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Children and trauma: How Sesame Street can help
Nearly half of American children have faced one adverse childhood experience (ACE), according to new analysis of the 2016 National Survey of Children’s Health, and more than 20% have had two ACEs or more. This may include abuse or neglect, witnessing violence, parental substance abuse, mental illness, or incarceration. And from news headlines, we are all too aware of other traumas children face, such as natural disasters and mass violence.
But we know that children are remarkably resilient, and trauma does not have to define their trajectory. With the right tools and support, the effects of trauma can be mitigated, and children can build coping skills and resiliency for a healthy, promising future.
When we began hearing from community service partners and child development experts that there was a critical need for resources to help children cope with trauma, we felt we could help.
Traumatic experiences can disrupt brain development, but when children have hope, when they feel seen and heard by caring adults who can guide them through those crucial resilience-building techniques, the impact of ACEs can be mitigated, and children can be set on the road to healing and stability.
With support from the Robert Wood Johnson Foundation and other funders, To do this, we enlisted the pediatric community and professionals in the field, grounding our approach in the latest research. Then we used our proven model to produce resources that could engage and comfort children while building coping skills and foster crucial nurturing connections between children and the adults in their lives.
Our free materials – some are targeted for children and others are for providers – include videos, storybooks, and digital activities in English and Spanish. They are all available at sesamestreetincommunities.org/topics/traumatic-experiences.
In one video called “Comfy Cozy Nest,” when Big Bird faces an unspecified difficult situation, he learns to think of his nest as a “safe space” with comforting items like his teddy bear and Granny Bird’s birdseed cookies. This is a place he can go in his imagination to make himself feel safe. In others, Elmo builds a blanket fort to feel secure and the Count teaches Cookie Monster a breathing strategy to help him relax.
In addition to engaging materials for children, providers can find professional development workshops, webinars, and other adult-facing content that includes, as part of our trauma content, a powerful animation to help parents and caregivers understand the impact of domestic violence from a child’s perspective.
No one plays a more vital role in children’s health and well-being than pediatricians, nurse practitioners, and family physicians. Our hope is that Sesame Street in Communities will allow us to work together, to help children everywhere grow smarter, stronger, and kinder.
Dr. Betancourt is the senior vice president for U.S. social impact at Sesame Workshop, the nonprofit media and educational organization behind Sesame Street, in New York.
Nearly half of American children have faced one adverse childhood experience (ACE), according to new analysis of the 2016 National Survey of Children’s Health, and more than 20% have had two ACEs or more. This may include abuse or neglect, witnessing violence, parental substance abuse, mental illness, or incarceration. And from news headlines, we are all too aware of other traumas children face, such as natural disasters and mass violence.
But we know that children are remarkably resilient, and trauma does not have to define their trajectory. With the right tools and support, the effects of trauma can be mitigated, and children can build coping skills and resiliency for a healthy, promising future.
When we began hearing from community service partners and child development experts that there was a critical need for resources to help children cope with trauma, we felt we could help.
Traumatic experiences can disrupt brain development, but when children have hope, when they feel seen and heard by caring adults who can guide them through those crucial resilience-building techniques, the impact of ACEs can be mitigated, and children can be set on the road to healing and stability.
With support from the Robert Wood Johnson Foundation and other funders, To do this, we enlisted the pediatric community and professionals in the field, grounding our approach in the latest research. Then we used our proven model to produce resources that could engage and comfort children while building coping skills and foster crucial nurturing connections between children and the adults in their lives.
Our free materials – some are targeted for children and others are for providers – include videos, storybooks, and digital activities in English and Spanish. They are all available at sesamestreetincommunities.org/topics/traumatic-experiences.
In one video called “Comfy Cozy Nest,” when Big Bird faces an unspecified difficult situation, he learns to think of his nest as a “safe space” with comforting items like his teddy bear and Granny Bird’s birdseed cookies. This is a place he can go in his imagination to make himself feel safe. In others, Elmo builds a blanket fort to feel secure and the Count teaches Cookie Monster a breathing strategy to help him relax.
In addition to engaging materials for children, providers can find professional development workshops, webinars, and other adult-facing content that includes, as part of our trauma content, a powerful animation to help parents and caregivers understand the impact of domestic violence from a child’s perspective.
No one plays a more vital role in children’s health and well-being than pediatricians, nurse practitioners, and family physicians. Our hope is that Sesame Street in Communities will allow us to work together, to help children everywhere grow smarter, stronger, and kinder.
Dr. Betancourt is the senior vice president for U.S. social impact at Sesame Workshop, the nonprofit media and educational organization behind Sesame Street, in New York.
Nearly half of American children have faced one adverse childhood experience (ACE), according to new analysis of the 2016 National Survey of Children’s Health, and more than 20% have had two ACEs or more. This may include abuse or neglect, witnessing violence, parental substance abuse, mental illness, or incarceration. And from news headlines, we are all too aware of other traumas children face, such as natural disasters and mass violence.
But we know that children are remarkably resilient, and trauma does not have to define their trajectory. With the right tools and support, the effects of trauma can be mitigated, and children can build coping skills and resiliency for a healthy, promising future.
When we began hearing from community service partners and child development experts that there was a critical need for resources to help children cope with trauma, we felt we could help.
Traumatic experiences can disrupt brain development, but when children have hope, when they feel seen and heard by caring adults who can guide them through those crucial resilience-building techniques, the impact of ACEs can be mitigated, and children can be set on the road to healing and stability.
With support from the Robert Wood Johnson Foundation and other funders, To do this, we enlisted the pediatric community and professionals in the field, grounding our approach in the latest research. Then we used our proven model to produce resources that could engage and comfort children while building coping skills and foster crucial nurturing connections between children and the adults in their lives.
Our free materials – some are targeted for children and others are for providers – include videos, storybooks, and digital activities in English and Spanish. They are all available at sesamestreetincommunities.org/topics/traumatic-experiences.
In one video called “Comfy Cozy Nest,” when Big Bird faces an unspecified difficult situation, he learns to think of his nest as a “safe space” with comforting items like his teddy bear and Granny Bird’s birdseed cookies. This is a place he can go in his imagination to make himself feel safe. In others, Elmo builds a blanket fort to feel secure and the Count teaches Cookie Monster a breathing strategy to help him relax.
In addition to engaging materials for children, providers can find professional development workshops, webinars, and other adult-facing content that includes, as part of our trauma content, a powerful animation to help parents and caregivers understand the impact of domestic violence from a child’s perspective.
No one plays a more vital role in children’s health and well-being than pediatricians, nurse practitioners, and family physicians. Our hope is that Sesame Street in Communities will allow us to work together, to help children everywhere grow smarter, stronger, and kinder.
Dr. Betancourt is the senior vice president for U.S. social impact at Sesame Workshop, the nonprofit media and educational organization behind Sesame Street, in New York.
Low tryptophan levels linked to IBD
Patients with inflammatory bowel disease (IBD) had significantly lower serum levels of the essential amino acid tryptophan than healthy controls in a large study reported in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.08.028).
Serum tryptophan levels also correlated inversely with both disease activity and C-reactive protein levels in patients with IBD, reported Susanna Nikolaus, MD, of University Hospital Schleswig-Holstein, Kiel, Germany, with her associates. “Tryptophan deficiency could contribute to development of IBD. Studies are needed to determine whether modification of intestinal tryptophan pathways affects [its] severity,” they wrote.
Several small case series have reported low levels of tryptophan in IBD and other autoimmune disorders, the investigators noted. Removing tryptophan from the diet has been found to increase susceptibility to colitis in mice, and supplementing with tryptophan or some of its metabolites has the opposite effect. For this study, the researchers used high-performance liquid chromatography to quantify tryptophan levels in serum samples from 535 consecutive patients with IBD and 100 matched controls. They used mass spectrometry to measure metabolites of tryptophan, enzyme-linked immunosorbent assay to measure interleukin-22 (IL-22) levels, and 16S rDNA amplicon sequencing to correlate tryptophan levels with fecal microbiota species. Finally, they used real-time polymerase chain reaction to measure levels of mRNA encoding tryptophan metabolites in colonic biopsy specimens.
Serum tryptophan levels were significantly lower in patients with IBD than controls (P = 5.3 x 10–6). The difference was starker in patients with Crohn’s disease (P = 1.1 x 10–10 vs. controls) compared with those with ulcerative colitis (P = 2.8 x 10–3 vs. controls), the investigators noted. Serum tryptophan levels also correlated inversely with disease activity in patients with Crohn’s disease (P = .01), while patients with ulcerative colitis showed a similar but nonsignificant trend (P = .07). Low tryptophan levels were associated with marked, statistically significant increases in C-reactive protein levels in both Crohn’s disease and ulcerative colitis. Tryptophan level also correlated inversely with leukocyte count, although the trend was less pronounced (P = .04).IBD was associated with several aberrations in the tryptophan kynurenine pathway, which is the primary means of catabolizing the amino acid. For example, compared with controls, patients with active IBD had significantly lower levels of mRNA encoding tryptophan 2,3-dioxygenase-2 (TDO2, a key enzyme in the kynurenine pathway) and solute carrier family 6 member 19 (SLC6A19, also called B0AT1, a neutral amino acid transporter). Patients with IBD also had significantly higher levels of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial, rate-limiting oxidation of tryptophan to kynurenine. Accordingly, patients with IBD had a significantly higher ratio of kynurenine to tryptophan than did controls, and this abnormality was associated with disease activity, especially in Crohn’s disease (P = .03).
Patients with IBD who had relatively higher tryptophan levels also tended to have more diverse gut microbiota than did patients with lower serum tryptophan levels, although differences among groups were not statistically significant, the investigators said. Serum concentration of IL-22 also correlated with disease activity in patients with IBD, and infliximab responders had a “significant and sustained increase” of tryptophan levels over time, compared with nonresponders.
Potsdam dietary questionnaires found no link between disease activity and dietary consumption of tryptophan, the researchers said. Additionally, they found no links between serum tryptophan levels and age, smoking status, or disease complications, such as fistulae or abscess formation.The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop drugs with inflammatory indications. The other investigators had no conflicts of interest.
In this interesting study, Nikolaus et al. found an association of decreased serum tryptophan in patients with inflammatory bowel disease (IBD), compared with control subjects. The authors also found an inverse correlation of serum tryptophan levels in patients with C-reactive protein in both ulcerative colitis and Crohn's disease and with active disease as defined by clinical disease activity scores in Crohn's disease. A validated food-frequency questionnaire found no difference in tryptophan consumption based on disease activity in a subset of patients, decreasing the likelihood that this association is secondary to altered dietary intake only and may be related to other mechanisms.
Sara Horst, MD, MPH, is an assistant professor, division of gastroenterology, hepatology & nutrition, Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, Nashville, Tenn. She had no relevant conflicts of interest.
In this interesting study, Nikolaus et al. found an association of decreased serum tryptophan in patients with inflammatory bowel disease (IBD), compared with control subjects. The authors also found an inverse correlation of serum tryptophan levels in patients with C-reactive protein in both ulcerative colitis and Crohn's disease and with active disease as defined by clinical disease activity scores in Crohn's disease. A validated food-frequency questionnaire found no difference in tryptophan consumption based on disease activity in a subset of patients, decreasing the likelihood that this association is secondary to altered dietary intake only and may be related to other mechanisms.
Sara Horst, MD, MPH, is an assistant professor, division of gastroenterology, hepatology & nutrition, Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, Nashville, Tenn. She had no relevant conflicts of interest.
In this interesting study, Nikolaus et al. found an association of decreased serum tryptophan in patients with inflammatory bowel disease (IBD), compared with control subjects. The authors also found an inverse correlation of serum tryptophan levels in patients with C-reactive protein in both ulcerative colitis and Crohn's disease and with active disease as defined by clinical disease activity scores in Crohn's disease. A validated food-frequency questionnaire found no difference in tryptophan consumption based on disease activity in a subset of patients, decreasing the likelihood that this association is secondary to altered dietary intake only and may be related to other mechanisms.
Sara Horst, MD, MPH, is an assistant professor, division of gastroenterology, hepatology & nutrition, Inflammatory Bowel Disease Center, Vanderbilt University Medical Center, Nashville, Tenn. She had no relevant conflicts of interest.
Patients with inflammatory bowel disease (IBD) had significantly lower serum levels of the essential amino acid tryptophan than healthy controls in a large study reported in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.08.028).
Serum tryptophan levels also correlated inversely with both disease activity and C-reactive protein levels in patients with IBD, reported Susanna Nikolaus, MD, of University Hospital Schleswig-Holstein, Kiel, Germany, with her associates. “Tryptophan deficiency could contribute to development of IBD. Studies are needed to determine whether modification of intestinal tryptophan pathways affects [its] severity,” they wrote.
Several small case series have reported low levels of tryptophan in IBD and other autoimmune disorders, the investigators noted. Removing tryptophan from the diet has been found to increase susceptibility to colitis in mice, and supplementing with tryptophan or some of its metabolites has the opposite effect. For this study, the researchers used high-performance liquid chromatography to quantify tryptophan levels in serum samples from 535 consecutive patients with IBD and 100 matched controls. They used mass spectrometry to measure metabolites of tryptophan, enzyme-linked immunosorbent assay to measure interleukin-22 (IL-22) levels, and 16S rDNA amplicon sequencing to correlate tryptophan levels with fecal microbiota species. Finally, they used real-time polymerase chain reaction to measure levels of mRNA encoding tryptophan metabolites in colonic biopsy specimens.
Serum tryptophan levels were significantly lower in patients with IBD than controls (P = 5.3 x 10–6). The difference was starker in patients with Crohn’s disease (P = 1.1 x 10–10 vs. controls) compared with those with ulcerative colitis (P = 2.8 x 10–3 vs. controls), the investigators noted. Serum tryptophan levels also correlated inversely with disease activity in patients with Crohn’s disease (P = .01), while patients with ulcerative colitis showed a similar but nonsignificant trend (P = .07). Low tryptophan levels were associated with marked, statistically significant increases in C-reactive protein levels in both Crohn’s disease and ulcerative colitis. Tryptophan level also correlated inversely with leukocyte count, although the trend was less pronounced (P = .04).IBD was associated with several aberrations in the tryptophan kynurenine pathway, which is the primary means of catabolizing the amino acid. For example, compared with controls, patients with active IBD had significantly lower levels of mRNA encoding tryptophan 2,3-dioxygenase-2 (TDO2, a key enzyme in the kynurenine pathway) and solute carrier family 6 member 19 (SLC6A19, also called B0AT1, a neutral amino acid transporter). Patients with IBD also had significantly higher levels of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial, rate-limiting oxidation of tryptophan to kynurenine. Accordingly, patients with IBD had a significantly higher ratio of kynurenine to tryptophan than did controls, and this abnormality was associated with disease activity, especially in Crohn’s disease (P = .03).
Patients with IBD who had relatively higher tryptophan levels also tended to have more diverse gut microbiota than did patients with lower serum tryptophan levels, although differences among groups were not statistically significant, the investigators said. Serum concentration of IL-22 also correlated with disease activity in patients with IBD, and infliximab responders had a “significant and sustained increase” of tryptophan levels over time, compared with nonresponders.
Potsdam dietary questionnaires found no link between disease activity and dietary consumption of tryptophan, the researchers said. Additionally, they found no links between serum tryptophan levels and age, smoking status, or disease complications, such as fistulae or abscess formation.The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop drugs with inflammatory indications. The other investigators had no conflicts of interest.
Patients with inflammatory bowel disease (IBD) had significantly lower serum levels of the essential amino acid tryptophan than healthy controls in a large study reported in the December issue of Gastroenterology (doi: 10.1053/j.gastro.2017.08.028).
Serum tryptophan levels also correlated inversely with both disease activity and C-reactive protein levels in patients with IBD, reported Susanna Nikolaus, MD, of University Hospital Schleswig-Holstein, Kiel, Germany, with her associates. “Tryptophan deficiency could contribute to development of IBD. Studies are needed to determine whether modification of intestinal tryptophan pathways affects [its] severity,” they wrote.
Several small case series have reported low levels of tryptophan in IBD and other autoimmune disorders, the investigators noted. Removing tryptophan from the diet has been found to increase susceptibility to colitis in mice, and supplementing with tryptophan or some of its metabolites has the opposite effect. For this study, the researchers used high-performance liquid chromatography to quantify tryptophan levels in serum samples from 535 consecutive patients with IBD and 100 matched controls. They used mass spectrometry to measure metabolites of tryptophan, enzyme-linked immunosorbent assay to measure interleukin-22 (IL-22) levels, and 16S rDNA amplicon sequencing to correlate tryptophan levels with fecal microbiota species. Finally, they used real-time polymerase chain reaction to measure levels of mRNA encoding tryptophan metabolites in colonic biopsy specimens.
