, it is hard to definitively label the Mediterranean diet as beneficial topsoriasis. However, individual components of the diet may be used as predictors of psoriasis severity, and the diet itself may be used in tandem with other treatments for psoriasis.
Gluten-Free Diet
Celiac disease is an inflammatory enteropathy caused by an immune reaction to the protein gliadin, which is found in foods containing gluten, such as wheat.5 Immune system assault on the intestinal enterocytes leads to the stripping away of villi, negatively affecting nutrient absorption. Multiple studies have reported an association between having psoriasis and having celiac disease as well as the reverse, including a 3-fold increased risk of celiac disease for patients with psoriasis in a 2017 meta-analysis.6 Even if patients with psoriasis did not have celiac disease, studies have found that a notable percentage of patients with psoriasis have elevated antigliadin IgA antibody levels.7 Many hypotheses have been proposed to explain this association. One article suggested that the malabsorption associated with celiac disease predisposes patients to vitamin D deficiency, which is a contributing risk factor for psoriasis.8 Other explanations involve common immune cells involved in the response to both diseases and a shared genetic background between the 2 diseases.8 As a gluten-free diet is standard for patients with celiac disease, it stands to reason that IgA could be used as a serum biomarker for patients who also could see improvements by adopting the diet.
This result could help explain the proportion of respondents to the 2017 survey who experienced improvements to their psoriasis if the gluten-free diet was in fact not triggering the inflammatory effects that a regular diet would, which also may help to explain the mixed results that the gluten-free diet has had as a treatment for psoriasis. One 3-month study of patients who were positive for antigliadin antibodies found that the majority (82%) experienced a decrease in antibody levels and affected skin area after following a gluten-free diet. Only half the patients had been diagnosed with celiac disease prior to the study, lending credibility to the idea that antigliadin antibody could be used as a marker for patients with psoriasis who would benefit from a gluten-free diet.9 Other case studies have reported no improvement of psoriasis following implementation of a gluten-free diet,10 despite the patients having elevated gliadin antibodies or celiac disease. More studies are required to discern the exact nature of the benefits of a gluten-free diet on psoriasis; however, it does serve as a promising option for patients with both psoriasis and celiac disease.
Ketogenic Diet
As obesity and weight gain are factors associated with psoriasis, some patients turn to diets that restrict calories with the goal of losing weight to improve their symptoms. One 2015 case report studied a patient who restored her response to systemic treatment of psoriasis following an intensive 4-week, calorie-restricted ketogenic diet.11 The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet. Animal studies have shown the diet to have anti-inflammatory effects, including lowering levels of proinflammatory cytokines and reduced fever.12 In the 2015 case report, the rapid and consistent weight loss experienced by the patient because of the ketogenic diet was thought to be the cause of the restoration of treatment effectiveness,11 which is interesting, since the role of the ketogenic diet was not to supplement any deficiencies but to move the patient to a physiologic state that was once again receptive to treatment. This finding suggests that a variety of diets could improve psoriasis symptoms, so long as they do not cause inflammation or reduce overall body mass. One study of patients on a calorie-restricted diet over 8 weeks did see a trend of patients on the diet showing improvement in both their PASI scores and Dermatology Life Quality Index, though the improvement was not statistically significant.13 To determine if the ketogenic diet has a significant association with psoriasis improvement, controlled, large-population studies should be performed in the future with age, sex, and weight-matched controls, which may be difficult to do. Further studies looking at the association between weight loss and psoriasis also could be another direction.
Vegetarian Diet
Both vegetarian and vegan diets have been evaluated for their efficacy in relieving symptoms of chronic inflammatory disorders. Although the 2 diets are similar in avoiding consumption of meat, fish, and poultry, vegan diets often have additional food restrictions, including avoiding eggs, honey, and dairy products. One study noted the impact of these diets on patients with a variety of skin conditions following a period of fasting. It was observed that some patients with psoriasis saw an improvement in their symptoms during the period when they were eating a vegetarian or vegan diet, which was attributed to a return to normal levels of activity of neutrophils, extrapolated from serum levels of lactoferrin.14 Vegetarian diets have been shown to be associated with higher ratios of anti-inflammatory to proinflammatory adipokines compared to omnivorous diets,15 as well as lower expression levels of proinflammatory genes in the gut microbiota and lower expression levels of IgE.16 Perhaps the anti-inflammatory impacts of the diet affected the symptoms of psoriasis. The benefits of a vegetarian diet also have been attributed to the high amount of potassium consumed,17 which is used in the body to synthesize cortisol, a common treatment for psoriasis. Potassium supplementation has been shown to raise serum cortisol levels in patients.6 Although additional studies are needed to discern the significance of potassium in the vegetarian diet, both hypotheses are reasonable explanations for the observations seen in these studies.
Vitamin D and Other Nutritional Supplements
Because it is not always feasible for patients to alter their diets, many have turned to dietary supplements as an alternative method of treatment and lifestyle change. Two of the more prominently represented nutritional additives in the literature are fish oils and vitamin D.18 Supplemental vitamin D is a prohormone that can be endogenously converted to its active 1,25-dihydroxyvitamin D.19 Vitamin D plays important roles in the regulation of calcium and magnesium in the bones as well as the maturation and differentiation of keratinocytes in the skin.16 Topical vitamin D analogues are standard treatments for psoriasis, as they are used to modulate the immune system to great effect.20 Some patients with psoriasis present with vitamin D insufficiency,21 and it stands to reason that oral supplementation may be a treatment option. There have been multiple studies assessing the efficacy of oral vitamin D for the treatment of psoriasis; however, in the only randomized and placebo-controlled trial, there was only a slight nonsignificant improvement in the group supplemented with vitamin D.20 Another small, open-label study reported remarkably improved PASI scores in 9 vitamin D–supplemented, dietary calcium–restricted patients.22 The lack of recent, large-sample studies makes it hard to draw notable conclusions from these studies.
The polyunsaturated fatty acids found in fish oils also have been considered as a treatment option for psoriasis.23 Millsop et al20 conducted an analysis of the literature reviewing the efficacy of fish oil in the treatment of psoriasis. Twelve of 15 compiled trials showed an improvement in psoriasis, ranging from slight improvements from baseline levels of the disease to statistically significant decreases in PASI scores (P<.05). It is notable that the amount of fish oil given in these studies varied widely, but the amount given did not necessarily correlate with strength of impact.20 For example, Mayser et al,24 Bittiner et al,25 and Grimminger et al26 each performed prospective, double-blind studies with
Studies also have shown little to no improvement in the use of fish oil to treat psoriasis. One such study was conducted by Soyland et al27 in 1993 in Norway. Utilizing a prospective, double-blind, placebo-controlled design over 4 months on 145 patients with moderate to severe psoriasis, researchers evaluated the treatment effectiveness via PASI scores; subjective reports from the patients; clinical manifestations; and factors such as cellular infiltration, desquamation, and redness. The results were mixed, with the placebo (corn oil) group having less redness and cellular desquamation and the fish oil group showing less cellular infiltration. In the other categories, there was no significant difference between the 2 groups, and researchers concluded there was no significant benefit to treating psoriasis using fish oil vs corn oil.27 As with many of the other diets, there have been no recent, large-scale studies performed on the effect of fish oil supplementation on psoriasis; however, of the studies we reviewed, none showed fish oil supplementation to have a significant negative impact on psoriasis.
Conclusion
Dietary modifications have a complex multifactorial effect on psoriasis, often dependent on the variations of psoriasis and the lifestyle of the patient, including level of exercise, activities such as smoking and drinking, and genetic susceptibilities to conditions such as obesity. Thus, it is difficult for one diet to have a significant impact on psoriasis symptoms that applies to the majority of individuals. However, it appears that certain foods or nutritional supplements can be modified from all diets for general improvement. Foods with systemic anti-inflammatory effects, such as olive oil and fish oil, seem to be beneficial in treating psoriasis. As an extension, a gluten-free diet may help psoriasis patients with celiac disease by reducing the inflammatory environment of the body. On the opposite side of the spectrum, proinflammatory foods such as dietary fat and alcohol should be avoided.28
In general, larger and more recent population-based studies are needed to add to the literature on this subject. Nationwide voluntary web-based surveys such as the NutriNet-Santé study in France may be one way to quickly amass large quantities of data (ClinicalTrials.gov Identifier NCT03335644). Participants are recruited through multimedia campaigns and return online questionnaires annually for 1 decade. A subset of participants also contributes biologic samples and participates in clinical examinations. This type of data gathering would capture many variables, provide a large sample size, and perhaps shed light on regional differences in diet and lifestyle that could then be targeted with treatments.
- Madrid Álvarez MB, Carretero Hernández G, González Quesada A, et al. Measurement of the psychological impact of psoriasis on patients receiving systemic treatment. Actas Dermosifiliogr (English edition). 2018;109:733-740.
- Afifi L, Danesh MJ, Lee KM, et al. Dietary behaviors in psoriasis: patient-reported outcomes from a U.S. national survey. Dermatol Ther (Heidelb). 2017;7:227-242.
- Phan C, Touvier M, Kesse-Guyot E, et al. Association between Mediterranean anti-inflammatory dietary profile and severity of psoriasis: results from the NutriNet-Santé cohort. JAMA Dermatol. 2018;154:1017-1024.
- Barrea L, Balato N, Di Somma C, et al. Nutrition and psoriasis: is there any association between the severity of the disease and adherence to the Mediterranean diet? J Transl Med. 2015;13:18.
- Bhatia BK, Millsop JW, Debbaneh M, et al. Diet and psoriasis, part II: celiac disease and role of a gluten-free diet. J Am Acad Dermatol. 2014;71:350-358.
- Ungprasert P, Wijarnpreecha K, Kittanamongkolchai W. Psoriasis and risk of celiac disease: a systematic review and meta-analysis. Indian J Dermatol. 2017;62:41-46.
- Kolchak NA, Tetarnikova MK, Theodoropoulou MS, et al. Prevalence of antigliadin IgA antibodies in psoriasis vulgaris and response of seropositive patients to a gluten-free diet. J Multidiscip Healthc. 2017;11:13-19.
- Ludvigsson JF, Lindelöf B, Zingone F, et al. Psoriasis in a nationwide cohort study of patients with celiac disease. J Invest Dermatol. 2011;131:2010-2016.
- De Bastiani R, Gabrielli M, Lora L, et al. Association between coeliac disease and psoriasis: Italian primary care multicentre study. Dermatology. 2015;230:156-160.
- Pietrzak D, Pietrzak A, Krasowska D, et al. Digestive system in psoriasis: an update. Arch Dermatol Res. 2017;309:679-693.
- Castaldo G, Galdo G, Rotondi Aufiero F, et al. Very low-calorie ketogenic diet may allow restoring response to systemic therapy in relapsing plaque psoriasis [published online November 11, 2015]. Obes Res Clin Pract. 2016;10:348-352.
- Dupuis N, Curatolo N, Benoist J-F, et al. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia. 2015;56:e95-e98.
- Jensen P, Zachariae C, Christensen R, et al. Effect of weight loss on the severity of psoriasis: a randomized clinical study. JAMA Dermatol. 2013;149:795-801.
- Lithell H, Bruce A, Gustafsson IB, et al. A fasting and vegetarian diet treatment trial on chronic inflammatory disorders. Acta Derm Venereol. 1983;63:397-403.
- Ambroszkiewicz J, Chełchowska M, Rowicka G, et al. Anti-inflammatory and pro-inflammatory adipokine profiles in children on vegetarian and omnivorous diets. Nutrients. 2018;10;pii E1241.
- Rastmanesh R. Psoriasis and vegetarian diets: a role for cortisol and potassium? Med Hypotheses. 2009;72:368.
- Zhang C, Björkman A, Cai K, et al. Impact of a 3-months vegetarian diet on the gut microbiota and immune repertoire. Front Immunol. 2018;9:908.
- Wolters M. Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol. 2005;153:706-714.
- Zuccotti E, Oliveri M, Girometta C, et al. Nutritional strategies for psoriasis: current scientific evidence in clinical trials. Eur Rev Med Pharmacol Sci. 2018;22:8537-8551.
- Millsop JW, Bhatia BK, Debbaneh M, et al. Diet and psoriasis: part 3. role of nutritional supplements. J Am Acad Dermatol. 2014;71:561-569.
- El-Moaty Zaher HA, El-Komy MHM, Hegazy RA, et al. Assessment of interleukin-17 and vitamin D serum levels in psoriatic patients. J Am Acad Dermatol. 2013;69:840-842.
- Finamor DC, Sinigaglia-Coimbra R, Neves LCM, et al. A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Dermatoendocrinol. 2013;5:222-234.
- Pona A, Haidari W, Kolli SS, et al. Diet and psoriasis. Dermatol Online J. 2019;25. https://escholarship.org/uc/item/1p37435s. Accessed April 14, 2019.
- Mayser P, Mrowietz U, Arenberger P, et al. ω-3 fatty acid–based lipid infusion in patients with chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, multicenter trial. J Am Acad Dermatol. 1998;38:539-547.
- Bittiner SB, Tucker WF, Cartwright I, et al. A double-blind, randomised, placebo-controlled trial of fish oil in psoriasis. Lancet. 1988;1:378-380.
- Grimminger F, Mayser P, Papavassilis C, et al. A double-blind, randomized, placebo-controlled trial of n-3 fatty acid based lipid infusion in acute, extended guttate psoriasis: rapid improvement of clinical manifestations and changes in neutrophil leukotriene profile. Clin Investig. 1993;71:634-643.
- Soyland E, Funk J, Rajka G, et al. Effect of dietary supplementation with very-long-chain n-3 fatty acids in patients with psoriasis. N Engl J Med. 1993;328:1812-1816.
- Cunningham E. Is there research to support a specific diet for psoriasis? J Acad Nutr Diet. 2014;114:508.
Psoriasis is a chronic cutaneous disease associated with immune-mediated inflammation. The disease has a complex etiology, with factors such as genetics, smoking, alcohol use, diet, and stress all believed to be implicated in its appearance and severity. Specific factors, including increased body mass index and weight gain, have been associated with a higher prevalence of psoriasis and are risk factors for the disease. Because psoriasis varies in severity and incidence, patients often can experience a substantial negative impact on their quality of life, with increased incidences of anxiety and depression.1 Because diet is an accessible and controllable variable, many patients choose to alter their diets to help relieve symptoms of the disease. This article aims to review and summarize the existing literature for possible relationships and correlations between diet and psoriasis.
Because diet is a factor contributing to psoriasis, it is a lifestyle change that patients often make. In a 2017 survey of 1206 patients with psoriasis, 86% reported modifying their diets.2 Furthermore, when patients were compared with control individuals of the same sex and of similar age, it was shown that those with psoriasis consumed statistically significant lower amounts of sugar, whole-grain fiber, dairy products, and calcium (P<.001). The survey also found that patient diets included significantly more fruits, vegetables, and legumes (P<.01). Although no single diet was adhered to by patients, 40% did report attempting a specialized diet to improve their psoriasis. The most common diets were gluten free (35.6%), low carbohydrate/high protein (16.6%), and Paleolithic (11.6%). In addition to these diets, the Mediterranean diet and a vegetarian diet were both among those reported to improve psoriatic symptoms. Finally, certain foods stood out as more frequently reported to affect symptoms, particularly fish oil, fruits, vegetables, and water, which were all reported by at least 10% of respondents to positively affect their psoriasis. Reductions in consumption of alcohol, gluten, nightshades, and junk foods were associated with skin improvements in at least 50% of patients.2 These baseline differences in diet informed our search of the literature and showed that dietary changes can serve as an important adjunct to treatment for many patients.
Mediterranean Diet
The Mediterranean diet consists of a high amount of fruits, vegetables, nuts and legumes, cereals, and olive oil, while restricting consumption of red meats, dairy products, and alcohol (besides red wine) at meals.3 Adherence to the diet has been associated with a reduced risk for cardiovascular diseases,4 rheumatoid arthritis, and Crohn disease,3 among others, possibly because the diet contains a high proportion and variety of foods that contain antioxidants and anti-inflammatory compounds, including the monounsaturated fatty acids (MUFAs) in olive oil and the polyphenols in fruits and vegetables. Consumption of both MUFAs and highly anti-inflammatory nutrients has been associated with reduced prevalence of risk factors for chronic inflammatory diseases, and consumption levels of MUFAs in particular have been reported to be a predictive factor in psoriasis severity.3
Recent studies have tried to quantify an association between consumption of the Mediterranean diet and psoriasis. One cross-sectional study in 2015 evaluated 62 patients with psoriasis for their adherence to the Mediterranean diet and psoriasis severity.4 Utilizing a 14-question evaluation, the study found that patients with a higher severity of psoriasis, as evaluated by a psoriasis area and severity index (PASI) score and C-reactive protein levels, had a lower adherence to the diet. Notably, consumption of extra-virgin olive oil was found to be an independent predictor of PASI score, and consumption of fish was an independent predictor of C-reactive protein levels.4
A second cross-sectional questionnaire study found similar results in a larger population of 3557 patients. The same association between patients with severe psoriasis and low levels of adherence to the Mediterranean diet was reported.3 Although neither study showed a causal relationship between the diet and psoriasis severity, both did report the potential impacts of proinflammatory and anti-inflammatory foods. General foods and nutrients listed by the studies as having anti-inflammatory properties include MUFAs; fish; vitamins A, C, D, and E; and omega-3 fatty acids.3 Because of the large number of confounding factors in dietary studies that rely on questionnaires, it is hard to definitively label the Mediterranean diet as beneficial topsoriasis. However, individual components of the diet may be used as predictors of psoriasis severity, and the diet itself may be used in tandem with other treatments for psoriasis.
Gluten-Free Diet
Celiac disease is an inflammatory enteropathy caused by an immune reaction to the protein gliadin, which is found in foods containing gluten, such as wheat.5 Immune system assault on the intestinal enterocytes leads to the stripping away of villi, negatively affecting nutrient absorption. Multiple studies have reported an association between having psoriasis and having celiac disease as well as the reverse, including a 3-fold increased risk of celiac disease for patients with psoriasis in a 2017 meta-analysis.6 Even if patients with psoriasis did not have celiac disease, studies have found that a notable percentage of patients with psoriasis have elevated antigliadin IgA antibody levels.7 Many hypotheses have been proposed to explain this association. One article suggested that the malabsorption associated with celiac disease predisposes patients to vitamin D deficiency, which is a contributing risk factor for psoriasis.8 Other explanations involve common immune cells involved in the response to both diseases and a shared genetic background between the 2 diseases.8 As a gluten-free diet is standard for patients with celiac disease, it stands to reason that IgA could be used as a serum biomarker for patients who also could see improvements by adopting the diet.