Serum tryptophan levels were significantly lower in patients with IBD than controls (P = 5.3 x 10–6). The difference was starker in patients with Crohn’s disease (P = 1.1 x 10–10 vs. controls) compared with those with ulcerative colitis (P = 2.8 x 10–3 vs. controls), the investigators noted. Serum tryptophan levels also correlated inversely with disease activity in patients with Crohn’s disease (P = .01), while patients with ulcerative colitis showed a similar but nonsignificant trend (P = .07). Low tryptophan levels were associated with marked, statistically significant increases in C-reactive protein levels in both Crohn’s disease and ulcerative colitis. Tryptophan level also correlated inversely with leukocyte count, although the trend was less pronounced (P = .04).IBD was associated with several aberrations in the tryptophan kynurenine pathway, which is the primary means of catabolizing the amino acid. For example, compared with controls, patients with active IBD had significantly lower levels of mRNA encoding tryptophan 2,3-dioxygenase-2 (TDO2, a key enzyme in the kynurenine pathway) and solute carrier family 6 member 19 (SLC6A19, also called B0AT1, a neutral amino acid transporter). Patients with IBD also had significantly higher levels of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial, rate-limiting oxidation of tryptophan to kynurenine. Accordingly, patients with IBD had a significantly higher ratio of kynurenine to tryptophan than did controls, and this abnormality was associated with disease activity, especially in Crohn’s disease (P = .03).
Patients with IBD who had relatively higher tryptophan levels also tended to have more diverse gut microbiota than did patients with lower serum tryptophan levels, although differences among groups were not statistically significant, the investigators said. Serum concentration of IL-22 also correlated with disease activity in patients with IBD, and infliximab responders had a “significant and sustained increase” of tryptophan levels over time, compared with nonresponders.
Potsdam dietary questionnaires found no link between disease activity and dietary consumption of tryptophan, the researchers said. Additionally, they found no links between serum tryptophan levels and age, smoking status, or disease complications, such as fistulae or abscess formation.The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop drugs with inflammatory indications. The other investigators had no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Patients with inflammatory bowel disease had significantly lower serum tryptophan levels than healthy controls.
Major finding: Serum tryptophan levels also correlated inversely with disease activity and C-reactive protein levels in patients with IBD.
Data source: An analysis of serum samples from 535 consecutive patients with IBD and 100 matched controls.
Disclosures: The investigators acknowledged grant support from the DFG Excellence Cluster “Inflammation at Interfaces” and BMBF e-med SYSINFLAME and H2020 SysCID. One coinvestigator reported employment by CONARIS Research Institute AG, which helps develop therapies with inflammatory indications. The other investigators had no conflicts of interest.
Constructing an inflammatory bowel disease patient–centered medical home
Inflammatory bowel diseases (IBDs) including Crohn’s disease and ulcerative colitis are life-long chronic diseases with high morbidity. There has been remarkable progress in the understanding of disease pathophysiology, leading to new medical therapies and surgical approaches for the management of IBD. These trends have resulted in a marked increase in the cost of IBD care, with current estimates ranging from $14 to $31 billion in both direct and indirect costs in the United States.1
IBD patients have unique behavioral, preventive, and therapeutic care requirements.2,3 Because of the complexity of care, there is a large degree of segmentation and fragmentation of IBD management across health care systems and among multiple providers. This siloed approach often falls short of seamless, efficient, high-quality, patient-centered care.
To address the increasing costs and fragmentation of chronic disease management, population-based health care has emerged as a new concept with an emphasis on reward for value, not volume. Two such examples of population-based health care include accountable care organizations and patient-centered medical homes. This concept relies on the development of new payment models and shifts the risk to the providers.4,5 Primary care providers play a central coordinating role in these new models.6,7 However, the role of specialists is less well defined, with limited sharing of risk for the care and costs of populations.
The IBD specialty medical home (SMH) implemented at the University of Pittsburgh Medical Center (UPMC) is an example of a new model of care. The IBD SMH is constructed to align incentives and provide up-front resources to manage a population of patients with IBD optimally – including treatment of their inflammatory disease, coexisting pain, and psychological issues.8-10 In the case of the IBD SMH, the gastroenterologist is the principal provider for a cohort of IBD patients. The gastroenterologist is responsible for the coordination and management of health care of this population and places the IBD patient at the center of the medical universe.
In this article, we draw from our rich partnership between the UPMC Health Plan (HP) and Health System to describe the construction and deployment of the IBD SMH. Although this model is new and we still are learning, we already have seen an improvement in the overall quality of life, decreased utilization, and reduction in total cost of care for this IBD SMH population.
Constructing an IBD medical home: where to begin?
In conjunction with the UPMC HP, we designed and established an IBD patient-centered SMH, designated in July 2015 as UPMC Total Care–Inflammatory Bowel Disease.11 The development of the medical home was facilitated by our unique integrated delivery and finance system. The UPMC HP provided important utilization data on their IBD population, which allowed for focused enrollment of the highest-utilizer patients. In addition, the UPMC HP funded positions that we hired directly as employees of our IBD SMH. These positions included the following: two nurse coordinators, two certified nurse practitioners, a dietitian, a social worker, and a psychiatrist. The UPMC HP also provided their own HP employees to work with our IBD SMH: The rare and chronic disease team included two nurses and a social worker who made house calls for a select group of patients (identified based on the frequency of their health care use). The HP also provided health coaches who worked directly with our patients on lifestyle modifications, such as smoking cessation and exercise programs. Finally, the UPMC HP worked with the IBD SMH to provide support for a variety of operational functions. Examples of these important efforts included data analytics through their department of health economics, regular collaboration to assist the provider team in modifying the program, publicizing the IBD SMH to their members, and facilitating approval of IBD medications through their pharmacy department.
We acknowledge that the development and implementation of an IBD SMH will vary from region to region and depend on the relationship of payers and providers. Thus, the blueprint of our UPMC IBD Medical Home may not be replicated readily in other centers or regions. However, there are several core elements that we believe are necessary in constructing any SMH: 1) a payer willing to partner with the provider, 2) a patient population with specific characteristics, 3) a physician champion, and 4) prespecified goals and measures of success.
Payer or health plan
A SMH is based on the premise that providers and payers working together can achieve more efficient, high-quality care for patients than either party working alone. Payers have essential resources for infrastructure support, preventive services delivery, marketing and engagement expertise, large databases for risk stratification and gap closure, and care management capacity to be a valuable partner. In the short term, philanthropy, grants, and crowd-sourcing options can be used to provide initial support for components of the SMH; however, these rarely are sustainable long-term options. Thus, the most critical collaboration necessary to considering a SMH is between payer(s) (insurance company or health plan) and the specialty provider.
Ideally, the local environment should consist of a single or a few large payers to ease SMH implementation. UPMC is a large integrated delivery (25 hospitals and more than 600 clinics) and financing system (more than 3 million members and is the dominant payer in the region), with a history of leveraging payer–provider partnerships to achieve better patient care, education, and research, and thus served as an ideal collaborator in the design and launch of the IBD SMH. Most physicians in the United States do not work in an integrated payer–provider health delivery system, and partnering with a large regional payer with an interest in specialty population-based chronic care is reasonable for constructing an SMH in your medical neighborhood.
Patient population
In addition to having a collaborative health plan with large population coverage, there must exist a substantial IBD population managed by gastroenterologists. There must be a sufficient number of high-utilizer, high-cost members to justify up-front capital expenditure and return on investment. To determine the feasibility and utility of creating an IBD SMH at UPMC, we collected baseline data on the following: 1) the number of IBD patients within our IBD center and health plan, 2) a hotspotting analysis for our Pennsylvania counties, and 3) health care utilization of the IBD population of interest. At the time of the SMH inception, there were 6,319 Crohn’s disease and ulcerative colitis patients (including all insurance plans) in our center, with more than 3,500 members insured by our HP. There was a 30% increase in new IBD patients to our center in the 3 years before starting the IBD SMH, and the HP had a 27% increase in overall IBD members. Based on a regional hotspotting analysis, $24.3 million of the annual total of $36.9 million was related to hospitalization costs from our IBD patients. The high-utilizer patients accounted for most of the total cost of care for our HP; 16% accounted for 48% of the per-member per-month cost and 29% accounted for 79% of the total annual cost. These baseline data supported justification for an IBD SMH.
Although there is no absolute minimum number of members (patients) required, and the SMH model can be scaled to various IBD populations, we believe that at least 1,000 patients covered by a single insurer must exist. The justification for the 1,000 patients is an estimate of the number of high-utilizer patients who would be required to justify a cost savings, and ultimately a return on investment. We calculated that at least 300 high-utilizer patients would need to be included in our IBD SMH to show a reduction in health care utilization and total cost of care. Therefore, if we assume that approximately 30% of any chronic disease population drives the majority of cost and represents the highest utilizers, we estimated that at least 1,000 patients should be covered by a single insurer.
For development of an SMH, there are two approaches that may be taken: Design the medical home for the entire Health Plan’s population of patients with the disease of interest, or focus only on the high-utilizing, most expensive patients. The latter will include a more complex and challenging cohort of patients, but likely will provide the opportunity to show a reduction in utilization and total cost of care than a broader all-comers population approach.
Physician champions
A successful SMH requires a physician (or health care provider) champion. IBD care within the SMH is unique and distinct from gastroenterologists’ classic training and specialty care. In addition to addressing the biologic disease, the emphasis is on whole-patient care: preventive care, behavioral medicine, socioeconomic considerations of the patient, and provision of care for nongastrointestinal symptoms and diseases. In an SMH, the specialist must be willing to incorporate and address all facets of health care to improve patient outcomes.
Goals and measures of success
To ensure successful deployment of an SMH, it is important to establish shared payer–provider goals and metrics during the construction phase of the medical home. These goals should include an enrollment target number for each year, quality improvement metrics, patient experience outcomes, and metrics for a reduction in health care utilization and total cost of care. Examples of our IBD SMH year 1 and year 2 goals are outlined in Supplementary Table 1 (at http://dx.doi.org/10.1016/j.cgh.2017.05.026). In the first year of our IBD SMH, we were able to achieve our goals, and publication of our results is forthcoming. We have enrolled more than 325 patients, retained 90%, reduced emergency room visits and hospitalizations by 50%, and significantly improved quality of life. Most of our patients have been assigned an HP coach and use the electronic medical portal to communicate with the medical home. Our patient satisfaction for physician communication was 99%.
Key components of the IBD medical home
Based on our experience, we believe the following are key components of a successful IBD SMH: 1) team-based care with physician extenders, nurse coordinators, schedulers, social workers, and dietitians as essential members of the IBD SMH; 2) effective care coordination to reduce barriers to comprehensive biopsychosocial care; 3) tracking of process and outcome metrics of interest; 4) appropriate use of technology to enhance clinical care; and 5) care access (e.g., open-access appointments), after-hours care, and follow-up care after emergency room visits and hospitalizations (Table 1).
Although the eventual goal of an IBD SMH is to consolidate health care for all IBD patients, the initial launch stages are more likely to succeed if the SMH focuses on the subgroup of IBD patients who use health care excessively, often in an unplanned fashion (e.g., emergency department visits or hospitalizations). In conjunction with a payer, it is easy to identify the most costly IBD patients in a cohort. For example, for initial enrollment, the UPMC IBD SMH selected patients between the ages of 18 and 55 years, with confirmed Crohn’s disease or ulcerative colitis, and evidence that IBD was a primary driver of patients’ health care utilization; the latter was defined if the majority of health care expenditures in the prior year was related to IBD (as judged by International Classification of Diseases, 9th and 10th revisions, primary and secondary diagnoses).
Team-based care
A central component to our IBD SMH was the creation of an integrated team. Supplementary Table 2 (at http://dx.doi.org/10.1016/j.cgh.2017.05.026) describes various positions that are vital for a successful SMH. For a team approach to be most effective, there needs to be clear definitions or roles and role overlaps so that team members can work as a cohesive, organized, and efficient unit. Physician extenders are critical to the model’s success and are trained to make routine IBD care decisions, provide basic primary care, and coordinate care with the gastroenterologist to meet patient needs. The staff-to-patient ratio requirements may vary from region to region and from SMH to SMH. The nurse coordinators and physician extenders assume the burden of day-to-day patient care, and are supervised by the gastroenterologist and psychiatrist. In our UPMC IBD SMH, the ratio of one nurse coordinator and one certified nurse practitioner per 500 patients is sufficient. In addition, one social worker, one dietitian, one scheduler, one gastroenterologist, and one psychiatrist per 1,000 patients is our current model. To date, we have enrolled more than 500 patients, and through funding from our UPMC HP, we have just hired our second nurse coordinator and second nurse practitioner in anticipation of 1,000 patients by year 4.
Care coordination and incorporation of technology
The team composition is organized to provide tiered care for optimal efficiency. For such a stepped care model to be effective and scalable, two components are essential. The first component is a care coordination system that allows for the reliable classification of the biological, psychological, social, and health systems barriers faced by patients. To this end, our SMH developed an IBD-specific complexity grid (Supplementary Table 3; at http://dx.doi.org/10.1016/j.cgh.2017.05.026) that was derived from a primary care model.12 The second component is the use of technology-enhanced care to scale delivery of services in a population health model. Examples of technology in our SMH include the use of telemedicine/telepsychiatry by secure video, health coach virtual visits, remote monitoring, and provider-assisted behavioral interventions that patients can access on their smart phones.
New payment models for specialty medical homes
The SMH transitions away from relative value unit–based reimbursement and toward a value-based paradigm. In the SMH, the gastroenterologist serves as the principal medical provider for the IBD patient. Both providers and payers will be able to refer patients to the SMH. Data on quality metrics will be tracked and physician extenders and nurse coordinators will help ensure that goals are met. Quality improvement, preventive medicine, telemedicine, and point-of-contact mental health care will replace the volume-based relative value unit system.
Alternative payment models will be required to support the SMH. Because of the novel nature of the SMH, the optimal payment model has yet to be determined, but probably will include either a shared savings or global cap approach, with an emphasis on the total cost of care reduction. This means that the specialist in the SMH must be aware of all care, and the cost of care, that the patient receives. Biologics and other IBD therapy costs are high and will continue to increase. The sustainable model must be sufficiently supple to not disincentivize the provider to use proven and effective, albeit expensive, therapy for patients who need it most. A close working relationship between the SMH providers and the health plan chief pharmacy officer will be essential. We expect that appropriate use of medications will lead to a medical cost offset with improved IBD outcomes, a reduction in health care utilization, and optimized work and life productivity.
Conclusions
In new models of care, specialty providers partner with payers in a patient-centered system to provide principal care for patients with chronic diseases, including IBD, in an effort to reduce costs and provide efficient, high-quality care. These models will require close collaborations with payers, a sufficiently large patient population, a physician champion, and a multidisciplinary staff targeting various aspects of health care. Successful implementation of such models will help reduce costs of care while improving the patient-centered experience and outcomes.
Supplementary material
To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2017.05.026.
References
1. Mehta F. Report: economic implications of inflammatory bowel disease and its management. Am J Manag Care. 2016;22(Suppl):s51-60.
2. Mikocka-Walus A., Knowles S.R., Keefer L., et al. Controversies revisited: a systematic review of the comorbidity of depression and anxiety with inflammatory bowel diseases. Inflamm Bowel Dis. 2016;22:752-62.
3. Regueiro M., Greer J.B., Szigethy E. Etiology and treatment of pain and psychosocial issues in patients with inflammatory bowel diseases. Gastroenterology. 2017;152:430-9.e4.
4. Silow-Carroll S., Edwards J.N., Rodin D. How Colorado, Minnesota, and Vermont are reforming care delivery and payment to improve health and lower costs. Issue Brief. (Commonw Fund) 2013;10:1-9.
5. Fogelman C., Gates T. A primary care perspective on U.S. health care: part 2: thinking globally, acting locally. J Lancaster Gen Hospital. 2013;8:101-5.
6. Rosenthal M.B., Sinaiko A.D., Eastman D., et al. Impact of the Rochester medical home initiative on primary care practices, quality, utilization, and costs. Med Care. 2015;53:967-73.
7. Friedberg M.W., Rosenthal M.B., Werner R.M., et al. Effects of a medical home and shared savings intervention on quality and utilization of care. JAMA Intern Med. 2015;175:1362-8.
8. Fernandes S.M., Sanders L.M. Patient-centered medical home for patients with complex congenital heart disease. Curr Opin Pediatr. 2015;27:581-6.
9. Mikocka-Walus A.A., Andrews J.M., Bernstein C.N., et al. Integrated models of care in managing inflammatory bowel disease: a discussion. Inflamm Bowel Dis. 2012;18:1582-7.
10. Kessler R., Miller B.F., Kelly M., et al. Mental health, substance abuse, and health behavior services in patient-centered medical homes. J Am Board Fam Med. 2014;27:637-44.
11. Regueiro M.D., McAnallen S.E., Greer J.B., et al. The inflammatory bowel disease specialty medical home: a new model of patient centered care. Inflamm Bowel Dis. 2016;22:1971-80.