This result could help explain the proportion of respondents to the 2017 survey who experienced improvements to their psoriasis if the gluten-free diet was in fact not triggering the inflammatory effects that a regular diet would, which also may help to explain the mixed results that the gluten-free diet has had as a treatment for psoriasis. One 3-month study of patients who were positive for antigliadin antibodies found that the majority (82%) experienced a decrease in antibody levels and affected skin area after following a gluten-free diet. Only half the patients had been diagnosed with celiac disease prior to the study, lending credibility to the idea that antigliadin antibody could be used as a marker for patients with psoriasis who would benefit from a gluten-free diet.9 Other case studies have reported no improvement of psoriasis following implementation of a gluten-free diet,10 despite the patients having elevated gliadin antibodies or celiac disease. More studies are required to discern the exact nature of the benefits of a gluten-free diet on psoriasis; however, it does serve as a promising option for patients with both psoriasis and celiac disease.
Ketogenic Diet
As obesity and weight gain are factors associated with psoriasis, some patients turn to diets that restrict calories with the goal of losing weight to improve their symptoms. One 2015 case report studied a patient who restored her response to systemic treatment of psoriasis following an intensive 4-week, calorie-restricted ketogenic diet.11 The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet. Animal studies have shown the diet to have anti-inflammatory effects, including lowering levels of proinflammatory cytokines and reduced fever.12 In the 2015 case report, the rapid and consistent weight loss experienced by the patient because of the ketogenic diet was thought to be the cause of the restoration of treatment effectiveness,11 which is interesting, since the role of the ketogenic diet was not to supplement any deficiencies but to move the patient to a physiologic state that was once again receptive to treatment. This finding suggests that a variety of diets could improve psoriasis symptoms, so long as they do not cause inflammation or reduce overall body mass. One study of patients on a calorie-restricted diet over 8 weeks did see a trend of patients on the diet showing improvement in both their PASI scores and Dermatology Life Quality Index, though the improvement was not statistically significant.13 To determine if the ketogenic diet has a significant association with psoriasis improvement, controlled, large-population studies should be performed in the future with age, sex, and weight-matched controls, which may be difficult to do. Further studies looking at the association between weight loss and psoriasis also could be another direction.
Vegetarian Diet
Both vegetarian and vegan diets have been evaluated for their efficacy in relieving symptoms of chronic inflammatory disorders. Although the 2 diets are similar in avoiding consumption of meat, fish, and poultry, vegan diets often have additional food restrictions, including avoiding eggs, honey, and dairy products. One study noted the impact of these diets on patients with a variety of skin conditions following a period of fasting. It was observed that some patients with psoriasis saw an improvement in their symptoms during the period when they were eating a vegetarian or vegan diet, which was attributed to a return to normal levels of activity of neutrophils, extrapolated from serum levels of lactoferrin.14 Vegetarian diets have been shown to be associated with higher ratios of anti-inflammatory to proinflammatory adipokines compared to omnivorous diets,15 as well as lower expression levels of proinflammatory genes in the gut microbiota and lower expression levels of IgE.16 Perhaps the anti-inflammatory impacts of the diet affected the symptoms of psoriasis. The benefits of a vegetarian diet also have been attributed to the high amount of potassium consumed,17 which is used in the body to synthesize cortisol, a common treatment for psoriasis. Potassium supplementation has been shown to raise serum cortisol levels in patients.6 Although additional studies are needed to discern the significance of potassium in the vegetarian diet, both hypotheses are reasonable explanations for the observations seen in these studies.
Vitamin D and Other Nutritional Supplements
Because it is not always feasible for patients to alter their diets, many have turned to dietary supplements as an alternative method of treatment and lifestyle change. Two of the more prominently represented nutritional additives in the literature are fish oils and vitamin D.18 Supplemental vitamin D is a prohormone that can be endogenously converted to its active 1,25-dihydroxyvitamin D.19 Vitamin D plays important roles in the regulation of calcium and magnesium in the bones as well as the maturation and differentiation of keratinocytes in the skin.16 Topical vitamin D analogues are standard treatments for psoriasis, as they are used to modulate the immune system to great effect.20 Some patients with psoriasis present with vitamin D insufficiency,21 and it stands to reason that oral supplementation may be a treatment option. There have been multiple studies assessing the efficacy of oral vitamin D for the treatment of psoriasis; however, in the only randomized and placebo-controlled trial, there was only a slight nonsignificant improvement in the group supplemented with vitamin D.20 Another small, open-label study reported remarkably improved PASI scores in 9 vitamin D–supplemented, dietary calcium–restricted patients.22 The lack of recent, large-sample studies makes it hard to draw notable conclusions from these studies.
The polyunsaturated fatty acids found in fish oils also have been considered as a treatment option for psoriasis.23 Millsop et al20 conducted an analysis of the literature reviewing the efficacy of fish oil in the treatment of psoriasis. Twelve of 15 compiled trials showed an improvement in psoriasis, ranging from slight improvements from baseline levels of the disease to statistically significant decreases in PASI scores (P<.05). It is notable that the amount of fish oil given in these studies varied widely, but the amount given did not necessarily correlate with strength of impact.20 For example, Mayser et al,24 Bittiner et al,25 and Grimminger et al26 each performed prospective, double-blind studies with
Studies also have shown little to no improvement in the use of fish oil to treat psoriasis. One such study was conducted by Soyland et al27 in 1993 in Norway. Utilizing a prospective, double-blind, placebo-controlled design over 4 months on 145 patients with moderate to severe psoriasis, researchers evaluated the treatment effectiveness via PASI scores; subjective reports from the patients; clinical manifestations; and factors such as cellular infiltration, desquamation, and redness. The results were mixed, with the placebo (corn oil) group having less redness and cellular desquamation and the fish oil group showing less cellular infiltration. In the other categories, there was no significant difference between the 2 groups, and researchers concluded there was no significant benefit to treating psoriasis using fish oil vs corn oil.27 As with many of the other diets, there have been no recent, large-scale studies performed on the effect of fish oil supplementation on psoriasis; however, of the studies we reviewed, none showed fish oil supplementation to have a significant negative impact on psoriasis.
Conclusion
Dietary modifications have a complex multifactorial effect on psoriasis, often dependent on the variations of psoriasis and the lifestyle of the patient, including level of exercise, activities such as smoking and drinking, and genetic susceptibilities to conditions such as obesity. Thus, it is difficult for one diet to have a significant impact on psoriasis symptoms that applies to the majority of individuals. However, it appears that certain foods or nutritional supplements can be modified from all diets for general improvement. Foods with systemic anti-inflammatory effects, such as olive oil and fish oil, seem to be beneficial in treating psoriasis. As an extension, a gluten-free diet may help psoriasis patients with celiac disease by reducing the inflammatory environment of the body. On the opposite side of the spectrum, proinflammatory foods such as dietary fat and alcohol should be avoided.28
In general, larger and more recent population-based studies are needed to add to the literature on this subject. Nationwide voluntary web-based surveys such as the NutriNet-Santé study in France may be one way to quickly amass large quantities of data (ClinicalTrials.gov Identifier NCT03335644). Participants are recruited through multimedia campaigns and return online questionnaires annually for 1 decade. A subset of participants also contributes biologic samples and participates in clinical examinations. This type of data gathering would capture many variables, provide a large sample size, and perhaps shed light on regional differences in diet and lifestyle that could then be targeted with treatments.
Psoriasis is a chronic cutaneous disease associated with immune-mediated inflammation. The disease has a complex etiology, with factors such as genetics, smoking, alcohol use, diet, and stress all believed to be implicated in its appearance and severity. Specific factors, including increased body mass index and weight gain, have been associated with a higher prevalence of psoriasis and are risk factors for the disease. Because psoriasis varies in severity and incidence, patients often can experience a substantial negative impact on their quality of life, with increased incidences of anxiety and depression.1 Because diet is an accessible and controllable variable, many patients choose to alter their diets to help relieve symptoms of the disease. This article aims to review and summarize the existing literature for possible relationships and correlations between diet and psoriasis.
Because diet is a factor contributing to psoriasis, it is a lifestyle change that patients often make. In a 2017 survey of 1206 patients with psoriasis, 86% reported modifying their diets.2 Furthermore, when patients were compared with control individuals of the same sex and of similar age, it was shown that those with psoriasis consumed statistically significant lower amounts of sugar, whole-grain fiber, dairy products, and calcium (P<.001). The survey also found that patient diets included significantly more fruits, vegetables, and legumes (P<.01). Although no single diet was adhered to by patients, 40% did report attempting a specialized diet to improve their psoriasis. The most common diets were gluten free (35.6%), low carbohydrate/high protein (16.6%), and Paleolithic (11.6%). In addition to these diets, the Mediterranean diet and a vegetarian diet were both among those reported to improve psoriatic symptoms. Finally, certain foods stood out as more frequently reported to affect symptoms, particularly fish oil, fruits, vegetables, and water, which were all reported by at least 10% of respondents to positively affect their psoriasis. Reductions in consumption of alcohol, gluten, nightshades, and junk foods were associated with skin improvements in at least 50% of patients.2 These baseline differences in diet informed our search of the literature and showed that dietary changes can serve as an important adjunct to treatment for many patients.
Mediterranean Diet
The Mediterranean diet consists of a high amount of fruits, vegetables, nuts and legumes, cereals, and olive oil, while restricting consumption of red meats, dairy products, and alcohol (besides red wine) at meals.3 Adherence to the diet has been associated with a reduced risk for cardiovascular diseases,4 rheumatoid arthritis, and Crohn disease,3 among others, possibly because the diet contains a high proportion and variety of foods that contain antioxidants and anti-inflammatory compounds, including the monounsaturated fatty acids (MUFAs) in olive oil and the polyphenols in fruits and vegetables. Consumption of both MUFAs and highly anti-inflammatory nutrients has been associated with reduced prevalence of risk factors for chronic inflammatory diseases, and consumption levels of MUFAs in particular have been reported to be a predictive factor in psoriasis severity.3
Recent studies have tried to quantify an association between consumption of the Mediterranean diet and psoriasis. One cross-sectional study in 2015 evaluated 62 patients with psoriasis for their adherence to the Mediterranean diet and psoriasis severity.4 Utilizing a 14-question evaluation, the study found that patients with a higher severity of psoriasis, as evaluated by a psoriasis area and severity index (PASI) score and C-reactive protein levels, had a lower adherence to the diet. Notably, consumption of extra-virgin olive oil was found to be an independent predictor of PASI score, and consumption of fish was an independent predictor of C-reactive protein levels.4
A second cross-sectional questionnaire study found similar results in a larger population of 3557 patients. The same association between patients with severe psoriasis and low levels of adherence to the Mediterranean diet was reported.3 Although neither study showed a causal relationship between the diet and psoriasis severity, both did report the potential impacts of proinflammatory and anti-inflammatory foods. General foods and nutrients listed by the studies as having anti-inflammatory properties include MUFAs; fish; vitamins A, C, D, and E; and omega-3 fatty acids.3 Because of the large number of confounding factors in dietary studies that rely on questionnaires, it is hard to definitively label the Mediterranean diet as beneficial topsoriasis. However, individual components of the diet may be used as predictors of psoriasis severity, and the diet itself may be used in tandem with other treatments for psoriasis.
Gluten-Free Diet
Celiac disease is an inflammatory enteropathy caused by an immune reaction to the protein gliadin, which is found in foods containing gluten, such as wheat.5 Immune system assault on the intestinal enterocytes leads to the stripping away of villi, negatively affecting nutrient absorption. Multiple studies have reported an association between having psoriasis and having celiac disease as well as the reverse, including a 3-fold increased risk of celiac disease for patients with psoriasis in a 2017 meta-analysis.6 Even if patients with psoriasis did not have celiac disease, studies have found that a notable percentage of patients with psoriasis have elevated antigliadin IgA antibody levels.7 Many hypotheses have been proposed to explain this association. One article suggested that the malabsorption associated with celiac disease predisposes patients to vitamin D deficiency, which is a contributing risk factor for psoriasis.8 Other explanations involve common immune cells involved in the response to both diseases and a shared genetic background between the 2 diseases.8 As a gluten-free diet is standard for patients with celiac disease, it stands to reason that IgA could be used as a serum biomarker for patients who also could see improvements by adopting the diet.
This result could help explain the proportion of respondents to the 2017 survey who experienced improvements to their psoriasis if the gluten-free diet was in fact not triggering the inflammatory effects that a regular diet would, which also may help to explain the mixed results that the gluten-free diet has had as a treatment for psoriasis. One 3-month study of patients who were positive for antigliadin antibodies found that the majority (82%) experienced a decrease in antibody levels and affected skin area after following a gluten-free diet. Only half the patients had been diagnosed with celiac disease prior to the study, lending credibility to the idea that antigliadin antibody could be used as a marker for patients with psoriasis who would benefit from a gluten-free diet.9 Other case studies have reported no improvement of psoriasis following implementation of a gluten-free diet,10 despite the patients having elevated gliadin antibodies or celiac disease. More studies are required to discern the exact nature of the benefits of a gluten-free diet on psoriasis; however, it does serve as a promising option for patients with both psoriasis and celiac disease.
Ketogenic Diet
As obesity and weight gain are factors associated with psoriasis, some patients turn to diets that restrict calories with the goal of losing weight to improve their symptoms. One 2015 case report studied a patient who restored her response to systemic treatment of psoriasis following an intensive 4-week, calorie-restricted ketogenic diet.11 The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet. Animal studies have shown the diet to have anti-inflammatory effects, including lowering levels of proinflammatory cytokines and reduced fever.12 In the 2015 case report, the rapid and consistent weight loss experienced by the patient because of the ketogenic diet was thought to be the cause of the restoration of treatment effectiveness,11 which is interesting, since the role of the ketogenic diet was not to supplement any deficiencies but to move the patient to a physiologic state that was once again receptive to treatment. This finding suggests that a variety of diets could improve psoriasis symptoms, so long as they do not cause inflammation or reduce overall body mass. One study of patients on a calorie-restricted diet over 8 weeks did see a trend of patients on the diet showing improvement in both their PASI scores and Dermatology Life Quality Index, though the improvement was not statistically significant.13 To determine if the ketogenic diet has a significant association with psoriasis improvement, controlled, large-population studies should be performed in the future with age, sex, and weight-matched controls, which may be difficult to do. Further studies looking at the association between weight loss and psoriasis also could be another direction.
Vegetarian Diet
Both vegetarian and vegan diets have been evaluated for their efficacy in relieving symptoms of chronic inflammatory disorders. Although the 2 diets are similar in avoiding consumption of meat, fish, and poultry, vegan diets often have additional food restrictions, including avoiding eggs, honey, and dairy products. One study noted the impact of these diets on patients with a variety of skin conditions following a period of fasting. It was observed that some patients with psoriasis saw an improvement in their symptoms during the period when they were eating a vegetarian or vegan diet, which was attributed to a return to normal levels of activity of neutrophils, extrapolated from serum levels of lactoferrin.14 Vegetarian diets have been shown to be associated with higher ratios of anti-inflammatory to proinflammatory adipokines compared to omnivorous diets,15 as well as lower expression levels of proinflammatory genes in the gut microbiota and lower expression levels of IgE.16 Perhaps the anti-inflammatory impacts of the diet affected the symptoms of psoriasis. The benefits of a vegetarian diet also have been attributed to the high amount of potassium consumed,17 which is used in the body to synthesize cortisol, a common treatment for psoriasis. Potassium supplementation has been shown to raise serum cortisol levels in patients.6 Although additional studies are needed to discern the significance of potassium in the vegetarian diet, both hypotheses are reasonable explanations for the observations seen in these studies.
Vitamin D and Other Nutritional Supplements
Because it is not always feasible for patients to alter their diets, many have turned to dietary supplements as an alternative method of treatment and lifestyle change. Two of the more prominently represented nutritional additives in the literature are fish oils and vitamin D.18 Supplemental vitamin D is a prohormone that can be endogenously converted to its active 1,25-dihydroxyvitamin D.19 Vitamin D plays important roles in the regulation of calcium and magnesium in the bones as well as the maturation and differentiation of keratinocytes in the skin.16 Topical vitamin D analogues are standard treatments for psoriasis, as they are used to modulate the immune system to great effect.20 Some patients with psoriasis present with vitamin D insufficiency,21 and it stands to reason that oral supplementation may be a treatment option. There have been multiple studies assessing the efficacy of oral vitamin D for the treatment of psoriasis; however, in the only randomized and placebo-controlled trial, there was only a slight nonsignificant improvement in the group supplemented with vitamin D.20 Another small, open-label study reported remarkably improved PASI scores in 9 vitamin D–supplemented, dietary calcium–restricted patients.22 The lack of recent, large-sample studies makes it hard to draw notable conclusions from these studies.
The polyunsaturated fatty acids found in fish oils also have been considered as a treatment option for psoriasis.23 Millsop et al20 conducted an analysis of the literature reviewing the efficacy of fish oil in the treatment of psoriasis. Twelve of 15 compiled trials showed an improvement in psoriasis, ranging from slight improvements from baseline levels of the disease to statistically significant decreases in PASI scores (P<.05). It is notable that the amount of fish oil given in these studies varied widely, but the amount given did not necessarily correlate with strength of impact.20 For example, Mayser et al,24 Bittiner et al,25 and Grimminger et al26 each performed prospective, double-blind studies with
Studies also have shown little to no improvement in the use of fish oil to treat psoriasis. One such study was conducted by Soyland et al27 in 1993 in Norway. Utilizing a prospective, double-blind, placebo-controlled design over 4 months on 145 patients with moderate to severe psoriasis, researchers evaluated the treatment effectiveness via PASI scores; subjective reports from the patients; clinical manifestations; and factors such as cellular infiltration, desquamation, and redness. The results were mixed, with the placebo (corn oil) group having less redness and cellular desquamation and the fish oil group showing less cellular infiltration. In the other categories, there was no significant difference between the 2 groups, and researchers concluded there was no significant benefit to treating psoriasis using fish oil vs corn oil.27 As with many of the other diets, there have been no recent, large-scale studies performed on the effect of fish oil supplementation on psoriasis; however, of the studies we reviewed, none showed fish oil supplementation to have a significant negative impact on psoriasis.