12. Lobo E., Ventura T., Navio M., et al. Identification of components of health complexity on internal medicine units by means of the INTERMED method. Int J Clin Pract. 2015;69:1377-86.
Dr. Regueiro and Dr. Click are in the division of gastroenterology, hepatology and nutrition, University of Pittsburgh Medical Center; Ms. Holder, Dr. Shrank, and Ms. McAnAllen are in the Insurance Services Division, University of Pittsburgh Medical Center, and Dr. Szigethy is in the Department of Psychiatry, University of Pittsburgh School of Medicine. Dr. Regueiro serves as a consultant for, on advisory boards for, and receives research support from Abbvie, Janssen, and Takeda; and Dr. Szigethy serves as a consultant for Abbvie. The remaining authors disclose no conflicts.
Inflammatory bowel diseases (IBDs) including Crohn’s disease and ulcerative colitis are life-long chronic diseases with high morbidity. There has been remarkable progress in the understanding of disease pathophysiology, leading to new medical therapies and surgical approaches for the management of IBD. These trends have resulted in a marked increase in the cost of IBD care, with current estimates ranging from $14 to $31 billion in both direct and indirect costs in the United States.1
IBD patients have unique behavioral, preventive, and therapeutic care requirements.2,3 Because of the complexity of care, there is a large degree of segmentation and fragmentation of IBD management across health care systems and among multiple providers. This siloed approach often falls short of seamless, efficient, high-quality, patient-centered care.
To address the increasing costs and fragmentation of chronic disease management, population-based health care has emerged as a new concept with an emphasis on reward for value, not volume. Two such examples of population-based health care include accountable care organizations and patient-centered medical homes. This concept relies on the development of new payment models and shifts the risk to the providers.4,5 Primary care providers play a central coordinating role in these new models.6,7 However, the role of specialists is less well defined, with limited sharing of risk for the care and costs of populations.
The IBD specialty medical home (SMH) implemented at the University of Pittsburgh Medical Center (UPMC) is an example of a new model of care. The IBD SMH is constructed to align incentives and provide up-front resources to manage a population of patients with IBD optimally – including treatment of their inflammatory disease, coexisting pain, and psychological issues.8-10 In the case of the IBD SMH, the gastroenterologist is the principal provider for a cohort of IBD patients. The gastroenterologist is responsible for the coordination and management of health care of this population and places the IBD patient at the center of the medical universe.
In this article, we draw from our rich partnership between the UPMC Health Plan (HP) and Health System to describe the construction and deployment of the IBD SMH. Although this model is new and we still are learning, we already have seen an improvement in the overall quality of life, decreased utilization, and reduction in total cost of care for this IBD SMH population.
Constructing an IBD medical home: where to begin?
In conjunction with the UPMC HP, we designed and established an IBD patient-centered SMH, designated in July 2015 as UPMC Total Care–Inflammatory Bowel Disease.11 The development of the medical home was facilitated by our unique integrated delivery and finance system. The UPMC HP provided important utilization data on their IBD population, which allowed for focused enrollment of the highest-utilizer patients. In addition, the UPMC HP funded positions that we hired directly as employees of our IBD SMH. These positions included the following: two nurse coordinators, two certified nurse practitioners, a dietitian, a social worker, and a psychiatrist. The UPMC HP also provided their own HP employees to work with our IBD SMH: The rare and chronic disease team included two nurses and a social worker who made house calls for a select group of patients (identified based on the frequency of their health care use). The HP also provided health coaches who worked directly with our patients on lifestyle modifications, such as smoking cessation and exercise programs. Finally, the UPMC HP worked with the IBD SMH to provide support for a variety of operational functions. Examples of these important efforts included data analytics through their department of health economics, regular collaboration to assist the provider team in modifying the program, publicizing the IBD SMH to their members, and facilitating approval of IBD medications through their pharmacy department.
We acknowledge that the development and implementation of an IBD SMH will vary from region to region and depend on the relationship of payers and providers. Thus, the blueprint of our UPMC IBD Medical Home may not be replicated readily in other centers or regions. However, there are several core elements that we believe are necessary in constructing any SMH: 1) a payer willing to partner with the provider, 2) a patient population with specific characteristics, 3) a physician champion, and 4) prespecified goals and measures of success.
Payer or health plan
A SMH is based on the premise that providers and payers working together can achieve more efficient, high-quality care for patients than either party working alone. Payers have essential resources for infrastructure support, preventive services delivery, marketing and engagement expertise, large databases for risk stratification and gap closure, and care management capacity to be a valuable partner. In the short term, philanthropy, grants, and crowd-sourcing options can be used to provide initial support for components of the SMH; however, these rarely are sustainable long-term options. Thus, the most critical collaboration necessary to considering a SMH is between payer(s) (insurance company or health plan) and the specialty provider.
Ideally, the local environment should consist of a single or a few large payers to ease SMH implementation. UPMC is a large integrated delivery (25 hospitals and more than 600 clinics) and financing system (more than 3 million members and is the dominant payer in the region), with a history of leveraging payer–provider partnerships to achieve better patient care, education, and research, and thus served as an ideal collaborator in the design and launch of the IBD SMH. Most physicians in the United States do not work in an integrated payer–provider health delivery system, and partnering with a large regional payer with an interest in specialty population-based chronic care is reasonable for constructing an SMH in your medical neighborhood.
Patient population
In addition to having a collaborative health plan with large population coverage, there must exist a substantial IBD population managed by gastroenterologists. There must be a sufficient number of high-utilizer, high-cost members to justify up-front capital expenditure and return on investment. To determine the feasibility and utility of creating an IBD SMH at UPMC, we collected baseline data on the following: 1) the number of IBD patients within our IBD center and health plan, 2) a hotspotting analysis for our Pennsylvania counties, and 3) health care utilization of the IBD population of interest. At the time of the SMH inception, there were 6,319 Crohn’s disease and ulcerative colitis patients (including all insurance plans) in our center, with more than 3,500 members insured by our HP. There was a 30% increase in new IBD patients to our center in the 3 years before starting the IBD SMH, and the HP had a 27% increase in overall IBD members. Based on a regional hotspotting analysis, $24.3 million of the annual total of $36.9 million was related to hospitalization costs from our IBD patients. The high-utilizer patients accounted for most of the total cost of care for our HP; 16% accounted for 48% of the per-member per-month cost and 29% accounted for 79% of the total annual cost. These baseline data supported justification for an IBD SMH.
Although there is no absolute minimum number of members (patients) required, and the SMH model can be scaled to various IBD populations, we believe that at least 1,000 patients covered by a single insurer must exist. The justification for the 1,000 patients is an estimate of the number of high-utilizer patients who would be required to justify a cost savings, and ultimately a return on investment. We calculated that at least 300 high-utilizer patients would need to be included in our IBD SMH to show a reduction in health care utilization and total cost of care. Therefore, if we assume that approximately 30% of any chronic disease population drives the majority of cost and represents the highest utilizers, we estimated that at least 1,000 patients should be covered by a single insurer.
For development of an SMH, there are two approaches that may be taken: Design the medical home for the entire Health Plan’s population of patients with the disease of interest, or focus only on the high-utilizing, most expensive patients. The latter will include a more complex and challenging cohort of patients, but likely will provide the opportunity to show a reduction in utilization and total cost of care than a broader all-comers population approach.
Physician champions
A successful SMH requires a physician (or health care provider) champion. IBD care within the SMH is unique and distinct from gastroenterologists’ classic training and specialty care. In addition to addressing the biologic disease, the emphasis is on whole-patient care: preventive care, behavioral medicine, socioeconomic considerations of the patient, and provision of care for nongastrointestinal symptoms and diseases. In an SMH, the specialist must be willing to incorporate and address all facets of health care to improve patient outcomes.
Goals and measures of success
To ensure successful deployment of an SMH, it is important to establish shared payer–provider goals and metrics during the construction phase of the medical home. These goals should include an enrollment target number for each year, quality improvement metrics, patient experience outcomes, and metrics for a reduction in health care utilization and total cost of care. Examples of our IBD SMH year 1 and year 2 goals are outlined in Supplementary Table 1 (at http://dx.doi.org/10.1016/j.cgh.2017.05.026). In the first year of our IBD SMH, we were able to achieve our goals, and publication of our results is forthcoming. We have enrolled more than 325 patients, retained 90%, reduced emergency room visits and hospitalizations by 50%, and significantly improved quality of life. Most of our patients have been assigned an HP coach and use the electronic medical portal to communicate with the medical home. Our patient satisfaction for physician communication was 99%.
Key components of the IBD medical home
Based on our experience, we believe the following are key components of a successful IBD SMH: 1) team-based care with physician extenders, nurse coordinators, schedulers, social workers, and dietitians as essential members of the IBD SMH; 2) effective care coordination to reduce barriers to comprehensive biopsychosocial care; 3) tracking of process and outcome metrics of interest; 4) appropriate use of technology to enhance clinical care; and 5) care access (e.g., open-access appointments), after-hours care, and follow-up care after emergency room visits and hospitalizations (Table 1).
Although the eventual goal of an IBD SMH is to consolidate health care for all IBD patients, the initial launch stages are more likely to succeed if the SMH focuses on the subgroup of IBD patients who use health care excessively, often in an unplanned fashion (e.g., emergency department visits or hospitalizations). In conjunction with a payer, it is easy to identify the most costly IBD patients in a cohort. For example, for initial enrollment, the UPMC IBD SMH selected patients between the ages of 18 and 55 years, with confirmed Crohn’s disease or ulcerative colitis, and evidence that IBD was a primary driver of patients’ health care utilization; the latter was defined if the majority of health care expenditures in the prior year was related to IBD (as judged by International Classification of Diseases, 9th and 10th revisions, primary and secondary diagnoses).
Team-based care
A central component to our IBD SMH was the creation of an integrated team. Supplementary Table 2 (at http://dx.doi.org/10.1016/j.cgh.2017.05.026) describes various positions that are vital for a successful SMH. For a team approach to be most effective, there needs to be clear definitions or roles and role overlaps so that team members can work as a cohesive, organized, and efficient unit. Physician extenders are critical to the model’s success and are trained to make routine IBD care decisions, provide basic primary care, and coordinate care with the gastroenterologist to meet patient needs. The staff-to-patient ratio requirements may vary from region to region and from SMH to SMH. The nurse coordinators and physician extenders assume the burden of day-to-day patient care, and are supervised by the gastroenterologist and psychiatrist. In our UPMC IBD SMH, the ratio of one nurse coordinator and one certified nurse practitioner per 500 patients is sufficient. In addition, one social worker, one dietitian, one scheduler, one gastroenterologist, and one psychiatrist per 1,000 patients is our current model. To date, we have enrolled more than 500 patients, and through funding from our UPMC HP, we have just hired our second nurse coordinator and second nurse practitioner in anticipation of 1,000 patients by year 4.
Care coordination and incorporation of technology
The team composition is organized to provide tiered care for optimal efficiency. For such a stepped care model to be effective and scalable, two components are essential. The first component is a care coordination system that allows for the reliable classification of the biological, psychological, social, and health systems barriers faced by patients. To this end, our SMH developed an IBD-specific complexity grid (Supplementary Table 3; at http://dx.doi.org/10.1016/j.cgh.2017.05.026) that was derived from a primary care model.12 The second component is the use of technology-enhanced care to scale delivery of services in a population health model. Examples of technology in our SMH include the use of telemedicine/telepsychiatry by secure video, health coach virtual visits, remote monitoring, and provider-assisted behavioral interventions that patients can access on their smart phones.
New payment models for specialty medical homes
The SMH transitions away from relative value unit–based reimbursement and toward a value-based paradigm. In the SMH, the gastroenterologist serves as the principal medical provider for the IBD patient. Both providers and payers will be able to refer patients to the SMH. Data on quality metrics will be tracked and physician extenders and nurse coordinators will help ensure that goals are met. Quality improvement, preventive medicine, telemedicine, and point-of-contact mental health care will replace the volume-based relative value unit system.
Alternative payment models will be required to support the SMH. Because of the novel nature of the SMH, the optimal payment model has yet to be determined, but probably will include either a shared savings or global cap approach, with an emphasis on the total cost of care reduction. This means that the specialist in the SMH must be aware of all care, and the cost of care, that the patient receives. Biologics and other IBD therapy costs are high and will continue to increase. The sustainable model must be sufficiently supple to not disincentivize the provider to use proven and effective, albeit expensive, therapy for patients who need it most. A close working relationship between the SMH providers and the health plan chief pharmacy officer will be essential. We expect that appropriate use of medications will lead to a medical cost offset with improved IBD outcomes, a reduction in health care utilization, and optimized work and life productivity.
Conclusions
In new models of care, specialty providers partner with payers in a patient-centered system to provide principal care for patients with chronic diseases, including IBD, in an effort to reduce costs and provide efficient, high-quality care. These models will require close collaborations with payers, a sufficiently large patient population, a physician champion, and a multidisciplinary staff targeting various aspects of health care. Successful implementation of such models will help reduce costs of care while improving the patient-centered experience and outcomes.
Supplementary material
To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2017.05.026.
References
1. Mehta F. Report: economic implications of inflammatory bowel disease and its management. Am J Manag Care. 2016;22(Suppl):s51-60.
2. Mikocka-Walus A., Knowles S.R., Keefer L., et al. Controversies revisited: a systematic review of the comorbidity of depression and anxiety with inflammatory bowel diseases. Inflamm Bowel Dis. 2016;22:752-62.
3. Regueiro M., Greer J.B., Szigethy E. Etiology and treatment of pain and psychosocial issues in patients with inflammatory bowel diseases. Gastroenterology. 2017;152:430-9.e4.
4. Silow-Carroll S., Edwards J.N., Rodin D. How Colorado, Minnesota, and Vermont are reforming care delivery and payment to improve health and lower costs. Issue Brief. (Commonw Fund) 2013;10:1-9.
5. Fogelman C., Gates T. A primary care perspective on U.S. health care: part 2: thinking globally, acting locally. J Lancaster Gen Hospital. 2013;8:101-5.
6. Rosenthal M.B., Sinaiko A.D., Eastman D., et al. Impact of the Rochester medical home initiative on primary care practices, quality, utilization, and costs. Med Care. 2015;53:967-73.
7. Friedberg M.W., Rosenthal M.B., Werner R.M., et al. Effects of a medical home and shared savings intervention on quality and utilization of care. JAMA Intern Med. 2015;175:1362-8.
8. Fernandes S.M., Sanders L.M. Patient-centered medical home for patients with complex congenital heart disease. Curr Opin Pediatr. 2015;27:581-6.
9. Mikocka-Walus A.A., Andrews J.M., Bernstein C.N., et al. Integrated models of care in managing inflammatory bowel disease: a discussion. Inflamm Bowel Dis. 2012;18:1582-7.
10. Kessler R., Miller B.F., Kelly M., et al. Mental health, substance abuse, and health behavior services in patient-centered medical homes. J Am Board Fam Med. 2014;27:637-44.
11. Regueiro M.D., McAnallen S.E., Greer J.B., et al. The inflammatory bowel disease specialty medical home: a new model of patient centered care. Inflamm Bowel Dis. 2016;22:1971-80.
12. Lobo E., Ventura T., Navio M., et al. Identification of components of health complexity on internal medicine units by means of the INTERMED method. Int J Clin Pract. 2015;69:1377-86.
Dr. Regueiro and Dr. Click are in the division of gastroenterology, hepatology and nutrition, University of Pittsburgh Medical Center; Ms. Holder, Dr. Shrank, and Ms. McAnAllen are in the Insurance Services Division, University of Pittsburgh Medical Center, and Dr. Szigethy is in the Department of Psychiatry, University of Pittsburgh School of Medicine. Dr. Regueiro serves as a consultant for, on advisory boards for, and receives research support from Abbvie, Janssen, and Takeda; and Dr. Szigethy serves as a consultant for Abbvie. The remaining authors disclose no conflicts.
Inflammatory bowel diseases (IBDs) including Crohn’s disease and ulcerative colitis are life-long chronic diseases with high morbidity. There has been remarkable progress in the understanding of disease pathophysiology, leading to new medical therapies and surgical approaches for the management of IBD. These trends have resulted in a marked increase in the cost of IBD care, with current estimates ranging from $14 to $31 billion in both direct and indirect costs in the United States.1
IBD patients have unique behavioral, preventive, and therapeutic care requirements.2,3 Because of the complexity of care, there is a large degree of segmentation and fragmentation of IBD management across health care systems and among multiple providers. This siloed approach often falls short of seamless, efficient, high-quality, patient-centered care.
To address the increasing costs and fragmentation of chronic disease management, population-based health care has emerged as a new concept with an emphasis on reward for value, not volume. Two such examples of population-based health care include accountable care organizations and patient-centered medical homes. This concept relies on the development of new payment models and shifts the risk to the providers.4,5 Primary care providers play a central coordinating role in these new models.6,7 However, the role of specialists is less well defined, with limited sharing of risk for the care and costs of populations.