Conclusion
Dietary modifications have a complex multifactorial effect on psoriasis, often dependent on the variations of psoriasis and the lifestyle of the patient, including level of exercise, activities such as smoking and drinking, and genetic susceptibilities to conditions such as obesity. Thus, it is difficult for one diet to have a significant impact on psoriasis symptoms that applies to the majority of individuals. However, it appears that certain foods or nutritional supplements can be modified from all diets for general improvement. Foods with systemic anti-inflammatory effects, such as olive oil and fish oil, seem to be beneficial in treating psoriasis. As an extension, a gluten-free diet may help psoriasis patients with celiac disease by reducing the inflammatory environment of the body. On the opposite side of the spectrum, proinflammatory foods such as dietary fat and alcohol should be avoided.28
In general, larger and more recent population-based studies are needed to add to the literature on this subject. Nationwide voluntary web-based surveys such as the NutriNet-Santé study in France may be one way to quickly amass large quantities of data (ClinicalTrials.gov Identifier NCT03335644). Participants are recruited through multimedia campaigns and return online questionnaires annually for 1 decade. A subset of participants also contributes biologic samples and participates in clinical examinations. This type of data gathering would capture many variables, provide a large sample size, and perhaps shed light on regional differences in diet and lifestyle that could then be targeted with treatments.
- Madrid Álvarez MB, Carretero Hernández G, González Quesada A, et al. Measurement of the psychological impact of psoriasis on patients receiving systemic treatment. Actas Dermosifiliogr (English edition). 2018;109:733-740.
- Afifi L, Danesh MJ, Lee KM, et al. Dietary behaviors in psoriasis: patient-reported outcomes from a U.S. national survey. Dermatol Ther (Heidelb). 2017;7:227-242.
- Phan C, Touvier M, Kesse-Guyot E, et al. Association between Mediterranean anti-inflammatory dietary profile and severity of psoriasis: results from the NutriNet-Santé cohort. JAMA Dermatol. 2018;154:1017-1024.
- Barrea L, Balato N, Di Somma C, et al. Nutrition and psoriasis: is there any association between the severity of the disease and adherence to the Mediterranean diet? J Transl Med. 2015;13:18.
- Bhatia BK, Millsop JW, Debbaneh M, et al. Diet and psoriasis, part II: celiac disease and role of a gluten-free diet. J Am Acad Dermatol. 2014;71:350-358.
- Ungprasert P, Wijarnpreecha K, Kittanamongkolchai W. Psoriasis and risk of celiac disease: a systematic review and meta-analysis. Indian J Dermatol. 2017;62:41-46.
- Kolchak NA, Tetarnikova MK, Theodoropoulou MS, et al. Prevalence of antigliadin IgA antibodies in psoriasis vulgaris and response of seropositive patients to a gluten-free diet. J Multidiscip Healthc. 2017;11:13-19.
- Ludvigsson JF, Lindelöf B, Zingone F, et al. Psoriasis in a nationwide cohort study of patients with celiac disease. J Invest Dermatol. 2011;131:2010-2016.
- De Bastiani R, Gabrielli M, Lora L, et al. Association between coeliac disease and psoriasis: Italian primary care multicentre study. Dermatology. 2015;230:156-160.
- Pietrzak D, Pietrzak A, Krasowska D, et al. Digestive system in psoriasis: an update. Arch Dermatol Res. 2017;309:679-693.
- Castaldo G, Galdo G, Rotondi Aufiero F, et al. Very low-calorie ketogenic diet may allow restoring response to systemic therapy in relapsing plaque psoriasis [published online November 11, 2015]. Obes Res Clin Pract. 2016;10:348-352.
- Dupuis N, Curatolo N, Benoist J-F, et al. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia. 2015;56:e95-e98.
- Jensen P, Zachariae C, Christensen R, et al. Effect of weight loss on the severity of psoriasis: a randomized clinical study. JAMA Dermatol. 2013;149:795-801.
- Lithell H, Bruce A, Gustafsson IB, et al. A fasting and vegetarian diet treatment trial on chronic inflammatory disorders. Acta Derm Venereol. 1983;63:397-403.
- Ambroszkiewicz J, Chełchowska M, Rowicka G, et al. Anti-inflammatory and pro-inflammatory adipokine profiles in children on vegetarian and omnivorous diets. Nutrients. 2018;10;pii E1241.
- Rastmanesh R. Psoriasis and vegetarian diets: a role for cortisol and potassium? Med Hypotheses. 2009;72:368.
- Zhang C, Björkman A, Cai K, et al. Impact of a 3-months vegetarian diet on the gut microbiota and immune repertoire. Front Immunol. 2018;9:908.
- Wolters M. Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol. 2005;153:706-714.
- Zuccotti E, Oliveri M, Girometta C, et al. Nutritional strategies for psoriasis: current scientific evidence in clinical trials. Eur Rev Med Pharmacol Sci. 2018;22:8537-8551.
- Millsop JW, Bhatia BK, Debbaneh M, et al. Diet and psoriasis: part 3. role of nutritional supplements. J Am Acad Dermatol. 2014;71:561-569.
- El-Moaty Zaher HA, El-Komy MHM, Hegazy RA, et al. Assessment of interleukin-17 and vitamin D serum levels in psoriatic patients. J Am Acad Dermatol. 2013;69:840-842.
- Finamor DC, Sinigaglia-Coimbra R, Neves LCM, et al. A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Dermatoendocrinol. 2013;5:222-234.
- Pona A, Haidari W, Kolli SS, et al. Diet and psoriasis. Dermatol Online J. 2019;25. https://escholarship.org/uc/item/1p37435s. Accessed April 14, 2019.
- Mayser P, Mrowietz U, Arenberger P, et al. ω-3 fatty acid–based lipid infusion in patients with chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, multicenter trial. J Am Acad Dermatol. 1998;38:539-547.
- Bittiner SB, Tucker WF, Cartwright I, et al. A double-blind, randomised, placebo-controlled trial of fish oil in psoriasis. Lancet. 1988;1:378-380.
- Grimminger F, Mayser P, Papavassilis C, et al. A double-blind, randomized, placebo-controlled trial of n-3 fatty acid based lipid infusion in acute, extended guttate psoriasis: rapid improvement of clinical manifestations and changes in neutrophil leukotriene profile. Clin Investig. 1993;71:634-643.
- Soyland E, Funk J, Rajka G, et al. Effect of dietary supplementation with very-long-chain n-3 fatty acids in patients with psoriasis. N Engl J Med. 1993;328:1812-1816.
- Cunningham E. Is there research to support a specific diet for psoriasis? J Acad Nutr Diet. 2014;114:508.
- Madrid Álvarez MB, Carretero Hernández G, González Quesada A, et al. Measurement of the psychological impact of psoriasis on patients receiving systemic treatment. Actas Dermosifiliogr (English edition). 2018;109:733-740.
- Afifi L, Danesh MJ, Lee KM, et al. Dietary behaviors in psoriasis: patient-reported outcomes from a U.S. national survey. Dermatol Ther (Heidelb). 2017;7:227-242.
- Phan C, Touvier M, Kesse-Guyot E, et al. Association between Mediterranean anti-inflammatory dietary profile and severity of psoriasis: results from the NutriNet-Santé cohort. JAMA Dermatol. 2018;154:1017-1024.
- Barrea L, Balato N, Di Somma C, et al. Nutrition and psoriasis: is there any association between the severity of the disease and adherence to the Mediterranean diet? J Transl Med. 2015;13:18.
- Bhatia BK, Millsop JW, Debbaneh M, et al. Diet and psoriasis, part II: celiac disease and role of a gluten-free diet. J Am Acad Dermatol. 2014;71:350-358.
- Ungprasert P, Wijarnpreecha K, Kittanamongkolchai W. Psoriasis and risk of celiac disease: a systematic review and meta-analysis. Indian J Dermatol. 2017;62:41-46.
- Kolchak NA, Tetarnikova MK, Theodoropoulou MS, et al. Prevalence of antigliadin IgA antibodies in psoriasis vulgaris and response of seropositive patients to a gluten-free diet. J Multidiscip Healthc. 2017;11:13-19.
- Ludvigsson JF, Lindelöf B, Zingone F, et al. Psoriasis in a nationwide cohort study of patients with celiac disease. J Invest Dermatol. 2011;131:2010-2016.
- De Bastiani R, Gabrielli M, Lora L, et al. Association between coeliac disease and psoriasis: Italian primary care multicentre study. Dermatology. 2015;230:156-160.
- Pietrzak D, Pietrzak A, Krasowska D, et al. Digestive system in psoriasis: an update. Arch Dermatol Res. 2017;309:679-693.
- Castaldo G, Galdo G, Rotondi Aufiero F, et al. Very low-calorie ketogenic diet may allow restoring response to systemic therapy in relapsing plaque psoriasis [published online November 11, 2015]. Obes Res Clin Pract. 2016;10:348-352.
- Dupuis N, Curatolo N, Benoist J-F, et al. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia. 2015;56:e95-e98.
- Jensen P, Zachariae C, Christensen R, et al. Effect of weight loss on the severity of psoriasis: a randomized clinical study. JAMA Dermatol. 2013;149:795-801.
- Lithell H, Bruce A, Gustafsson IB, et al. A fasting and vegetarian diet treatment trial on chronic inflammatory disorders. Acta Derm Venereol. 1983;63:397-403.
- Ambroszkiewicz J, Chełchowska M, Rowicka G, et al. Anti-inflammatory and pro-inflammatory adipokine profiles in children on vegetarian and omnivorous diets. Nutrients. 2018;10;pii E1241.
- Rastmanesh R. Psoriasis and vegetarian diets: a role for cortisol and potassium? Med Hypotheses. 2009;72:368.
- Zhang C, Björkman A, Cai K, et al. Impact of a 3-months vegetarian diet on the gut microbiota and immune repertoire. Front Immunol. 2018;9:908.
- Wolters M. Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol. 2005;153:706-714.
- Zuccotti E, Oliveri M, Girometta C, et al. Nutritional strategies for psoriasis: current scientific evidence in clinical trials. Eur Rev Med Pharmacol Sci. 2018;22:8537-8551.
- Millsop JW, Bhatia BK, Debbaneh M, et al. Diet and psoriasis: part 3. role of nutritional supplements. J Am Acad Dermatol. 2014;71:561-569.
- El-Moaty Zaher HA, El-Komy MHM, Hegazy RA, et al. Assessment of interleukin-17 and vitamin D serum levels in psoriatic patients. J Am Acad Dermatol. 2013;69:840-842.
- Finamor DC, Sinigaglia-Coimbra R, Neves LCM, et al. A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Dermatoendocrinol. 2013;5:222-234.
- Pona A, Haidari W, Kolli SS, et al. Diet and psoriasis. Dermatol Online J. 2019;25. https://escholarship.org/uc/item/1p37435s. Accessed April 14, 2019.
- Mayser P, Mrowietz U, Arenberger P, et al. ω-3 fatty acid–based lipid infusion in patients with chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, multicenter trial. J Am Acad Dermatol. 1998;38:539-547.
- Bittiner SB, Tucker WF, Cartwright I, et al. A double-blind, randomised, placebo-controlled trial of fish oil in psoriasis. Lancet. 1988;1:378-380.
- Grimminger F, Mayser P, Papavassilis C, et al. A double-blind, randomized, placebo-controlled trial of n-3 fatty acid based lipid infusion in acute, extended guttate psoriasis: rapid improvement of clinical manifestations and changes in neutrophil leukotriene profile. Clin Investig. 1993;71:634-643.
- Soyland E, Funk J, Rajka G, et al. Effect of dietary supplementation with very-long-chain n-3 fatty acids in patients with psoriasis. N Engl J Med. 1993;328:1812-1816.
- Cunningham E. Is there research to support a specific diet for psoriasis? J Acad Nutr Diet. 2014;114:508.
Practice Points
- No single food, supplement, or diet has been shown to have a notable positive impact on all variations of psoriasis. However, foods with systemic anti-inflammatory effects may be worth testing and adding to the patient’s diet.
- A considerable proportion of patients with psoriasis also have elevated levels of antigliadin antibody. If patients have celiac disease or high levels of antigliadin antibody, switching them to a gluten-free diet could have a positive impact on their psoriasis.
- Elevated body mass index, weight gain, smoking, and obesity are all associated with a higher risk for psoriasis appearance and severity.
Translating the 2019 AAD-NPF Guidelines of Care for the Management of Psoriasis With Biologics to Clinical Practice
Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.1 The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.2 These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.
In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.3 The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.4 Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.
The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.3 The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.
Choosing a Biologic
Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.
All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.
In pregnant women or those are anticipating pregnancy, certolizumab may be considered, as it is the only biologic shown to have minimal to no placental transfer. Other TNF-α inhibitors may undergo active placental transfer, particularly during the latter half of pregnancy,5 and the greatest theoretical risk of transfer occurs in the third trimester. Although these drugs may not directly harm the fetus, they do cause fetal immunosuppression for up to the first 3 months of life. All TNF-α inhibitors are considered safe during lactation. There are inadequate data regarding the safety of other classes of biologics during pregnancy and lactation.
Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.
There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,6 and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,9 a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.
Initiation of Therapy
Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4+ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.
Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.
Assessment and Optimization of Treatment Response
Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.
If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.
In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.10 These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.
Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.
Considerations During Active Therapy
In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.
Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.
Because infliximab treatment poses an elevated risk of liver injury,11 liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.12
It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.13 Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.14 It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.
Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.15 Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.16 Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,15 but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.
Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.17 Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.18 Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.
Switching Biologics
Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.19 Changing therapy to a biologic within the same class is generally effective,20 and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.
Resuming Biologic Treatment Following Cessation
In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.
Final Thoughts
These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.
- Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol. 2017;31:205-212.
- Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol. 2009;60:218-224.
- Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics [published online February 13, 2019]. J Am Acad Dermatol. 2019;80:1029-1072.
- Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850.
- Förger F, Villiger PM. Treatment of rheumatoid arthritis during pregnancy: present and future. Expert Rev Clin Immunol. 2016;12:937-944.
- Gooderham M, Elewski B, Pariser D, et al. Incidence of serious gastrointestinal events and inflammatory bowel disease among tildrakizumab-treated patients with moderate-to-severe plaque psoriasis: data from 3 large randomized clinical trials [abstract]. J Am Acad Dermatol. 2018;79(suppl 1):AB166.
- Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318-328.
- Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286
- Beck KM, Koo J. Brodalumab for the treatment of plaque psoriasis: up-to-date. Expert Opin Biol Ther. 2019;19:287-292.
- Fouéré S, Adjadj L, Pawin H. How patients experience psoriasis: results from a European survey. J Eur Acad Dermatol Venereol. 2005;19(suppl 3):2-6.
- Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419-1425, 1425.e1-3; quiz e19-20.
- Saunte DM, Mrowietz U, Puig L, et al. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol. 2017;177:47-62.
- Huber F, Ehrensperger B, Hatz C, et al. Safety of live vaccines on immunosuppressive or immunomodulatory therapy—a retrospective study in three Swiss Travel Clinics [published online January 1, 2018]. J Travel Med. doi:10.1093/jtm/tax082.
- Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
- Fiorentino D, Ho V, Lebwohl MG, et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol. 2017;77:845-854.e5.
- Haynes K, Beukelman T, Curtis JR, et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis Rheum. 2013;65:48-58.
- Fabiano A, De Simone C, Gisondi P, et al. Management of patients with psoriasis treated with biologic drugs needing a surgical treatment. Drug Dev Res. 2014;75(suppl 1):S24-S26.
- Choi YM, Debbaneh M, Weinberg JM, et al. From the Medical Board of the National Psoriasis Foundation: perioperative management of systemic immunomodulatory agents in patients with psoriasis and psoriatic arthritis. J Am Acad Dermatol. 2016;75:798-805.e7.
- Honda H, Umezawa Y, Kikuchi S, et al. Switching of biologics in psoriasis: reasons and results. J Dermatol. 2017;44:1015-1019.
- Bracke S, Lambert J. Viewpoint on handling anti-TNF failure in psoriasis. Arch Dermatol Res. 2013;305:945-950.
Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.1 The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.2 These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.
In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.3 The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.4 Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.
The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.3 The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.
Choosing a Biologic
Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.
All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.
In pregnant women or those are anticipating pregnancy, certolizumab may be considered, as it is the only biologic shown to have minimal to no placental transfer. Other TNF-α inhibitors may undergo active placental transfer, particularly during the latter half of pregnancy,5 and the greatest theoretical risk of transfer occurs in the third trimester. Although these drugs may not directly harm the fetus, they do cause fetal immunosuppression for up to the first 3 months of life. All TNF-α inhibitors are considered safe during lactation. There are inadequate data regarding the safety of other classes of biologics during pregnancy and lactation.
Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.
There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,6 and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,9 a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.
Initiation of Therapy
Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4+ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.
Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.
Assessment and Optimization of Treatment Response
Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.
If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.
In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.10 These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.
Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.
Considerations During Active Therapy
In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.
Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.
Because infliximab treatment poses an elevated risk of liver injury,11 liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.12
It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.13 Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.14 It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.
Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.15 Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.16 Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,15 but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.
Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.17 Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.18 Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.
Switching Biologics
Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.19 Changing therapy to a biologic within the same class is generally effective,20 and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.
Resuming Biologic Treatment Following Cessation
In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.
Final Thoughts
These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.
Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.1 The disease is moderate to severe for approximately 1 in 6 individuals with psoriasis.2 These patients, particularly those with symptoms that are refractory to topical therapy and/or phototherapy, can benefit from the use of biologic agents, which are monoclonal antibodies and fusion proteins engineered to inhibit the action of cytokines that drive psoriatic inflammation.
In February 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of biologics in treating adult patients with psoriasis.3 The prior guidelines were released in 2008 when just 3 biologics—etanercept, infliximab, and adalimumab—were approved by the US Food and Drug Administration (FDA) for the management of psoriasis. These older recommendations were mostly based on studies of the efficacy and safety of biologics for patients with psoriatic arthritis.4 Over the last 11 years, 8 novel biologics have gained FDA approval, and numerous large phase 2 and phase 3 trials evaluating the risks and benefits of biologics have been conducted. The new guidelines contain considerably more detail and are based on evidence more specific to psoriasis rather than to psoriatic arthritis. Given the large repertoire of biologics available today and the increased amount of published research regarding each one, these guidelines may aid dermatologists in choosing the optimal biologic and managing therapy.