The IBD specialty medical home (SMH) implemented at the University of Pittsburgh Medical Center (UPMC) is an example of a new model of care. The IBD SMH is constructed to align incentives and provide up-front resources to manage a population of patients with IBD optimally – including treatment of their inflammatory disease, coexisting pain, and psychological issues.8-10 In the case of the IBD SMH, the gastroenterologist is the principal provider for a cohort of IBD patients. The gastroenterologist is responsible for the coordination and management of health care of this population and places the IBD patient at the center of the medical universe.
In this article, we draw from our rich partnership between the UPMC Health Plan (HP) and Health System to describe the construction and deployment of the IBD SMH. Although this model is new and we still are learning, we already have seen an improvement in the overall quality of life, decreased utilization, and reduction in total cost of care for this IBD SMH population.
Constructing an IBD medical home: where to begin?
In conjunction with the UPMC HP, we designed and established an IBD patient-centered SMH, designated in July 2015 as UPMC Total Care–Inflammatory Bowel Disease.11 The development of the medical home was facilitated by our unique integrated delivery and finance system. The UPMC HP provided important utilization data on their IBD population, which allowed for focused enrollment of the highest-utilizer patients. In addition, the UPMC HP funded positions that we hired directly as employees of our IBD SMH. These positions included the following: two nurse coordinators, two certified nurse practitioners, a dietitian, a social worker, and a psychiatrist. The UPMC HP also provided their own HP employees to work with our IBD SMH: The rare and chronic disease team included two nurses and a social worker who made house calls for a select group of patients (identified based on the frequency of their health care use). The HP also provided health coaches who worked directly with our patients on lifestyle modifications, such as smoking cessation and exercise programs. Finally, the UPMC HP worked with the IBD SMH to provide support for a variety of operational functions. Examples of these important efforts included data analytics through their department of health economics, regular collaboration to assist the provider team in modifying the program, publicizing the IBD SMH to their members, and facilitating approval of IBD medications through their pharmacy department.
We acknowledge that the development and implementation of an IBD SMH will vary from region to region and depend on the relationship of payers and providers. Thus, the blueprint of our UPMC IBD Medical Home may not be replicated readily in other centers or regions. However, there are several core elements that we believe are necessary in constructing any SMH: 1) a payer willing to partner with the provider, 2) a patient population with specific characteristics, 3) a physician champion, and 4) prespecified goals and measures of success.
Payer or health plan
A SMH is based on the premise that providers and payers working together can achieve more efficient, high-quality care for patients than either party working alone. Payers have essential resources for infrastructure support, preventive services delivery, marketing and engagement expertise, large databases for risk stratification and gap closure, and care management capacity to be a valuable partner. In the short term, philanthropy, grants, and crowd-sourcing options can be used to provide initial support for components of the SMH; however, these rarely are sustainable long-term options. Thus, the most critical collaboration necessary to considering a SMH is between payer(s) (insurance company or health plan) and the specialty provider.
Ideally, the local environment should consist of a single or a few large payers to ease SMH implementation. UPMC is a large integrated delivery (25 hospitals and more than 600 clinics) and financing system (more than 3 million members and is the dominant payer in the region), with a history of leveraging payer–provider partnerships to achieve better patient care, education, and research, and thus served as an ideal collaborator in the design and launch of the IBD SMH. Most physicians in the United States do not work in an integrated payer–provider health delivery system, and partnering with a large regional payer with an interest in specialty population-based chronic care is reasonable for constructing an SMH in your medical neighborhood.
Patient population
In addition to having a collaborative health plan with large population coverage, there must exist a substantial IBD population managed by gastroenterologists. There must be a sufficient number of high-utilizer, high-cost members to justify up-front capital expenditure and return on investment. To determine the feasibility and utility of creating an IBD SMH at UPMC, we collected baseline data on the following: 1) the number of IBD patients within our IBD center and health plan, 2) a hotspotting analysis for our Pennsylvania counties, and 3) health care utilization of the IBD population of interest. At the time of the SMH inception, there were 6,319 Crohn’s disease and ulcerative colitis patients (including all insurance plans) in our center, with more than 3,500 members insured by our HP. There was a 30% increase in new IBD patients to our center in the 3 years before starting the IBD SMH, and the HP had a 27% increase in overall IBD members. Based on a regional hotspotting analysis, $24.3 million of the annual total of $36.9 million was related to hospitalization costs from our IBD patients. The high-utilizer patients accounted for most of the total cost of care for our HP; 16% accounted for 48% of the per-member per-month cost and 29% accounted for 79% of the total annual cost. These baseline data supported justification for an IBD SMH.
Although there is no absolute minimum number of members (patients) required, and the SMH model can be scaled to various IBD populations, we believe that at least 1,000 patients covered by a single insurer must exist. The justification for the 1,000 patients is an estimate of the number of high-utilizer patients who would be required to justify a cost savings, and ultimately a return on investment. We calculated that at least 300 high-utilizer patients would need to be included in our IBD SMH to show a reduction in health care utilization and total cost of care. Therefore, if we assume that approximately 30% of any chronic disease population drives the majority of cost and represents the highest utilizers, we estimated that at least 1,000 patients should be covered by a single insurer.
For development of an SMH, there are two approaches that may be taken: Design the medical home for the entire Health Plan’s population of patients with the disease of interest, or focus only on the high-utilizing, most expensive patients. The latter will include a more complex and challenging cohort of patients, but likely will provide the opportunity to show a reduction in utilization and total cost of care than a broader all-comers population approach.
Physician champions
A successful SMH requires a physician (or health care provider) champion. IBD care within the SMH is unique and distinct from gastroenterologists’ classic training and specialty care. In addition to addressing the biologic disease, the emphasis is on whole-patient care: preventive care, behavioral medicine, socioeconomic considerations of the patient, and provision of care for nongastrointestinal symptoms and diseases. In an SMH, the specialist must be willing to incorporate and address all facets of health care to improve patient outcomes.
Goals and measures of success
To ensure successful deployment of an SMH, it is important to establish shared payer–provider goals and metrics during the construction phase of the medical home. These goals should include an enrollment target number for each year, quality improvement metrics, patient experience outcomes, and metrics for a reduction in health care utilization and total cost of care. Examples of our IBD SMH year 1 and year 2 goals are outlined in Supplementary Table 1 (at http://dx.doi.org/10.1016/j.cgh.2017.05.026). In the first year of our IBD SMH, we were able to achieve our goals, and publication of our results is forthcoming. We have enrolled more than 325 patients, retained 90%, reduced emergency room visits and hospitalizations by 50%, and significantly improved quality of life. Most of our patients have been assigned an HP coach and use the electronic medical portal to communicate with the medical home. Our patient satisfaction for physician communication was 99%.
Key components of the IBD medical home
Based on our experience, we believe the following are key components of a successful IBD SMH: 1) team-based care with physician extenders, nurse coordinators, schedulers, social workers, and dietitians as essential members of the IBD SMH; 2) effective care coordination to reduce barriers to comprehensive biopsychosocial care; 3) tracking of process and outcome metrics of interest; 4) appropriate use of technology to enhance clinical care; and 5) care access (e.g., open-access appointments), after-hours care, and follow-up care after emergency room visits and hospitalizations (Table 1).
Although the eventual goal of an IBD SMH is to consolidate health care for all IBD patients, the initial launch stages are more likely to succeed if the SMH focuses on the subgroup of IBD patients who use health care excessively, often in an unplanned fashion (e.g., emergency department visits or hospitalizations). In conjunction with a payer, it is easy to identify the most costly IBD patients in a cohort. For example, for initial enrollment, the UPMC IBD SMH selected patients between the ages of 18 and 55 years, with confirmed Crohn’s disease or ulcerative colitis, and evidence that IBD was a primary driver of patients’ health care utilization; the latter was defined if the majority of health care expenditures in the prior year was related to IBD (as judged by International Classification of Diseases, 9th and 10th revisions, primary and secondary diagnoses).
Team-based care
A central component to our IBD SMH was the creation of an integrated team. Supplementary Table 2 (at http://dx.doi.org/10.1016/j.cgh.2017.05.026) describes various positions that are vital for a successful SMH. For a team approach to be most effective, there needs to be clear definitions or roles and role overlaps so that team members can work as a cohesive, organized, and efficient unit. Physician extenders are critical to the model’s success and are trained to make routine IBD care decisions, provide basic primary care, and coordinate care with the gastroenterologist to meet patient needs. The staff-to-patient ratio requirements may vary from region to region and from SMH to SMH. The nurse coordinators and physician extenders assume the burden of day-to-day patient care, and are supervised by the gastroenterologist and psychiatrist. In our UPMC IBD SMH, the ratio of one nurse coordinator and one certified nurse practitioner per 500 patients is sufficient. In addition, one social worker, one dietitian, one scheduler, one gastroenterologist, and one psychiatrist per 1,000 patients is our current model. To date, we have enrolled more than 500 patients, and through funding from our UPMC HP, we have just hired our second nurse coordinator and second nurse practitioner in anticipation of 1,000 patients by year 4.
Care coordination and incorporation of technology
The team composition is organized to provide tiered care for optimal efficiency. For such a stepped care model to be effective and scalable, two components are essential. The first component is a care coordination system that allows for the reliable classification of the biological, psychological, social, and health systems barriers faced by patients. To this end, our SMH developed an IBD-specific complexity grid (Supplementary Table 3; at http://dx.doi.org/10.1016/j.cgh.2017.05.026) that was derived from a primary care model.12 The second component is the use of technology-enhanced care to scale delivery of services in a population health model. Examples of technology in our SMH include the use of telemedicine/telepsychiatry by secure video, health coach virtual visits, remote monitoring, and provider-assisted behavioral interventions that patients can access on their smart phones.
New payment models for specialty medical homes
The SMH transitions away from relative value unit–based reimbursement and toward a value-based paradigm. In the SMH, the gastroenterologist serves as the principal medical provider for the IBD patient. Both providers and payers will be able to refer patients to the SMH. Data on quality metrics will be tracked and physician extenders and nurse coordinators will help ensure that goals are met. Quality improvement, preventive medicine, telemedicine, and point-of-contact mental health care will replace the volume-based relative value unit system.
Alternative payment models will be required to support the SMH. Because of the novel nature of the SMH, the optimal payment model has yet to be determined, but probably will include either a shared savings or global cap approach, with an emphasis on the total cost of care reduction. This means that the specialist in the SMH must be aware of all care, and the cost of care, that the patient receives. Biologics and other IBD therapy costs are high and will continue to increase. The sustainable model must be sufficiently supple to not disincentivize the provider to use proven and effective, albeit expensive, therapy for patients who need it most. A close working relationship between the SMH providers and the health plan chief pharmacy officer will be essential. We expect that appropriate use of medications will lead to a medical cost offset with improved IBD outcomes, a reduction in health care utilization, and optimized work and life productivity.
Conclusions
In new models of care, specialty providers partner with payers in a patient-centered system to provide principal care for patients with chronic diseases, including IBD, in an effort to reduce costs and provide efficient, high-quality care. These models will require close collaborations with payers, a sufficiently large patient population, a physician champion, and a multidisciplinary staff targeting various aspects of health care. Successful implementation of such models will help reduce costs of care while improving the patient-centered experience and outcomes.
Supplementary material
To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2017.05.026.
References
1. Mehta F. Report: economic implications of inflammatory bowel disease and its management. Am J Manag Care. 2016;22(Suppl):s51-60.
2. Mikocka-Walus A., Knowles S.R., Keefer L., et al. Controversies revisited: a systematic review of the comorbidity of depression and anxiety with inflammatory bowel diseases. Inflamm Bowel Dis. 2016;22:752-62.
3. Regueiro M., Greer J.B., Szigethy E. Etiology and treatment of pain and psychosocial issues in patients with inflammatory bowel diseases. Gastroenterology. 2017;152:430-9.e4.
4. Silow-Carroll S., Edwards J.N., Rodin D. How Colorado, Minnesota, and Vermont are reforming care delivery and payment to improve health and lower costs. Issue Brief. (Commonw Fund) 2013;10:1-9.
5. Fogelman C., Gates T. A primary care perspective on U.S. health care: part 2: thinking globally, acting locally. J Lancaster Gen Hospital. 2013;8:101-5.
6. Rosenthal M.B., Sinaiko A.D., Eastman D., et al. Impact of the Rochester medical home initiative on primary care practices, quality, utilization, and costs. Med Care. 2015;53:967-73.
7. Friedberg M.W., Rosenthal M.B., Werner R.M., et al. Effects of a medical home and shared savings intervention on quality and utilization of care. JAMA Intern Med. 2015;175:1362-8.
8. Fernandes S.M., Sanders L.M. Patient-centered medical home for patients with complex congenital heart disease. Curr Opin Pediatr. 2015;27:581-6.
9. Mikocka-Walus A.A., Andrews J.M., Bernstein C.N., et al. Integrated models of care in managing inflammatory bowel disease: a discussion. Inflamm Bowel Dis. 2012;18:1582-7.
10. Kessler R., Miller B.F., Kelly M., et al. Mental health, substance abuse, and health behavior services in patient-centered medical homes. J Am Board Fam Med. 2014;27:637-44.
11. Regueiro M.D., McAnallen S.E., Greer J.B., et al. The inflammatory bowel disease specialty medical home: a new model of patient centered care. Inflamm Bowel Dis. 2016;22:1971-80.
12. Lobo E., Ventura T., Navio M., et al. Identification of components of health complexity on internal medicine units by means of the INTERMED method. Int J Clin Pract. 2015;69:1377-86.
Dr. Regueiro and Dr. Click are in the division of gastroenterology, hepatology and nutrition, University of Pittsburgh Medical Center; Ms. Holder, Dr. Shrank, and Ms. McAnAllen are in the Insurance Services Division, University of Pittsburgh Medical Center, and Dr. Szigethy is in the Department of Psychiatry, University of Pittsburgh School of Medicine. Dr. Regueiro serves as a consultant for, on advisory boards for, and receives research support from Abbvie, Janssen, and Takeda; and Dr. Szigethy serves as a consultant for Abbvie. The remaining authors disclose no conflicts.
Barbara Vickrey, MD, MPH
Unsuspected Lymphomatoid Granulomatosis in a Patient With Antisynthetase Syndrome
Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)–related extranodal angiocentric lymphoproliferative disorder. Most patients are adults in the fifth decade of life, and men are twice as likely as women to be affected.1 The most common site of involvement is the lungs, which has been observed in more than 90% of patients.2 The skin is the most common extrapulmonary site of involvement with variable manifestations including “rash,” subcutaneous nodules, and ulceration. Although a small subset of patients experience remission without treatment, most patients report a progressive course with median survival of less than 2 years.1,2 Clinical diagnosis often is challenging due to underrecognition of this rare condition by multidisciplinary physicians.
Case Report
A 60-year-old woman presented with fatigue, night sweats, poor appetite, unintentional weight loss, and dyspnea with minor exertion of 2 weeks’ duration. Her medical history was remarkable for antisynthetase syndrome manifested as polymyositis and interstitial lung disease, as well as recurrent breast cancer treated with wide excision, chemotherapy, and radiation therapy completed 2 months prior. Antisynthetase syndrome was controlled with azathioprine for 2 years, which was stopped during chemotherapy but restarted to treat worsened myalgia 4 months prior to presentation. Two weeks prior to hospital admission, she was treated with antibiotics at an outside hospital for presumed pneumonia without improvement. Upon admission to our hospital she was pancytopenic. Chest computed tomography showed interval development of extensive patchy ground-glass opacities in all lung lobes with areas of confluent consolidation. Broad infectious workup was negative. Given the time course of presentation and anterior accentuation of the lung infiltrates, the greatest clinical concern was radiation pneumonitis followed by drug toxicity. A bone marrow biopsy was hypocellular but without evidence of malignancy. Her pancytopenia was thought to be induced by azathioprine and/or antibiotics. Antibiotics were discontinued and prednisone was started for treatment of presumed radiation pneumonitis.
A few days later, the patient developed new skin lesions and worsening bilateral leg edema. There were multiple small erythematous and hemorrhagic papules, macules, and blisters on the medial aspect of the right lower leg and ankle, each measuring less than 1 cm in diameter (Figure 1). The clinical differential diagnosis included vasculitis related to an underlying collagen vascular disease, atypical edema blisters, and drug hypersensitivity reaction. A punch biopsy of one of the lesions showed a moderately dense superficial and deep perivascular lymphoid infiltrate with marked papillary dermal edema and early subepidermal split (Figure 2). The infiltrate was comprised of small- to medium-sized lymphocytes admixed with large cells, histiocytes, and plasma cells (Figure 3). Immunohistochemistry revealed a predominance of CD3+ and CD4+ small- to medium-sized T cells. CD20 highlighted the large angiocentric B cells (Figure 4), which also were positive on EBV-encoded small RNA (EBER) in situ hybridization (Figure 5). A diagnosis of LYG was rendered. Approximately 40 to 50 EBV-positive large B cells were present per high-power field (HPF), consistent with grade 2 disease.
Soon after diagnosis, follow-up computed tomography of the chest, abdomen, and pelvis revealed suspicious lesions in the kidneys, liver, spleen, and inguinal and iliac lymph nodes. The ground-glass opacities in the lungs continued to progress, with 2 additional nodules noted in the right upper and lower lobes. Four days later, core needle biopsies of the right inguinal lymph node showed a large B-cell lymphoma with extensive necrosis (Figure 6). EBER in situ hybridization was suboptimal, probably due to extensive necrosis.
She was started on etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) for 5 days before developing Klebsiella pneumoniae sepsis and acute kidney injury. She was transferred to the critical care unit due to increasing oxygen requirement. Despite medical interventions, she continued to decompensate and elected to transition to palliative care. She died 6 weeks after the initial presentation. Her family did not request an autopsy.
Comment
Lymphomatoid granulomatosis is a rare lymphoproliferative disorder associated with various immunocompromised states including primary immunodeficiency disorders, human immunodeficiency virus infection, and immunosuppression for organ transplantation and autoimmune diseases. Our patient was receiving azathioprine for antisynthetase syndrome, which put her at risk for EBV infection and LYG. Azathioprine rarely has been reported as a possible culprit of LYG,3,4 but there are no known reported cases that were related to antisynthetase syndrome. There are multiple reports of development of LYG in patients receiving methotrexate for rheumatoid arthritis.5-10 Other iatrogenic causes reported in the literature include thiopurines11,12 and imatinib.13,14
The clinical diagnosis of our patient was particularly challenging given her complicated medical history including interstitial lung disease, predisposition to infection secondary to immunosuppression, and recent radiation therapy to the chest. This case illustrates the importance of maintaining a high index of suspicion for LYG in immunosuppressed patients presenting with lung infiltrates.
Presentation
Radiologically, LYG typically manifests as nodular densities accentuated in the lower lung lobes, which may become confluent.15 Because the nodular pattern in LYG is nonspecific and may mimic sarcoidosis, hypersensitivity pneumonitis, vasculitis, and infectious and neoplastic diseases,16 open lung biopsy often is required to establish the diagnosis in the absence of more accessible lesions.
Cutaneous lesions are seen in 40% to 50% of patients2 and may be the presenting sign of LYG. In a retrospective study, 16% (3/19) of LYG patients presented with cutaneous lesions months before diagnostic pulmonary lesions were identified.17 The skin is the most accessible site for biopsy, allowing definitive tissue diagnosis even when the condition is not clinically suspected. Therefore, dermatologists and dermatopathologists should be aware of this rare entity.
The clinical morphologies of the skin lesions are nonspecific, ranging from erythematous papules and subcutaneous nodules to indurated plaques. Ulceration may be present. The lesions may be widely disseminated or limited to the arms and legs. Our patient presented with erythematous and hemorrhagic papules, macules, and blisters on the lower leg. The hemorrhagic and blistering nature of some of these lesions in our patient may be attributable to thrombocytopenia and lymphedema in addition to LYG.
Histopathology and Differential
The skin biopsy from our patient demonstrated typical features of LYG, namely EBV-positive neoplastic large B cells in a background of predominating reactive T cells.18 The neoplastic large cells frequently invade blood vessels, leading to luminal narrowing without necrosis of the vessel walls. Grading is based on the density of EBV-positive large B cells: grade 1 is defined as fewer than 5 cells per HPF; grade 2, 5 to 50 cells per HPF; and grade 3, more than 50 cells per HPF.18 Grade 2 or 3 disease predicts worse outcome,2 as observed in our case. It is important for pathologists and clinicians to be aware that the proportion of EBV-positive large B cells is variable even within a single lesion; therefore, more than 1 biopsy may be necessary for appropriate grading and management.1,17 Additionally, skin biopsy may have a lower sensitivity for detecting EBV-positive B cells compared to lung biopsy, possibly due to sampling error in small biopsies.17
The histopathologic features of LYG frequently overlap with other lymphomas. Due to the abundance of T cells, LYG may be misclassified as T-cell/histiocyte-rich large B-cell lymphoma.19 Because the latter is not associated with EBV, EBER in situ hybridization is helpful in distinguishing the 2 conditions. On the other hand, EBER in situ hybridization has no value in discriminating LYG and extranodal natural killer (NK)/T-cell lymphoma, as both are EBV driven. Unlike LYG, the neoplastic EBV-positive cells in extranodal NK/T-cell lymphoma make up the majority of the infiltrate and exhibit an NK-cell immunophenotype (positive CD56 and cytoplasmic CD3 epsilon).20 Pulmonary involvement also is uncommon in NK/T-cell lymphoma.
Aside from lymphomas, LYG also resembles granulomatosis with polyangiitis (GPA)(formerly known as Wegener granulomatosis). Clinically, both LYG and GPA can present with constitutional symptoms, as well as lung, kidney, and skin lesions. The 2 conditions differ microscopically, with leukocytoclastic vasculitis and necrotizing granulomatous inflammation being characteristic of GPA but absent in LYG.1,21 Neutrophils and eosinophils are much more likely to be present in GPA.22,23
Disease Progression
Although LYG is an extranodal disease, there is a 7% to 45% risk of progression to nodal lymphoma in patients with high-grade disease.2,22,24 Our patient progressed to nodal large B-cell lymphoma shortly after the diagnosis of high-grade LYG. She developed additional lesions in the liver, spleen, and kidneys, and ultimately succumbed to the disease. Prior studies have shown higher mortality in patients with bilateral lung involvement and neurologic abnormalities, whereas cutaneous involvement does not affect outcome.2
Treatment
A prospective study used an initial treatment regimen of cyclophosphamide and prednisone but mortality was high.24 More recently, chemotherapy regimens including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), CVP or CHOP combined with rituximab, C-MOPP (cyclophosphamide, vincristine, prednisone, and procarbazine), EPOCH, and rituximab with high-dose cytarabine have been used with variable success for grades 2 and 3 LYG.17,23,25,26 Antiviral and immunomodulatory (interferon alfa) therapy has been used to induce remission in a majority of patients with grades 1 or 2 LYG.3,17,27,28 There is a report of successful treatment of relapsed LYG with the retinoid agent bexarotene.29 Autologous or allogeneic stem cell transplantation was effective for some patients with refractory or relapsed LYG.30 Further studies are needed to clarify optimal treatment of LYG, especially high-grade disease.
Conclusion
We report a rare case of LYG in a patient with antisynthetase syndrome, which highlights the critical role of skin biopsy in establishing the diagnosis of LYG when the clinical and radiologic presentations are obscured by other comorbidities. Dermatologists should be familiar with this rare disease and maintain a low threshold for biopsy in immunocompromised patients presenting with nodular lung infiltrates and/or nonspecific skin lesions.
- Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol. 2010;34:E35-E48.
- Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer. 1979;43:360-373.
- Connors W, Griffiths C, Patel J, et al. Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease. BMC Gastroenterol. 2014;14:127.
- Katherine Martin L, Porcu P, Baiocchi RA, et al. Primary central nervous system lymphomatoid granulomatosis in a patient receiving azathioprine therapy. Clin Adv Hematol Oncol. 2009;7:65-68.
- Barakat A, Grover K, Peshin R. Rituximab for pulmonary lymphomatoid granulomatosis which developed as a complication of methotrexate and azathioprine therapy for rheumatoid arthritis. Springerplus. 2014;3:751.
- Kobayashi S, Kikuchi Y, Sato K, et al. Reversible iatrogenic, MTX-associated EBV-driven lymphoproliferation with histopathological features of a lymphomatoid granulomatosis in a patient with rheumatoid arthritis. Ann Hematol. 2013;92:1561-1564.
- Kameda H, Okuyama A, Tamaru J, et al. Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis. Clin Rheumatol. 2007;26:1585-1589.
- Oiwa H, Mihara K, Kan T, et al. Grade 3 lymphomatoid granulomatosis in a patient receiving methotrexate therapy for rheumatoid arthritis. Intern Med. 2014;53:1873-1875.
- Blanchart K, Paciencia M, Seguin A, et al. Fatal pulmonary lymphomatoid granulomatosis in a patient taking methotrexate for rheumatoid arthritis. Minerva Anestesiol. 2014;80:119-120.
- Schalk E, Krogel C, Scheinpflug K, et al. Lymphomatoid granulomatosis in a patient with rheumatoid arthritis receiving methotrexate: successful treatment with the anti-CD20 antibody mabthera. Onkologie. 2009;32:440-441.
- Subramaniam K, Cherian M, Jain S, et al. Two rare cases of Epstein-Barr virus-associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications. Intern Med J. 2013;43:1339-1342.
- Destombe S, Bouron-DalSoglio D, Rougemont AL, et al. Lymphomatoid granulomatosis: a unique complication of Crohn disease and its treatment in pediatrics. J Pediatr Gastroenterol Nutr. 2010;50:559-561.
- Yazdi AS, Metzler G, Weyrauch S, et al. Lymphomatoid granulomatosis induced by imatinib treatment. Arch Dermatol. 2007;143:1222-1223.
- Salmons N, Gregg RJ, Pallalau A, et al. Lymphomatoid granulomatosis in a patient previously diagnosed with a gastrointestinal stromal tumour and treated with imatinib. J Clin Pathol. 2007;60:199-201.
- Dee PM, Arora NS, Innes DJ Jr. The pulmonary manifestations of lymphomatoid granulomatosis. Radiology. 1982;143:613-618.
- Rezai P, Hart EM, Patel SK. Case 169: lymphomatoid granulomatosis. Radiology. 2011;259:604-609.
- Beaty MW, Toro J, Sorbara L, et al. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol. 2001;25:1111-1120.
- Pittaluga S, Wilson WH, Jaffe E. Lymphomatoid granulomatosis. In: Swerdlow S, Campo E, Harris NL, et al, eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer; 2008:247-249.
- Abramson JS. T-cell/histiocyte-rich B-cell lymphoma: biology, diagnosis, and management. Oncologist. 2006;11:384-392.
- Jaffe E. Nasal and nasal-type T/NK cell lymphoma: a unique form of lymphoma associated with the Epstein-Barr virus. Histopathology. 1995;27:581-583.
- Barksdale SK, Hallahan CW, Kerr GS, et al. Cutaneous pathology in Wegener’s granulomatosis: a clinicopathologic study of 74 biopsies in 46 patients. Am J Surg Pathol. 1995;19:161-172.
- Koss MN, Hochholzer L, Langloss JM, et al. Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients. Pathology. 1986;18:283-288.
- Aoki T, Harada Y, Matsubara E, et al. Long-term remission after multiple relapses in an elderly patient with lymphomatoid granulomatosis after rituximab and high-dose cytarabine chemotherapy without stem-cell transplantation. J Clin Oncol. 2013;31:E390-E393.
- Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomatosis: prospective clinical and therapeutic experience over 10 years. N Engl J Med. 1982;306:68-74.
- Jung KH, Sung HJ, Lee JH, et al. A case of pulmonary lymphomatoid granulomatosis successfully treated by combination chemotherapy with rituximab. Chemotherapy. 2009;55:386-390.
- Hernandez-Marques C, Lassaletta A, Torrelo A, et al. Rituximab in lymphomatoid granulomatosis. J Pediatr Hematol Oncol. 2014;36:E69-E74.
- Wilson WH, Gutierrez M, Raffeld M, et al. Lymphomatoid granulomatosis: phase 2 study of dose-adjusted interferon-alfa or EPOCH chemotherapy. Blood. 1999;94:599A.
- Wilson WH, Kingma DW, Raffeld M, et al. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood. 1996;87:4531-4537.
- Berg SE, Downs LH, Torigian DA, et al. Successful treatment of relapsed lymphomatoid granulomatosis with bexarotene. Cancer Biol Ther. 2008;7:1544-1546.
- Siegloch K, Schmitz N, Wu HS, et al. Hematopoietic stem cell transplantation in patients with lymphomatoid granulomatosis: a European group for blood and marrow transplantation report. Biol Blood Marrow Transplant. 2013;19:1522-1525.
Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)–related extranodal angiocentric lymphoproliferative disorder. Most patients are adults in the fifth decade of life, and men are twice as likely as women to be affected.1 The most common site of involvement is the lungs, which has been observed in more than 90% of patients.2 The skin is the most common extrapulmonary site of involvement with variable manifestations including “rash,” subcutaneous nodules, and ulceration. Although a small subset of patients experience remission without treatment, most patients report a progressive course with median survival of less than 2 years.1,2 Clinical diagnosis often is challenging due to underrecognition of this rare condition by multidisciplinary physicians.
Case Report
A 60-year-old woman presented with fatigue, night sweats, poor appetite, unintentional weight loss, and dyspnea with minor exertion of 2 weeks’ duration. Her medical history was remarkable for antisynthetase syndrome manifested as polymyositis and interstitial lung disease, as well as recurrent breast cancer treated with wide excision, chemotherapy, and radiation therapy completed 2 months prior. Antisynthetase syndrome was controlled with azathioprine for 2 years, which was stopped during chemotherapy but restarted to treat worsened myalgia 4 months prior to presentation. Two weeks prior to hospital admission, she was treated with antibiotics at an outside hospital for presumed pneumonia without improvement. Upon admission to our hospital she was pancytopenic. Chest computed tomography showed interval development of extensive patchy ground-glass opacities in all lung lobes with areas of confluent consolidation. Broad infectious workup was negative. Given the time course of presentation and anterior accentuation of the lung infiltrates, the greatest clinical concern was radiation pneumonitis followed by drug toxicity. A bone marrow biopsy was hypocellular but without evidence of malignancy. Her pancytopenia was thought to be induced by azathioprine and/or antibiotics. Antibiotics were discontinued and prednisone was started for treatment of presumed radiation pneumonitis.
A few days later, the patient developed new skin lesions and worsening bilateral leg edema. There were multiple small erythematous and hemorrhagic papules, macules, and blisters on the medial aspect of the right lower leg and ankle, each measuring less than 1 cm in diameter (Figure 1). The clinical differential diagnosis included vasculitis related to an underlying collagen vascular disease, atypical edema blisters, and drug hypersensitivity reaction. A punch biopsy of one of the lesions showed a moderately dense superficial and deep perivascular lymphoid infiltrate with marked papillary dermal edema and early subepidermal split (Figure 2). The infiltrate was comprised of small- to medium-sized lymphocytes admixed with large cells, histiocytes, and plasma cells (Figure 3). Immunohistochemistry revealed a predominance of CD3+ and CD4+ small- to medium-sized T cells. CD20 highlighted the large angiocentric B cells (Figure 4), which also were positive on EBV-encoded small RNA (EBER) in situ hybridization (Figure 5). A diagnosis of LYG was rendered. Approximately 40 to 50 EBV-positive large B cells were present per high-power field (HPF), consistent with grade 2 disease.
Soon after diagnosis, follow-up computed tomography of the chest, abdomen, and pelvis revealed suspicious lesions in the kidneys, liver, spleen, and inguinal and iliac lymph nodes. The ground-glass opacities in the lungs continued to progress, with 2 additional nodules noted in the right upper and lower lobes. Four days later, core needle biopsies of the right inguinal lymph node showed a large B-cell lymphoma with extensive necrosis (Figure 6). EBER in situ hybridization was suboptimal, probably due to extensive necrosis.
She was started on etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) for 5 days before developing Klebsiella pneumoniae sepsis and acute kidney injury. She was transferred to the critical care unit due to increasing oxygen requirement. Despite medical interventions, she continued to decompensate and elected to transition to palliative care. She died 6 weeks after the initial presentation. Her family did not request an autopsy.
Comment
Lymphomatoid granulomatosis is a rare lymphoproliferative disorder associated with various immunocompromised states including primary immunodeficiency disorders, human immunodeficiency virus infection, and immunosuppression for organ transplantation and autoimmune diseases. Our patient was receiving azathioprine for antisynthetase syndrome, which put her at risk for EBV infection and LYG. Azathioprine rarely has been reported as a possible culprit of LYG,3,4 but there are no known reported cases that were related to antisynthetase syndrome. There are multiple reports of development of LYG in patients receiving methotrexate for rheumatoid arthritis.5-10 Other iatrogenic causes reported in the literature include thiopurines11,12 and imatinib.13,14
The clinical diagnosis of our patient was particularly challenging given her complicated medical history including interstitial lung disease, predisposition to infection secondary to immunosuppression, and recent radiation therapy to the chest. This case illustrates the importance of maintaining a high index of suspicion for LYG in immunosuppressed patients presenting with lung infiltrates.