The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and adverse events of the 10 biologics that have been FDA approved for the treatment of psoriasis as of March 2019, plus risankizumab, which was pending FDA approval at the time of publication and was later approved in April 2019. They also address dosing regimens, potential to combine biologics with other therapies, and different forms of psoriasis for which each may be effective.3 The purpose of this discussion is to present these guidelines in a condensed form to prescribers of biologic therapies and review the most clinically significant considerations during each step of treatment. Of note, we highlight only treatment of adult patients and do not discuss information relevant to risankizumab, as it was not FDA approved when the AAD-NPF guidelines were released.
Choosing a Biologic
Biologic therapy may be considered for patients with psoriasis that affects more than 3% of the body’s surface and is recalcitrant to localized therapies. There is no particular first-line biologic recommended for all patients with psoriasis; rather, choice of therapy should be individualized to the patient, considering factors such as body parts affected, comorbidities, lifestyle, and drug cost.
All 10 FDA-approved biologics (Table) have been ranked by the AAD and NPF as having grade A evidence for efficacy as monotherapy in the treatment of moderate to severe plaque-type psoriasis. Involvement of difficult-to-treat areas may be considered when choosing a specific therapy. The tumor necrosis factor α (TNF-α) inhibitors etanercept and adalimumab, the IL-17 inhibitor secukinumab, and the IL-23 inhibitor guselkumab have the greatest evidence for efficacy in treatment of nail disease. For scalp involvement, etanercept and guselkumab have the highest-quality evidence, and for palmoplantar disease, adalimumab, secukinumab, and guselkumab are considered the most effective. The TNF-α inhibitors are considered the optimal treatment option for concurrent psoriatic arthritis, though the IL-12/IL-23 inhibitor ustekinumab and the IL-17 inhibitors secukinumab and ixekizumab also have shown grade A evidence of efficacy. Of note, because TNF-α inhibitors received the earliest FDA approval, there is most evidence available for this class. Therapies with lower evidence quality for certain forms of psoriasis may show real-world effectiveness in individual patients, though more trials will be necessary to generate a body of evidence to change these clinical recommendations.
In pregnant women or those are anticipating pregnancy, certolizumab may be considered, as it is the only biologic shown to have minimal to no placental transfer. Other TNF-α inhibitors may undergo active placental transfer, particularly during the latter half of pregnancy,5 and the greatest theoretical risk of transfer occurs in the third trimester. Although these drugs may not directly harm the fetus, they do cause fetal immunosuppression for up to the first 3 months of life. All TNF-α inhibitors are considered safe during lactation. There are inadequate data regarding the safety of other classes of biologics during pregnancy and lactation.
Overweight and obese patients also require unique considerations when choosing a biologic. Infliximab is the only approved psoriasis biologic that utilizes proportional-to-weight dosing and hence may be particularly efficacious in patients with higher body mass. Ustekinumab dosing also takes patient weight into consideration; patients heavier than 100 kg should receive 90-mg doses at initiation and during maintenance compared to 45 mg for patients who weigh 100 kg or less. Other approved biologics also may be utilized in these patients but may require closer monitoring of treatment efficacy.
There are few serious contraindications for specific biologic therapies. Any history of allergic reaction to a particular therapy is an absolute contraindication to its use. In patients for whom IL-17 inhibitor treatment is being considered, inflammatory bowel disease (IBD) should be ruled out given the likelihood that IL-17 could reactivate or worsen IBD. Of note, TNF-α inhibitors and ustekinumab are approved therapies for patients with IBD and may be recommended in patients with comorbid psoriasis. Phase 2 and phase 3 trials have found no reactivation or worsening of IBD in patients with psoriasis who were treated with the IL-23 inhibitor tildrakizumab,6 and phase 2 trials of treatment of IBD with guselkumab are currently underway (ClinicalTrials.gov Identifier NCT03466411). In patients with New York Heart Association class III and class IV congestive heart failure or multiple sclerosis, initiation of TNF-α inhibitors should be avoided. Among 3 phase 3 trials encompassing nearly 3000 patients treated with the IL-17 inhibitor brodalumab, a total of 3 patients died by suicide7,8; hence, the FDA has issued a black box warning cautioning against use of this drug in patients with history of suicidal ideation or recent suicidal behavior. Although a causal relationship between brodalumab and suicide has not been well established,9 a thorough psychiatric history should be obtained in those initiating treatment with brodalumab.
Initiation of Therapy
Prior to initiating biologic therapy, it is important to obtain a complete blood cell count, complete metabolic panel, tuberculosis testing, and hepatitis B virus (HBV) and hepatitis C virus serologies. Testing for human immunodeficiency virus may be pursued at the clinician’s discretion. It is important to address any positive or concerning results prior to starting biologics. In patients with active infections, therapy may be initiated alongside guidance from an infectious disease specialist. Those with a positive purified protein derivative test, T-SPOT test, or QuantiFERON-TB Gold test must be referred for chest radiographs to rule out active tuberculosis. Patients with active HBV infection should receive appropriate referral to initiate antiviral therapy as well as core antibody testing, and those with active hepatitis C virus infection may only receive biologics under the combined discretion of a dermatologist and an appropriate specialist. Patients with human immunodeficiency virus must concurrently receive highly active antiretroviral therapy, show normal CD4+ T-cell count and undetectable viral load, and have no recent history of opportunistic infection.
Therapy should be commenced using specific dosing regimens, which are unique for each biologic (Table). Patients also must be educated on routine follow-up to assess treatment response and tolerability.
Assessment and Optimization of Treatment Response
Patients taking biologics may experience primary treatment failure, defined as lack of response to therapy from initiation. One predisposing factor may be increased body mass; patients who are overweight and obese are less likely to respond to standard regimens of TNF-α inhibitors and 45-mg dosing of ustekinumab. In most cases, however, the cause of primary nonresponse is unpredictable. For patients in whom therapy has failed within the recommended initial time frame (Table), dose escalation or shortening of dosing intervals may be pursued. Recommended dosing adjustments are outlined in the Table. Alternatively, patients may be switched to a different biologic.
If desired effectiveness is not reached with biologic monotherapy, topical corticosteroids, topical vitamin D analogues, or narrowband UVB light therapy may be concurrently used for difficult-to-treat areas. Evidence for safety and effectiveness of systemic adjuncts to biologics is moderate to low, warranting caution with their use. Methotrexate, cyclosporine, and apremilast have synergistic effects with biologics, though they may increase the risk for immunosuppression-related complications. Acitretin, an oral retinoid, likely is the most reasonable systemic adjunct to biologics because of its lack of immunosuppressive properties.
In patients with a suboptimal response to biologics, particularly those taking therapies that require frequent dosing, poor compliance should be considered.10 These patients may be switched to a biologic with less-frequent maintenance dosing (Table). Ustekinumab and tildrakizumab may be the best options for optimizing compliance, as they require dosing only once every 12 weeks after administration of loading doses.
Secondary treatment failure is diminished efficacy of treatment following successful initial response despite no changes in regimen. The best-known factor contributing to secondary nonresponse to biologics is the development of antidrug antibodies (ADAs), a phenomenon known as immunogenicity. The development of efficacy-limiting ADAs has been observed in response to most biologics, though ADAs against etanercept and guselkumab do not limit therapeutic response. Patients taking adalimumab and infliximab have particularly well-documented efficacy-limiting immunogenicity, and those who develop ADAs to infliximab are considered more prone to developing infusion reactions. Methotrexate, which limits antibody formation, may concomitantly be prescribed in patients who experience secondary treatment failure. It should be considered in all patients taking infliximab to increase efficacy and tolerability of therapy.
Considerations During Active Therapy
In addition to monitoring adherence and response to regimens, dermatologists must be heavily involved in counseling patients regarding the risks and adverse effects associated with these therapies. During maintenance therapy with biologics, patients must follow up with the prescriber at minimum every 3 to 6 months to evaluate for continued efficacy of treatment, extent of side effects, and effects of treatment on overall health and quality of life. Given the immunosuppressive effects of biologics, annual testing for tuberculosis should be considered in high-risk individuals. In those who are considered at low risk, tuberculosis testing may be done at the discretion of the dermatologist. In those with a history of HBV infection, HBV serologies should be pursued routinely given the risk for reactivation.
Annual screening for nonmelanoma skin cancer should be performed in all patients taking biologics. Tumor necrosis factor α inhibitor therapy in particular confers an elevated risk for cutaneous squamous cell carcinoma, especially in patients who are immunosuppressed at baseline and those with history of UV phototherapy. Use of acitretin alongside TNF-α inhibitors or ustekinumab may prevent squamous cell carcinoma formation in high-risk patients.