Presentation
Radiologically, LYG typically manifests as nodular densities accentuated in the lower lung lobes, which may become confluent.15 Because the nodular pattern in LYG is nonspecific and may mimic sarcoidosis, hypersensitivity pneumonitis, vasculitis, and infectious and neoplastic diseases,16 open lung biopsy often is required to establish the diagnosis in the absence of more accessible lesions.
Cutaneous lesions are seen in 40% to 50% of patients2 and may be the presenting sign of LYG. In a retrospective study, 16% (3/19) of LYG patients presented with cutaneous lesions months before diagnostic pulmonary lesions were identified.17 The skin is the most accessible site for biopsy, allowing definitive tissue diagnosis even when the condition is not clinically suspected. Therefore, dermatologists and dermatopathologists should be aware of this rare entity.
The clinical morphologies of the skin lesions are nonspecific, ranging from erythematous papules and subcutaneous nodules to indurated plaques. Ulceration may be present. The lesions may be widely disseminated or limited to the arms and legs. Our patient presented with erythematous and hemorrhagic papules, macules, and blisters on the lower leg. The hemorrhagic and blistering nature of some of these lesions in our patient may be attributable to thrombocytopenia and lymphedema in addition to LYG.
Histopathology and Differential
The skin biopsy from our patient demonstrated typical features of LYG, namely EBV-positive neoplastic large B cells in a background of predominating reactive T cells.18 The neoplastic large cells frequently invade blood vessels, leading to luminal narrowing without necrosis of the vessel walls. Grading is based on the density of EBV-positive large B cells: grade 1 is defined as fewer than 5 cells per HPF; grade 2, 5 to 50 cells per HPF; and grade 3, more than 50 cells per HPF.18 Grade 2 or 3 disease predicts worse outcome,2 as observed in our case. It is important for pathologists and clinicians to be aware that the proportion of EBV-positive large B cells is variable even within a single lesion; therefore, more than 1 biopsy may be necessary for appropriate grading and management.1,17 Additionally, skin biopsy may have a lower sensitivity for detecting EBV-positive B cells compared to lung biopsy, possibly due to sampling error in small biopsies.17
The histopathologic features of LYG frequently overlap with other lymphomas. Due to the abundance of T cells, LYG may be misclassified as T-cell/histiocyte-rich large B-cell lymphoma.19 Because the latter is not associated with EBV, EBER in situ hybridization is helpful in distinguishing the 2 conditions. On the other hand, EBER in situ hybridization has no value in discriminating LYG and extranodal natural killer (NK)/T-cell lymphoma, as both are EBV driven. Unlike LYG, the neoplastic EBV-positive cells in extranodal NK/T-cell lymphoma make up the majority of the infiltrate and exhibit an NK-cell immunophenotype (positive CD56 and cytoplasmic CD3 epsilon).20 Pulmonary involvement also is uncommon in NK/T-cell lymphoma.
Aside from lymphomas, LYG also resembles granulomatosis with polyangiitis (GPA)(formerly known as Wegener granulomatosis). Clinically, both LYG and GPA can present with constitutional symptoms, as well as lung, kidney, and skin lesions. The 2 conditions differ microscopically, with leukocytoclastic vasculitis and necrotizing granulomatous inflammation being characteristic of GPA but absent in LYG.1,21 Neutrophils and eosinophils are much more likely to be present in GPA.22,23
Disease Progression
Although LYG is an extranodal disease, there is a 7% to 45% risk of progression to nodal lymphoma in patients with high-grade disease.2,22,24 Our patient progressed to nodal large B-cell lymphoma shortly after the diagnosis of high-grade LYG. She developed additional lesions in the liver, spleen, and kidneys, and ultimately succumbed to the disease. Prior studies have shown higher mortality in patients with bilateral lung involvement and neurologic abnormalities, whereas cutaneous involvement does not affect outcome.2
Treatment
A prospective study used an initial treatment regimen of cyclophosphamide and prednisone but mortality was high.24 More recently, chemotherapy regimens including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), CVP or CHOP combined with rituximab, C-MOPP (cyclophosphamide, vincristine, prednisone, and procarbazine), EPOCH, and rituximab with high-dose cytarabine have been used with variable success for grades 2 and 3 LYG.17,23,25,26 Antiviral and immunomodulatory (interferon alfa) therapy has been used to induce remission in a majority of patients with grades 1 or 2 LYG.3,17,27,28 There is a report of successful treatment of relapsed LYG with the retinoid agent bexarotene.29 Autologous or allogeneic stem cell transplantation was effective for some patients with refractory or relapsed LYG.30 Further studies are needed to clarify optimal treatment of LYG, especially high-grade disease.
Conclusion
We report a rare case of LYG in a patient with antisynthetase syndrome, which highlights the critical role of skin biopsy in establishing the diagnosis of LYG when the clinical and radiologic presentations are obscured by other comorbidities. Dermatologists should be familiar with this rare disease and maintain a low threshold for biopsy in immunocompromised patients presenting with nodular lung infiltrates and/or nonspecific skin lesions.
Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)–related extranodal angiocentric lymphoproliferative disorder. Most patients are adults in the fifth decade of life, and men are twice as likely as women to be affected.1 The most common site of involvement is the lungs, which has been observed in more than 90% of patients.2 The skin is the most common extrapulmonary site of involvement with variable manifestations including “rash,” subcutaneous nodules, and ulceration. Although a small subset of patients experience remission without treatment, most patients report a progressive course with median survival of less than 2 years.1,2 Clinical diagnosis often is challenging due to underrecognition of this rare condition by multidisciplinary physicians.
Case Report
A 60-year-old woman presented with fatigue, night sweats, poor appetite, unintentional weight loss, and dyspnea with minor exertion of 2 weeks’ duration. Her medical history was remarkable for antisynthetase syndrome manifested as polymyositis and interstitial lung disease, as well as recurrent breast cancer treated with wide excision, chemotherapy, and radiation therapy completed 2 months prior. Antisynthetase syndrome was controlled with azathioprine for 2 years, which was stopped during chemotherapy but restarted to treat worsened myalgia 4 months prior to presentation. Two weeks prior to hospital admission, she was treated with antibiotics at an outside hospital for presumed pneumonia without improvement. Upon admission to our hospital she was pancytopenic. Chest computed tomography showed interval development of extensive patchy ground-glass opacities in all lung lobes with areas of confluent consolidation. Broad infectious workup was negative. Given the time course of presentation and anterior accentuation of the lung infiltrates, the greatest clinical concern was radiation pneumonitis followed by drug toxicity. A bone marrow biopsy was hypocellular but without evidence of malignancy. Her pancytopenia was thought to be induced by azathioprine and/or antibiotics. Antibiotics were discontinued and prednisone was started for treatment of presumed radiation pneumonitis.
A few days later, the patient developed new skin lesions and worsening bilateral leg edema. There were multiple small erythematous and hemorrhagic papules, macules, and blisters on the medial aspect of the right lower leg and ankle, each measuring less than 1 cm in diameter (Figure 1). The clinical differential diagnosis included vasculitis related to an underlying collagen vascular disease, atypical edema blisters, and drug hypersensitivity reaction. A punch biopsy of one of the lesions showed a moderately dense superficial and deep perivascular lymphoid infiltrate with marked papillary dermal edema and early subepidermal split (Figure 2). The infiltrate was comprised of small- to medium-sized lymphocytes admixed with large cells, histiocytes, and plasma cells (Figure 3). Immunohistochemistry revealed a predominance of CD3+ and CD4+ small- to medium-sized T cells. CD20 highlighted the large angiocentric B cells (Figure 4), which also were positive on EBV-encoded small RNA (EBER) in situ hybridization (Figure 5). A diagnosis of LYG was rendered. Approximately 40 to 50 EBV-positive large B cells were present per high-power field (HPF), consistent with grade 2 disease.
Soon after diagnosis, follow-up computed tomography of the chest, abdomen, and pelvis revealed suspicious lesions in the kidneys, liver, spleen, and inguinal and iliac lymph nodes. The ground-glass opacities in the lungs continued to progress, with 2 additional nodules noted in the right upper and lower lobes. Four days later, core needle biopsies of the right inguinal lymph node showed a large B-cell lymphoma with extensive necrosis (Figure 6). EBER in situ hybridization was suboptimal, probably due to extensive necrosis.
She was started on etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) for 5 days before developing Klebsiella pneumoniae sepsis and acute kidney injury. She was transferred to the critical care unit due to increasing oxygen requirement. Despite medical interventions, she continued to decompensate and elected to transition to palliative care. She died 6 weeks after the initial presentation. Her family did not request an autopsy.
Comment
Lymphomatoid granulomatosis is a rare lymphoproliferative disorder associated with various immunocompromised states including primary immunodeficiency disorders, human immunodeficiency virus infection, and immunosuppression for organ transplantation and autoimmune diseases. Our patient was receiving azathioprine for antisynthetase syndrome, which put her at risk for EBV infection and LYG. Azathioprine rarely has been reported as a possible culprit of LYG,3,4 but there are no known reported cases that were related to antisynthetase syndrome. There are multiple reports of development of LYG in patients receiving methotrexate for rheumatoid arthritis.5-10 Other iatrogenic causes reported in the literature include thiopurines11,12 and imatinib.13,14
The clinical diagnosis of our patient was particularly challenging given her complicated medical history including interstitial lung disease, predisposition to infection secondary to immunosuppression, and recent radiation therapy to the chest. This case illustrates the importance of maintaining a high index of suspicion for LYG in immunosuppressed patients presenting with lung infiltrates.
Presentation
Radiologically, LYG typically manifests as nodular densities accentuated in the lower lung lobes, which may become confluent.15 Because the nodular pattern in LYG is nonspecific and may mimic sarcoidosis, hypersensitivity pneumonitis, vasculitis, and infectious and neoplastic diseases,16 open lung biopsy often is required to establish the diagnosis in the absence of more accessible lesions.
Cutaneous lesions are seen in 40% to 50% of patients2 and may be the presenting sign of LYG. In a retrospective study, 16% (3/19) of LYG patients presented with cutaneous lesions months before diagnostic pulmonary lesions were identified.17 The skin is the most accessible site for biopsy, allowing definitive tissue diagnosis even when the condition is not clinically suspected. Therefore, dermatologists and dermatopathologists should be aware of this rare entity.
The clinical morphologies of the skin lesions are nonspecific, ranging from erythematous papules and subcutaneous nodules to indurated plaques. Ulceration may be present. The lesions may be widely disseminated or limited to the arms and legs. Our patient presented with erythematous and hemorrhagic papules, macules, and blisters on the lower leg. The hemorrhagic and blistering nature of some of these lesions in our patient may be attributable to thrombocytopenia and lymphedema in addition to LYG.
Histopathology and Differential
The skin biopsy from our patient demonstrated typical features of LYG, namely EBV-positive neoplastic large B cells in a background of predominating reactive T cells.18 The neoplastic large cells frequently invade blood vessels, leading to luminal narrowing without necrosis of the vessel walls. Grading is based on the density of EBV-positive large B cells: grade 1 is defined as fewer than 5 cells per HPF; grade 2, 5 to 50 cells per HPF; and grade 3, more than 50 cells per HPF.18 Grade 2 or 3 disease predicts worse outcome,2 as observed in our case. It is important for pathologists and clinicians to be aware that the proportion of EBV-positive large B cells is variable even within a single lesion; therefore, more than 1 biopsy may be necessary for appropriate grading and management.1,17 Additionally, skin biopsy may have a lower sensitivity for detecting EBV-positive B cells compared to lung biopsy, possibly due to sampling error in small biopsies.17
The histopathologic features of LYG frequently overlap with other lymphomas. Due to the abundance of T cells, LYG may be misclassified as T-cell/histiocyte-rich large B-cell lymphoma.19 Because the latter is not associated with EBV, EBER in situ hybridization is helpful in distinguishing the 2 conditions. On the other hand, EBER in situ hybridization has no value in discriminating LYG and extranodal natural killer (NK)/T-cell lymphoma, as both are EBV driven. Unlike LYG, the neoplastic EBV-positive cells in extranodal NK/T-cell lymphoma make up the majority of the infiltrate and exhibit an NK-cell immunophenotype (positive CD56 and cytoplasmic CD3 epsilon).20 Pulmonary involvement also is uncommon in NK/T-cell lymphoma.
Aside from lymphomas, LYG also resembles granulomatosis with polyangiitis (GPA)(formerly known as Wegener granulomatosis). Clinically, both LYG and GPA can present with constitutional symptoms, as well as lung, kidney, and skin lesions. The 2 conditions differ microscopically, with leukocytoclastic vasculitis and necrotizing granulomatous inflammation being characteristic of GPA but absent in LYG.1,21 Neutrophils and eosinophils are much more likely to be present in GPA.22,23
Disease Progression
Although LYG is an extranodal disease, there is a 7% to 45% risk of progression to nodal lymphoma in patients with high-grade disease.2,22,24 Our patient progressed to nodal large B-cell lymphoma shortly after the diagnosis of high-grade LYG. She developed additional lesions in the liver, spleen, and kidneys, and ultimately succumbed to the disease. Prior studies have shown higher mortality in patients with bilateral lung involvement and neurologic abnormalities, whereas cutaneous involvement does not affect outcome.2
Treatment
A prospective study used an initial treatment regimen of cyclophosphamide and prednisone but mortality was high.24 More recently, chemotherapy regimens including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), CVP or CHOP combined with rituximab, C-MOPP (cyclophosphamide, vincristine, prednisone, and procarbazine), EPOCH, and rituximab with high-dose cytarabine have been used with variable success for grades 2 and 3 LYG.17,23,25,26 Antiviral and immunomodulatory (interferon alfa) therapy has been used to induce remission in a majority of patients with grades 1 or 2 LYG.3,17,27,28 There is a report of successful treatment of relapsed LYG with the retinoid agent bexarotene.29 Autologous or allogeneic stem cell transplantation was effective for some patients with refractory or relapsed LYG.30 Further studies are needed to clarify optimal treatment of LYG, especially high-grade disease.
Conclusion
We report a rare case of LYG in a patient with antisynthetase syndrome, which highlights the critical role of skin biopsy in establishing the diagnosis of LYG when the clinical and radiologic presentations are obscured by other comorbidities. Dermatologists should be familiar with this rare disease and maintain a low threshold for biopsy in immunocompromised patients presenting with nodular lung infiltrates and/or nonspecific skin lesions.
- Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol. 2010;34:E35-E48.
- Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer. 1979;43:360-373.
- Connors W, Griffiths C, Patel J, et al. Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease. BMC Gastroenterol. 2014;14:127.
- Katherine Martin L, Porcu P, Baiocchi RA, et al. Primary central nervous system lymphomatoid granulomatosis in a patient receiving azathioprine therapy. Clin Adv Hematol Oncol. 2009;7:65-68.
- Barakat A, Grover K, Peshin R. Rituximab for pulmonary lymphomatoid granulomatosis which developed as a complication of methotrexate and azathioprine therapy for rheumatoid arthritis. Springerplus. 2014;3:751.
- Kobayashi S, Kikuchi Y, Sato K, et al. Reversible iatrogenic, MTX-associated EBV-driven lymphoproliferation with histopathological features of a lymphomatoid granulomatosis in a patient with rheumatoid arthritis. Ann Hematol. 2013;92:1561-1564.
- Kameda H, Okuyama A, Tamaru J, et al. Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis. Clin Rheumatol. 2007;26:1585-1589.
- Oiwa H, Mihara K, Kan T, et al. Grade 3 lymphomatoid granulomatosis in a patient receiving methotrexate therapy for rheumatoid arthritis. Intern Med. 2014;53:1873-1875.
- Blanchart K, Paciencia M, Seguin A, et al. Fatal pulmonary lymphomatoid granulomatosis in a patient taking methotrexate for rheumatoid arthritis. Minerva Anestesiol. 2014;80:119-120.
- Schalk E, Krogel C, Scheinpflug K, et al. Lymphomatoid granulomatosis in a patient with rheumatoid arthritis receiving methotrexate: successful treatment with the anti-CD20 antibody mabthera. Onkologie. 2009;32:440-441.
- Subramaniam K, Cherian M, Jain S, et al. Two rare cases of Epstein-Barr virus-associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications. Intern Med J. 2013;43:1339-1342.
- Destombe S, Bouron-DalSoglio D, Rougemont AL, et al. Lymphomatoid granulomatosis: a unique complication of Crohn disease and its treatment in pediatrics. J Pediatr Gastroenterol Nutr. 2010;50:559-561.
- Yazdi AS, Metzler G, Weyrauch S, et al. Lymphomatoid granulomatosis induced by imatinib treatment. Arch Dermatol. 2007;143:1222-1223.
- Salmons N, Gregg RJ, Pallalau A, et al. Lymphomatoid granulomatosis in a patient previously diagnosed with a gastrointestinal stromal tumour and treated with imatinib. J Clin Pathol. 2007;60:199-201.
- Dee PM, Arora NS, Innes DJ Jr. The pulmonary manifestations of lymphomatoid granulomatosis. Radiology. 1982;143:613-618.
- Rezai P, Hart EM, Patel SK. Case 169: lymphomatoid granulomatosis. Radiology. 2011;259:604-609.
- Beaty MW, Toro J, Sorbara L, et al. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol. 2001;25:1111-1120.
- Pittaluga S, Wilson WH, Jaffe E. Lymphomatoid granulomatosis. In: Swerdlow S, Campo E, Harris NL, et al, eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer; 2008:247-249.
- Abramson JS. T-cell/histiocyte-rich B-cell lymphoma: biology, diagnosis, and management. Oncologist. 2006;11:384-392.
- Jaffe E. Nasal and nasal-type T/NK cell lymphoma: a unique form of lymphoma associated with the Epstein-Barr virus. Histopathology. 1995;27:581-583.
- Barksdale SK, Hallahan CW, Kerr GS, et al. Cutaneous pathology in Wegener’s granulomatosis: a clinicopathologic study of 74 biopsies in 46 patients. Am J Surg Pathol. 1995;19:161-172.
- Koss MN, Hochholzer L, Langloss JM, et al. Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients. Pathology. 1986;18:283-288.
- Aoki T, Harada Y, Matsubara E, et al. Long-term remission after multiple relapses in an elderly patient with lymphomatoid granulomatosis after rituximab and high-dose cytarabine chemotherapy without stem-cell transplantation. J Clin Oncol. 2013;31:E390-E393.
- Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomatosis: prospective clinical and therapeutic experience over 10 years. N Engl J Med. 1982;306:68-74.
- Jung KH, Sung HJ, Lee JH, et al. A case of pulmonary lymphomatoid granulomatosis successfully treated by combination chemotherapy with rituximab. Chemotherapy. 2009;55:386-390.
- Hernandez-Marques C, Lassaletta A, Torrelo A, et al. Rituximab in lymphomatoid granulomatosis. J Pediatr Hematol Oncol. 2014;36:E69-E74.
- Wilson WH, Gutierrez M, Raffeld M, et al. Lymphomatoid granulomatosis: phase 2 study of dose-adjusted interferon-alfa or EPOCH chemotherapy. Blood. 1999;94:599A.
- Wilson WH, Kingma DW, Raffeld M, et al. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood. 1996;87:4531-4537.
- Berg SE, Downs LH, Torigian DA, et al. Successful treatment of relapsed lymphomatoid granulomatosis with bexarotene. Cancer Biol Ther. 2008;7:1544-1546.
- Siegloch K, Schmitz N, Wu HS, et al. Hematopoietic stem cell transplantation in patients with lymphomatoid granulomatosis: a European group for blood and marrow transplantation report. Biol Blood Marrow Transplant. 2013;19:1522-1525.
- Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol. 2010;34:E35-E48.
- Katzenstein AL, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer. 1979;43:360-373.
- Connors W, Griffiths C, Patel J, et al. Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease. BMC Gastroenterol. 2014;14:127.
- Katherine Martin L, Porcu P, Baiocchi RA, et al. Primary central nervous system lymphomatoid granulomatosis in a patient receiving azathioprine therapy. Clin Adv Hematol Oncol. 2009;7:65-68.
- Barakat A, Grover K, Peshin R. Rituximab for pulmonary lymphomatoid granulomatosis which developed as a complication of methotrexate and azathioprine therapy for rheumatoid arthritis. Springerplus. 2014;3:751.
- Kobayashi S, Kikuchi Y, Sato K, et al. Reversible iatrogenic, MTX-associated EBV-driven lymphoproliferation with histopathological features of a lymphomatoid granulomatosis in a patient with rheumatoid arthritis. Ann Hematol. 2013;92:1561-1564.
- Kameda H, Okuyama A, Tamaru J, et al. Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis. Clin Rheumatol. 2007;26:1585-1589.
- Oiwa H, Mihara K, Kan T, et al. Grade 3 lymphomatoid granulomatosis in a patient receiving methotrexate therapy for rheumatoid arthritis. Intern Med. 2014;53:1873-1875.
- Blanchart K, Paciencia M, Seguin A, et al. Fatal pulmonary lymphomatoid granulomatosis in a patient taking methotrexate for rheumatoid arthritis. Minerva Anestesiol. 2014;80:119-120.
- Schalk E, Krogel C, Scheinpflug K, et al. Lymphomatoid granulomatosis in a patient with rheumatoid arthritis receiving methotrexate: successful treatment with the anti-CD20 antibody mabthera. Onkologie. 2009;32:440-441.
- Subramaniam K, Cherian M, Jain S, et al. Two rare cases of Epstein-Barr virus-associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications. Intern Med J. 2013;43:1339-1342.
- Destombe S, Bouron-DalSoglio D, Rougemont AL, et al. Lymphomatoid granulomatosis: a unique complication of Crohn disease and its treatment in pediatrics. J Pediatr Gastroenterol Nutr. 2010;50:559-561.
- Yazdi AS, Metzler G, Weyrauch S, et al. Lymphomatoid granulomatosis induced by imatinib treatment. Arch Dermatol. 2007;143:1222-1223.
- Salmons N, Gregg RJ, Pallalau A, et al. Lymphomatoid granulomatosis in a patient previously diagnosed with a gastrointestinal stromal tumour and treated with imatinib. J Clin Pathol. 2007;60:199-201.
- Dee PM, Arora NS, Innes DJ Jr. The pulmonary manifestations of lymphomatoid granulomatosis. Radiology. 1982;143:613-618.
- Rezai P, Hart EM, Patel SK. Case 169: lymphomatoid granulomatosis. Radiology. 2011;259:604-609.
- Beaty MW, Toro J, Sorbara L, et al. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol. 2001;25:1111-1120.
- Pittaluga S, Wilson WH, Jaffe E. Lymphomatoid granulomatosis. In: Swerdlow S, Campo E, Harris NL, et al, eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer; 2008:247-249.
- Abramson JS. T-cell/histiocyte-rich B-cell lymphoma: biology, diagnosis, and management. Oncologist. 2006;11:384-392.
- Jaffe E. Nasal and nasal-type T/NK cell lymphoma: a unique form of lymphoma associated with the Epstein-Barr virus. Histopathology. 1995;27:581-583.
- Barksdale SK, Hallahan CW, Kerr GS, et al. Cutaneous pathology in Wegener’s granulomatosis: a clinicopathologic study of 74 biopsies in 46 patients. Am J Surg Pathol. 1995;19:161-172.
- Koss MN, Hochholzer L, Langloss JM, et al. Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients. Pathology. 1986;18:283-288.
- Aoki T, Harada Y, Matsubara E, et al. Long-term remission after multiple relapses in an elderly patient with lymphomatoid granulomatosis after rituximab and high-dose cytarabine chemotherapy without stem-cell transplantation. J Clin Oncol. 2013;31:E390-E393.
- Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomatosis: prospective clinical and therapeutic experience over 10 years. N Engl J Med. 1982;306:68-74.
- Jung KH, Sung HJ, Lee JH, et al. A case of pulmonary lymphomatoid granulomatosis successfully treated by combination chemotherapy with rituximab. Chemotherapy. 2009;55:386-390.
- Hernandez-Marques C, Lassaletta A, Torrelo A, et al. Rituximab in lymphomatoid granulomatosis. J Pediatr Hematol Oncol. 2014;36:E69-E74.
- Wilson WH, Gutierrez M, Raffeld M, et al. Lymphomatoid granulomatosis: phase 2 study of dose-adjusted interferon-alfa or EPOCH chemotherapy. Blood. 1999;94:599A.
- Wilson WH, Kingma DW, Raffeld M, et al. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood. 1996;87:4531-4537.
- Berg SE, Downs LH, Torigian DA, et al. Successful treatment of relapsed lymphomatoid granulomatosis with bexarotene. Cancer Biol Ther. 2008;7:1544-1546.
- Siegloch K, Schmitz N, Wu HS, et al. Hematopoietic stem cell transplantation in patients with lymphomatoid granulomatosis: a European group for blood and marrow transplantation report. Biol Blood Marrow Transplant. 2013;19:1522-1525.
Practice Points
- Lymphomatoid granulomatosis (LYG) is a rare extranodal angiocentric large B-cell lymphoma driven by the Epstein-Barr virus.
- Lymphomatoid granulomatosis should be suspected when immunocompromised patients present with nodular lung infiltrates and/or nonspecific skin lesions.
- Skin biopsy serves a critical role in establishing the diagnosis of LYG, especially when clinical and radiologic findings are obscured by other comorbidities.
Expert Panel: Little support for delaying cosmetic procedures after isotretinoin
In most cases, there is little evidence to support delaying cosmetic procedures, such as laser therapy or chemical peels, in patients who have recently been treated with isotretinoin for acne, according to a consensus statement from the American Society of Dermatologic Surgery (ASDS).
An expert panel convened by the ASDS issued specific recommendations that supported safe, early initiation of cosmetic procedures in most cases. It noted that the likelihood of any potential harms from initiating cosmetic procedures after recent isotretinoin treatment is “low to very low” and that such harms have been reported only in case reports and case series.
Notable exceptions included dermabrasion and full-face ablative resurfacing; the experts recommended against having such procedures within 6 months of isotretinoin use because of potentially increased risks of adverse events in some patients.
“Potential benefits of this guideline include early access to scar treatments for many patients who are at the highest risk for scarring and, thereby, potentially improved patient quality of life,” Abigail Waldman, MD, of the department of dermatology at Brigham and Women’s Hospital, Boston, and her coauthors wrote in the consensus statement (Dermatol Surg. 2017 Oct;43[10]:1249-62). This is the first consensus statement document published by the ASDS to address this topic.
Isotretinoin was approved by the Food and Drug Administration in 1982 for treating severe and nodulocystic acne. Because of a perceived higher risk of scarring or irritation associated with isotretinoin use, standard clinical practice has been to avoid performing laser procedures, chemical peels, waxing, dermabrasion, and incisional or excisional cutaneous surgeries on patients within 6 months of their using isotretinoin, according to the authors. A warning regarding the potential for scarring with cosmetic procedures meant to smooth the skin is even included in the patient information leaflet for isotretinoin.
“This is in contradistinction to the observation that nodulocystic or severe inflammatory acne patients who have recently completed treatment with isotretinoin are among those most likely to benefit from treatment of their acne scars with modalities such as laser, dermabrasion, or chemical peels,” the experts wrote in the consensus recommendations.
Following a review of the 36 source documents, the task force concluded that, for patients currently or recently receiving isotretinoin, evidence was “insufficient” to justify delaying treatment with superficial chemical peels, vascular lasers, and nonablative modalities, such as hair removal lasers and lights. They also stated that superficial and focal dermabrasion “may also be safe when performed by a well-trained clinician” in a clinical setting.
The panel recommendations covered the following four key areas:
- Dermabrasion. Treating specific facial areas while the patient is on isotretinoin or within 6 months of discontinuation “is not associated with increased risk of scar or delay in wound healing, and there is no evidence in the literature that supports a need to delay treatment,” they wrote. In contrast, they did not recommend full-face or mechanical dermabrasion with rotary devices within the 6-month window because it may be “associated with increased risk of adverse events in selected patients.”
- Lasers and energy devices. Similarly, the panel found no evidence that would justify delaying use of vascular lasers, hair removal lasers and lights, and nonablative or ablative fractional devices among patients recently treated with isotretinoin. However, they said fully ablative treatment of the entire face or regions other than the face should “generally be avoided until 6 months after completion of isotretinoin treatment because of the likely elevated risk of avoidable adverse events.”
- Chemical peels. Patients currently on isotretinoin or who have recently discontinued it can safely undergo superficial chemical peels, according to the panel. For medium or deep chemical peels, there was “insufficient data … to preclude a recommendation in this case,” the panel wrote.
- Other surgeries. Because of the risk of dry eyes, isotretinoin should be discontinued prior to laser eye surgery. For incisional and excisional cutaneous surgery, the data on isotretinoin were insufficient to make any recommendations, the experts concluded, though they acknowledged that in some cases, the surgeries may be “medically necessary.”
Most of these recommendations were based on case series and cohort studies, the panel said, rather than higher-quality, randomized clinical trials, which are “generally impractical and not likely forthcoming in this setting.” Moreover, they cautioned that insufficient evidence to make a recommendation should not be misconstrued as a confirmation of safety or a warning about risk.
Overall, the results of the analysis suggested that “procedural interventions during or soon after isotretinoin treatment can safely and effectively address acne scarring and similar disorders, thus providing relief to patients without the need for protracted waiting,” the authors wrote.
In August, another expert panel’s recommendations were published, which concluded that skin procedures, including superficial chemical peels, laser hair removal, minor cutaneous surgery, manual dermabrasion, and fractional ablative and fractional nonablative laser procedures, can be performed safely on patients who have recently been or are currently being treated with isotretinoin (JAMA Dermatol. 2017 Aug 1;153[8]:802-9).
The authors of the ASDS statement reported no relevant financial conflicts.
In most cases, there is little evidence to support delaying cosmetic procedures, such as laser therapy or chemical peels, in patients who have recently been treated with isotretinoin for acne, according to a consensus statement from the American Society of Dermatologic Surgery (ASDS).
An expert panel convened by the ASDS issued specific recommendations that supported safe, early initiation of cosmetic procedures in most cases. It noted that the likelihood of any potential harms from initiating cosmetic procedures after recent isotretinoin treatment is “low to very low” and that such harms have been reported only in case reports and case series.
Notable exceptions included dermabrasion and full-face ablative resurfacing; the experts recommended against having such procedures within 6 months of isotretinoin use because of potentially increased risks of adverse events in some patients.
“Potential benefits of this guideline include early access to scar treatments for many patients who are at the highest risk for scarring and, thereby, potentially improved patient quality of life,” Abigail Waldman, MD, of the department of dermatology at Brigham and Women’s Hospital, Boston, and her coauthors wrote in the consensus statement (Dermatol Surg. 2017 Oct;43[10]:1249-62). This is the first consensus statement document published by the ASDS to address this topic.
Isotretinoin was approved by the Food and Drug Administration in 1982 for treating severe and nodulocystic acne. Because of a perceived higher risk of scarring or irritation associated with isotretinoin use, standard clinical practice has been to avoid performing laser procedures, chemical peels, waxing, dermabrasion, and incisional or excisional cutaneous surgeries on patients within 6 months of their using isotretinoin, according to the authors. A warning regarding the potential for scarring with cosmetic procedures meant to smooth the skin is even included in the patient information leaflet for isotretinoin.
“This is in contradistinction to the observation that nodulocystic or severe inflammatory acne patients who have recently completed treatment with isotretinoin are among those most likely to benefit from treatment of their acne scars with modalities such as laser, dermabrasion, or chemical peels,” the experts wrote in the consensus recommendations.
Following a review of the 36 source documents, the task force concluded that, for patients currently or recently receiving isotretinoin, evidence was “insufficient” to justify delaying treatment with superficial chemical peels, vascular lasers, and nonablative modalities, such as hair removal lasers and lights. They also stated that superficial and focal dermabrasion “may also be safe when performed by a well-trained clinician” in a clinical setting.
The panel recommendations covered the following four key areas:
- Dermabrasion. Treating specific facial areas while the patient is on isotretinoin or within 6 months of discontinuation “is not associated with increased risk of scar or delay in wound healing, and there is no evidence in the literature that supports a need to delay treatment,” they wrote. In contrast, they did not recommend full-face or mechanical dermabrasion with rotary devices within the 6-month window because it may be “associated with increased risk of adverse events in selected patients.”
- Lasers and energy devices. Similarly, the panel found no evidence that would justify delaying use of vascular lasers, hair removal lasers and lights, and nonablative or ablative fractional devices among patients recently treated with isotretinoin. However, they said fully ablative treatment of the entire face or regions other than the face should “generally be avoided until 6 months after completion of isotretinoin treatment because of the likely elevated risk of avoidable adverse events.”
- Chemical peels. Patients currently on isotretinoin or who have recently discontinued it can safely undergo superficial chemical peels, according to the panel. For medium or deep chemical peels, there was “insufficient data … to preclude a recommendation in this case,” the panel wrote.
- Other surgeries. Because of the risk of dry eyes, isotretinoin should be discontinued prior to laser eye surgery. For incisional and excisional cutaneous surgery, the data on isotretinoin were insufficient to make any recommendations, the experts concluded, though they acknowledged that in some cases, the surgeries may be “medically necessary.”
Most of these recommendations were based on case series and cohort studies, the panel said, rather than higher-quality, randomized clinical trials, which are “generally impractical and not likely forthcoming in this setting.” Moreover, they cautioned that insufficient evidence to make a recommendation should not be misconstrued as a confirmation of safety or a warning about risk.