Because infliximab treatment poses an elevated risk of liver injury,11 liver function tests should be repeated 3 months following initiation of treatment and then every 6 to 12 months subsequently if results are normal. Periodic assessment of suicidal ideation is recommended in patients on brodalumab therapy, which may necessitate more frequent follow-up visits and potentially psychiatry referrals in certain patients. Patients taking IL-17 inhibitors, particularly those who are concurrently taking methotrexate, are at increased risk for developing mucocutaneous Candida infections; these patients should be monitored for such infections and treated appropriately.12
It is additionally important for prescribing dermatologists to ensure that patients on biologics are following up with their general providers to receive timely age-appropriate preventative screenings and vaccines. Inactivated vaccinations may be administered during therapy with any biologic; however, live vaccinations may induce systemic infection in those who are immunocompromised, which theoretically includes individuals taking biologic agents, though incidence data in this patient population are scarce.13 Some experts believe that administration of live vaccines warrants temporary discontinuation of biologic therapy for 2 to 3 half-lives before and after vaccination (Table). Others recommend stopping treatment at least 4 weeks before and until 2 weeks after vaccination. For patients taking biologics with half-lives greater than 20 days, which would theoretically require stopping the drug 2 months prior to vaccination, the benefit of vaccination should be weighed against the risk of prolonged discontinuation of therapy. Until recently, this recommendation was particularly important, as a live herpes zoster vaccination was recommended by the Centers for Disease Control and Prevention for adults older than 60 years. In 2017, a new inactivated herpes zoster vaccine was introduced and is now the preferred vaccine for all patients older than 50 years.14 It is especially important that patients on biologics receive this vaccine to avoid temporary drug discontinuation.
Evidence that any particular class of biologics increases risk for solid tumors or lymphoreticular malignancy is limited. One case-control analysis reported that more than 12 months of treatment with TNF-α inhibitors may increase risk for malignancy; however, the confidence interval reported hardly allows for statistical significance.15 Another retrospective cohort study found no elevated incidence of cancer in patients on TNF-α inhibitors compared to nonbiologic comparators.16 Ustekinumab was shown to confer no increased risk for malignancy in 1 large study,15 but no large studies have been conducted for other classes of drugs. Given the limited and inconclusive evidence available, the guidelines recommend that age-appropriate cancer screenings recommended for the general population should be pursued in patients taking biologics.
Surgery while taking biologics may lead to stress-induced augmentation of immunosuppression, resulting in elevated risk of infection.17 Low-risk surgeries that do not warrant discontinuation of treatment include endoscopic, ophthalmologic, dermatologic, orthopedic, and breast procedures. In patients preparing for elective surgery in which respiratory, gastrointestinal, or genitourinary tracts will be entered, biologics may be discontinued at least 3 half-lives (Table) prior to surgery if the dermatologist and surgeon collaboratively deem that risk of infection outweighs benefit of continued therapy.18 Therapy may be resumed within 1 to 2 weeks postoperatively if there are no surgical complications.
Switching Biologics
Changing therapy to another biologic should be considered if there is no response to treatment or the patient experiences adverse effects while taking a particular biologic. Because evidence is limited regarding the ideal time frame between discontinuation of a prior medication and initiation of a new biologic, this interval should be determined at the discretion of the provider based on the patient’s disease severity and response to prior treatment. For individuals who experience primary or secondary treatment failure while maintaining appropriate dosing and treatment compliance, switching to a different biologic is recommended to maximize treatment response.19 Changing therapy to a biologic within the same class is generally effective,20 and switching to a biologic with another mechanism of action should be considered if a class-specific adverse effect is the major reason for altering the regimen. Nonetheless, some patients may be unresponsive to biologic changes. Further research is necessary to determine which biologics may be most effective when previously used biologics have failed and particular factors that may predispose patients to biologic unresponsiveness.
Resuming Biologic Treatment Following Cessation
In cases where therapy is discontinued for any reason, it may be necessary to repeat initiation dosing when resuming treatment. In patients with severe or flaring disease or if more than 3 to 4 half-lives have passed since the most recent dose, it may be necessary to restart therapy with the loading dose (Table). Unfortunately, restarting therapy may preclude some patients from experiencing the maximal response that they attained prior to cessation. In such cases, switching biologic therapy to a different class may prove beneficial.
Final Thoughts
These recommendations contain valuable information that will assist dermatologists when initiating biologics and managing outcomes of their psoriasis patients. It is, however, crucial to bear in mind that these guidelines serve as merely a tool. Given the paucity of comprehensive research, particularly regarding some of the more recently approved therapies, there are many questions that are unanswered within the guidelines. Their utility for each individual patient situation is therefore limited, and clinical judgement may outweigh the information presented. The recommendations nevertheless provide a pivotal and unprecedented framework that promotes discourse among patients, dermatologists, and other providers to optimize the efficacy of biologic therapy for psoriasis.
- Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol. 2017;31:205-212.
- Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol. 2009;60:218-224.
- Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics [published online February 13, 2019]. J Am Acad Dermatol. 2019;80:1029-1072.
- Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850.
- Förger F, Villiger PM. Treatment of rheumatoid arthritis during pregnancy: present and future. Expert Rev Clin Immunol. 2016;12:937-944.
- Gooderham M, Elewski B, Pariser D, et al. Incidence of serious gastrointestinal events and inflammatory bowel disease among tildrakizumab-treated patients with moderate-to-severe plaque psoriasis: data from 3 large randomized clinical trials [abstract]. J Am Acad Dermatol. 2018;79(suppl 1):AB166.
- Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318-328.
- Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286
- Beck KM, Koo J. Brodalumab for the treatment of plaque psoriasis: up-to-date. Expert Opin Biol Ther. 2019;19:287-292.
- Fouéré S, Adjadj L, Pawin H. How patients experience psoriasis: results from a European survey. J Eur Acad Dermatol Venereol. 2005;19(suppl 3):2-6.
- Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419-1425, 1425.e1-3; quiz e19-20.
- Saunte DM, Mrowietz U, Puig L, et al. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol. 2017;177:47-62.
- Huber F, Ehrensperger B, Hatz C, et al. Safety of live vaccines on immunosuppressive or immunomodulatory therapy—a retrospective study in three Swiss Travel Clinics [published online January 1, 2018]. J Travel Med. doi:10.1093/jtm/tax082.
- Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
- Fiorentino D, Ho V, Lebwohl MG, et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol. 2017;77:845-854.e5.
- Haynes K, Beukelman T, Curtis JR, et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis Rheum. 2013;65:48-58.
- Fabiano A, De Simone C, Gisondi P, et al. Management of patients with psoriasis treated with biologic drugs needing a surgical treatment. Drug Dev Res. 2014;75(suppl 1):S24-S26.
- Choi YM, Debbaneh M, Weinberg JM, et al. From the Medical Board of the National Psoriasis Foundation: perioperative management of systemic immunomodulatory agents in patients with psoriasis and psoriatic arthritis. J Am Acad Dermatol. 2016;75:798-805.e7.
- Honda H, Umezawa Y, Kikuchi S, et al. Switching of biologics in psoriasis: reasons and results. J Dermatol. 2017;44:1015-1019.
- Bracke S, Lambert J. Viewpoint on handling anti-TNF failure in psoriasis. Arch Dermatol Res. 2013;305:945-950.
- Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol. 2017;31:205-212.
- Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol. 2009;60:218-224.
- Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics [published online February 13, 2019]. J Am Acad Dermatol. 2019;80:1029-1072.
- Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850.
- Förger F, Villiger PM. Treatment of rheumatoid arthritis during pregnancy: present and future. Expert Rev Clin Immunol. 2016;12:937-944.
- Gooderham M, Elewski B, Pariser D, et al. Incidence of serious gastrointestinal events and inflammatory bowel disease among tildrakizumab-treated patients with moderate-to-severe plaque psoriasis: data from 3 large randomized clinical trials [abstract]. J Am Acad Dermatol. 2018;79(suppl 1):AB166.
- Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318-328.
- Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286
- Beck KM, Koo J. Brodalumab for the treatment of plaque psoriasis: up-to-date. Expert Opin Biol Ther. 2019;19:287-292.
- Fouéré S, Adjadj L, Pawin H. How patients experience psoriasis: results from a European survey. J Eur Acad Dermatol Venereol. 2005;19(suppl 3):2-6.
- Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419-1425, 1425.e1-3; quiz e19-20.
- Saunte DM, Mrowietz U, Puig L, et al. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol. 2017;177:47-62.
- Huber F, Ehrensperger B, Hatz C, et al. Safety of live vaccines on immunosuppressive or immunomodulatory therapy—a retrospective study in three Swiss Travel Clinics [published online January 1, 2018]. J Travel Med. doi:10.1093/jtm/tax082.
- Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
- Fiorentino D, Ho V, Lebwohl MG, et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol. 2017;77:845-854.e5.
- Haynes K, Beukelman T, Curtis JR, et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis Rheum. 2013;65:48-58.
- Fabiano A, De Simone C, Gisondi P, et al. Management of patients with psoriasis treated with biologic drugs needing a surgical treatment. Drug Dev Res. 2014;75(suppl 1):S24-S26.
- Choi YM, Debbaneh M, Weinberg JM, et al. From the Medical Board of the National Psoriasis Foundation: perioperative management of systemic immunomodulatory agents in patients with psoriasis and psoriatic arthritis. J Am Acad Dermatol. 2016;75:798-805.e7.
- Honda H, Umezawa Y, Kikuchi S, et al. Switching of biologics in psoriasis: reasons and results. J Dermatol. 2017;44:1015-1019.
- Bracke S, Lambert J. Viewpoint on handling anti-TNF failure in psoriasis. Arch Dermatol Res. 2013;305:945-950.
Practice Points
- There are currently 11 biologics approved for psoriasis, but there is no first-line or optimalbiologic. The choice must be made using clinical judgment based on a variety of medical and social factors.
- Frequent assessment for efficacy of and adverse events due to biologic therapy is warranted, as lack of response, loss of response, or severe side effects may warrant addition of concurrent therapies or switching to a different biologic.
- There are important considerations to make when immunizing and planning for surgery in patients on biologics.