Overall, the results of the analysis suggested that “procedural interventions during or soon after isotretinoin treatment can safely and effectively address acne scarring and similar disorders, thus providing relief to patients without the need for protracted waiting,” the authors wrote.
In August, another expert panel’s recommendations were published, which concluded that skin procedures, including superficial chemical peels, laser hair removal, minor cutaneous surgery, manual dermabrasion, and fractional ablative and fractional nonablative laser procedures, can be performed safely on patients who have recently been or are currently being treated with isotretinoin (JAMA Dermatol. 2017 Aug 1;153[8]:802-9).
The authors of the ASDS statement reported no relevant financial conflicts.
In most cases, there is little evidence to support delaying cosmetic procedures, such as laser therapy or chemical peels, in patients who have recently been treated with isotretinoin for acne, according to a consensus statement from the American Society of Dermatologic Surgery (ASDS).
An expert panel convened by the ASDS issued specific recommendations that supported safe, early initiation of cosmetic procedures in most cases. It noted that the likelihood of any potential harms from initiating cosmetic procedures after recent isotretinoin treatment is “low to very low” and that such harms have been reported only in case reports and case series.
Notable exceptions included dermabrasion and full-face ablative resurfacing; the experts recommended against having such procedures within 6 months of isotretinoin use because of potentially increased risks of adverse events in some patients.
“Potential benefits of this guideline include early access to scar treatments for many patients who are at the highest risk for scarring and, thereby, potentially improved patient quality of life,” Abigail Waldman, MD, of the department of dermatology at Brigham and Women’s Hospital, Boston, and her coauthors wrote in the consensus statement (Dermatol Surg. 2017 Oct;43[10]:1249-62). This is the first consensus statement document published by the ASDS to address this topic.
Isotretinoin was approved by the Food and Drug Administration in 1982 for treating severe and nodulocystic acne. Because of a perceived higher risk of scarring or irritation associated with isotretinoin use, standard clinical practice has been to avoid performing laser procedures, chemical peels, waxing, dermabrasion, and incisional or excisional cutaneous surgeries on patients within 6 months of their using isotretinoin, according to the authors. A warning regarding the potential for scarring with cosmetic procedures meant to smooth the skin is even included in the patient information leaflet for isotretinoin.
“This is in contradistinction to the observation that nodulocystic or severe inflammatory acne patients who have recently completed treatment with isotretinoin are among those most likely to benefit from treatment of their acne scars with modalities such as laser, dermabrasion, or chemical peels,” the experts wrote in the consensus recommendations.
Following a review of the 36 source documents, the task force concluded that, for patients currently or recently receiving isotretinoin, evidence was “insufficient” to justify delaying treatment with superficial chemical peels, vascular lasers, and nonablative modalities, such as hair removal lasers and lights. They also stated that superficial and focal dermabrasion “may also be safe when performed by a well-trained clinician” in a clinical setting.
The panel recommendations covered the following four key areas:
- Dermabrasion. Treating specific facial areas while the patient is on isotretinoin or within 6 months of discontinuation “is not associated with increased risk of scar or delay in wound healing, and there is no evidence in the literature that supports a need to delay treatment,” they wrote. In contrast, they did not recommend full-face or mechanical dermabrasion with rotary devices within the 6-month window because it may be “associated with increased risk of adverse events in selected patients.”
- Lasers and energy devices. Similarly, the panel found no evidence that would justify delaying use of vascular lasers, hair removal lasers and lights, and nonablative or ablative fractional devices among patients recently treated with isotretinoin. However, they said fully ablative treatment of the entire face or regions other than the face should “generally be avoided until 6 months after completion of isotretinoin treatment because of the likely elevated risk of avoidable adverse events.”
- Chemical peels. Patients currently on isotretinoin or who have recently discontinued it can safely undergo superficial chemical peels, according to the panel. For medium or deep chemical peels, there was “insufficient data … to preclude a recommendation in this case,” the panel wrote.
- Other surgeries. Because of the risk of dry eyes, isotretinoin should be discontinued prior to laser eye surgery. For incisional and excisional cutaneous surgery, the data on isotretinoin were insufficient to make any recommendations, the experts concluded, though they acknowledged that in some cases, the surgeries may be “medically necessary.”
Most of these recommendations were based on case series and cohort studies, the panel said, rather than higher-quality, randomized clinical trials, which are “generally impractical and not likely forthcoming in this setting.” Moreover, they cautioned that insufficient evidence to make a recommendation should not be misconstrued as a confirmation of safety or a warning about risk.
Overall, the results of the analysis suggested that “procedural interventions during or soon after isotretinoin treatment can safely and effectively address acne scarring and similar disorders, thus providing relief to patients without the need for protracted waiting,” the authors wrote.
In August, another expert panel’s recommendations were published, which concluded that skin procedures, including superficial chemical peels, laser hair removal, minor cutaneous surgery, manual dermabrasion, and fractional ablative and fractional nonablative laser procedures, can be performed safely on patients who have recently been or are currently being treated with isotretinoin (JAMA Dermatol. 2017 Aug 1;153[8]:802-9).
The authors of the ASDS statement reported no relevant financial conflicts.
FROM DERMATOLOGIC SURGERY
Key clinical point: Contrary to current recommendations,
Major finding: Experts convened by the American Society of Dermatologic Surgery found that, in most cases, the likelihood of potential harms of initiating cosmetic procedures after recent isotretinoin use is “low to very low,” and those that did occur were reported only in case reports and case series rather than in higher-quality clinical trials.
Data source: A consensus review of 36 source documents obtained by a literature review, the results of which were then validated by peer review.
Disclosures: The authors reported no relevant financial conflicts.
Vesiculobullous and Pustular Diseases in Newborns
Vesiculobullous eruptions in neonates can readily generate anxiety from parents/guardians and pediatricians over both infectious and noninfectious causes. The role of the dermatology resident is critical to help diminish fear over common vesicular presentations or to escalate care in rarer situations if a more obscure or ominous diagnosis is clouding the patient’s clinical presentation and well-being. This article summarizes both common and uncommon vesiculobullous neonatal diseases to augment precise and efficient diagnoses in this vulnerable patient population.
Steps for Evaluating a Vesiculopustular Eruption
Receiving a consultation for a newborn with widespread vesicles can be a daunting scenario for a dermatology resident. Fear of missing an ominous diagnosis or aggressively treating a newborn for an erroneous infection when the diagnosis is actually a benign presentation can lead to an anxiety-provoking situation. Additionally, performing a procedure on a newborn can cause personal uneasiness. Dr. Lawrence A. Schachner, an eminent pediatric dermatologist at the University of Miami Miller School of Medicine (Miami, Florida), recently lectured on 5 key steps (Table 1) for the evaluation of a vesiculobullous eruption in the newborn to maximize the accuracy of diagnosis and patient care.1
First, draw out the fluid from the vesicle to send for bacterial and viral culture as well as Gram stain. Second, snip the roof of the vesicle to perform potassium hydroxide examination for yeast or fungi and frozen pathology when indicated. Third, use the base of the vesicle to obtain cells for a Tzanck smear to identify the predominant cell infiltrate, such as multinucleated giant cells in herpes simplex virus or eosinophils in erythema toxicum neonatorum (ETN). Fourth, a mineral oil preparation can be performed on several lesions, especially if a burrow is observed, to rule out bullous scabies in the appropriate clinical presentation. Lastly, a perilesional or lesional punch biopsy can be performed if the above steps have not yet clinched the diagnosis.2 By utilizing these steps, the resident efficiently utilizes 1 lesion to narrow down a formidable differential list of bullous disorders in the newborn.
Specific Diagnoses
A number of common diagnoses can present during the newborn period and can usually be readily diagnosed by clinical manifestations alone; a summary of these eruptions is provided in Table 2. Erythema toxicum neonatorum is the most common pustular eruption in neonates and presents in up to 50% of full-term infants at days 1 to 2 of life. Inflammatory pustules surrounded by characteristic blotchy erythema are displayed on the face, trunk, arms, and legs, usually sparing the palms and soles.3 Erythema toxicum neonatorum typically is a clinical diagnosis; however, it can be confirmed by demonstrating the predominance of eosinophils on Tzanck smear.
Transient neonatal pustular melanosis (TNPM) also presents in full-term infants; usually favors darkly pigmented neonates; and exhibits either pustules with a collarette of scale that lack surrounding erythema or with residual brown macules on the face, genitals, and acral surfaces. Postinflammatory pigmentary alteration on lesion clearance is another clue to diagnosis. Similarly, it is a clinical diagnosis but can be confirmed with a Tzanck smear demonstrating neutrophils as the major cell infiltrate.
In a prospective 1-year multicenter study performed by Reginatto et al,4 2831 neonates born in southern Brazil underwent a skin examination by a dermatologist within 72 hours of birth to characterize the prevalence and demographics of ETN and TNPM. They found a 21.3% (602 cases) prevalence of ETN compared to a 3.4% (97 cases) prevalence of TNPM, but they noted that most patients were white, and thus the diagnosis of TNPM likely is less prevalent in this group, as it favors darkly pigmented individuals. Additional predisposing factors associated with ETN were male gender, an Apgar score of 8 to 10 at 1 minute, non–neonatal intensive care unit (NICU) patients, and lack of gestational risk factors. The TNPM population was much smaller, though the authors were able to conclude that the disease also was correlated with healthy, non-NICU patients. The authors hypothesized that there may be a role of immune system maturity in the pathogenesis of ETN and thus dermatology residents should be aware of the setting of their consultation.4 A NICU consultation for ETN should raise suspicion, as ETN and TNPM favor healthy infants who likely are not residing in the NICU; we are reminded of the target populations for these disease processes.
Additional common causes of vesicular eruptions in neonates can likewise be diagnosed chiefly with clinical inspection. Miliaria presents with tiny superficial crystalline vesicles on the neck and back of newborns due to elevated temperature and resultant obstruction of the eccrine sweat ducts. Reassurance can be provided, as spontaneous resolution occurs with cooling and limitation of occlusive clothing and swaddling.2
Infants at a few weeks of life may present with a noncomedonal pustular eruption on the cheeks, forehead, and scalp commonly known as neonatal acne or neonatal cephalic pustulosis. The driving factor is thought to be an abnormal response to Malassezia and can be treated with ketoconazole cream or expectant management.2
Cutaneous candidiasis is the most common infectious cause of vesicles in the neonate and can present in 2 fashions. Neonatal candidiasis is common, presenting a week after birth and manifesting as oral thrush and red plaques with satellite pustules in the diaper area. Congenital candidiasis is due to infection in utero, presents prior to 1 week of life, exhibits diffuse erythroderma, and requires timely parenteral antifungals.5 Newborns and preterm infants are at higher risk for systemic disease, while full-term infants may experience a mild course of skin-limited lesions.
It is imperative to rule out other infectious etiologies in ill-appearing neonates with vesicles such as herpes simplex virus, bacterial infections, syphilis, and vertically transmitted TORCH (toxoplasmosis, other infections rubella, cytomegalovirus infection, and herpes simplex) diagnoses.6 Herpes simplex virus classically presents with grouped vesicles on an erythematous base; however, such characteristic lesions may be subtle in the newborn. The site of skin involvement usually is the area that first comes into contact with maternal lesions, such as the face for a newborn delivered in a cephalic presentation.2 It is critical to be cognizant of this diagnosis, as a delay in antiviral therapy can result in neurologic consequences due to disseminated disease.
If the clinical picture of vesiculobullous disease in the newborn is not as clear, less common causes must be considered. Infantile acropustulosis presents with recurring crops of pustules on the hands and feet at several months of age. The most common differential diagnosis is scabies; therefore, a mineral oil preparation should be performed to rule out this common mimicker. Potent topical corticosteroids are first-line therapy, and episodes generally resolve with time.
Another mimicker of pustules in neonates includes deficiency of IL-1ra, a rare entity described in 2009.7 Deficiency of IL-1ra is an autoinflammatory syndrome of skin and bone due to unopposed action of IL-1 with life-threatening inflammation; infants present with pustules, lytic bone lesions, elevated erythrocyte sedimentation rate and C-reactive protein, and failure to thrive.8 The characteristic mutation was discovered when the infants dramatically responded to therapy with anakinra, an IL-1ra.
Eosinophilic pustular folliculitis is an additional pustular dermatosis that manifests with lesions predominately in the head and neck area, and unlike the adult population, it usually is self-resolving and not associated with other comorbidities in newborns.2
Incontinentia pigmenti is an X-linked dominant syndrome due to a genetic mutation in NEMO, nuclear factor κβ essential modulator, which protects against apoptosis.3 Incontinentia pigmenti presents in newborn girls shortly after birth with vesicles in a blaschkoid distribution before evolving through 4 unique stages of vesicular lesions, verrucous lesions, hyperpigmentation, and ultimately resolves with residual hypopigmentation in the affected area.
Lastly, neonatal Behçet disease can present with vesicles in the mouth and genital region due to transfer of maternal antibodies. It is self-limiting in nature and would be readily diagnosed with a known maternal history, though judicious screening for infections may be needed in specific settings.2
Conclusion
In summary, a vast array of benign and worrisome dermatoses present in the neonatal period. A thorough history and physical examination, including the temporality of the lesions, the health status of the newborn, and the maternal history, can help delineate the diagnosis. The 5-step method presented can further elucidate the underlying mechanism and reduce an overwhelming differential diagnosis list by reviewing each finding yielded from each step. Dermatology residents should feel comfortable addressing this unique patient population to ameliorate unclear cutaneous diagnoses for pediatricians.
Acknowledgment
A special thank you to Lawrence A. Schachner, MD (Miami, Florida), for his help providing resources and guidance for this topic.
- Schachner L. Vesiculopustular dermatosis in neonates and infants. Lecture presented at: University of Miami Department of Dermatology & Cutaneous Surgery Grand Rounds; August 23, 2017; Miami, Florida.
- Eichenfield LF, Lee PW, Larraide M, et al. Neonatal skin and skin disorders. In: Schachner LA, Hansen RC, eds. Pediatric Dermatology. 4th ed. Philadelphia, PA: Elsevier Mosby; 2011:299-373.
- Goddard DS, Gilliam AE, Frieden IJ. Vesiculobullous and erosive diseases in the newborn. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:523-537.
- Reginatto FP, Muller FM, Peruzzo J, et al. Epidemiology and predisposing factors for erythema toxicum neonatorum and transient neonatal pustular melanosis: a multicenter study [published online May 25, 2017]. Pediatr Dermatol. 2017;34:422-426.
- Aruna C, Seetharam K. Congenital candidiasis. Indian Dermatol Online J. 2014;5(suppl 1):S44-S47.
- O’Connor NR, McLaughlin MR, Ham P. Newborn skin: part I. common rashes. Am Fam Physician. 2008;77:47-52.
- Reddy S, Jia S, Geoffrey R, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360:2438-2444.
- Minkis K, Aksentijevich I, Goldbach-Mansky R, et al. Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis. Arch Dermatol. 2012;148:747-752.
Vesiculobullous eruptions in neonates can readily generate anxiety from parents/guardians and pediatricians over both infectious and noninfectious causes. The role of the dermatology resident is critical to help diminish fear over common vesicular presentations or to escalate care in rarer situations if a more obscure or ominous diagnosis is clouding the patient’s clinical presentation and well-being. This article summarizes both common and uncommon vesiculobullous neonatal diseases to augment precise and efficient diagnoses in this vulnerable patient population.
Steps for Evaluating a Vesiculopustular Eruption
Receiving a consultation for a newborn with widespread vesicles can be a daunting scenario for a dermatology resident. Fear of missing an ominous diagnosis or aggressively treating a newborn for an erroneous infection when the diagnosis is actually a benign presentation can lead to an anxiety-provoking situation. Additionally, performing a procedure on a newborn can cause personal uneasiness. Dr. Lawrence A. Schachner, an eminent pediatric dermatologist at the University of Miami Miller School of Medicine (Miami, Florida), recently lectured on 5 key steps (Table 1) for the evaluation of a vesiculobullous eruption in the newborn to maximize the accuracy of diagnosis and patient care.1
First, draw out the fluid from the vesicle to send for bacterial and viral culture as well as Gram stain. Second, snip the roof of the vesicle to perform potassium hydroxide examination for yeast or fungi and frozen pathology when indicated. Third, use the base of the vesicle to obtain cells for a Tzanck smear to identify the predominant cell infiltrate, such as multinucleated giant cells in herpes simplex virus or eosinophils in erythema toxicum neonatorum (ETN). Fourth, a mineral oil preparation can be performed on several lesions, especially if a burrow is observed, to rule out bullous scabies in the appropriate clinical presentation. Lastly, a perilesional or lesional punch biopsy can be performed if the above steps have not yet clinched the diagnosis.2 By utilizing these steps, the resident efficiently utilizes 1 lesion to narrow down a formidable differential list of bullous disorders in the newborn.
Specific Diagnoses
A number of common diagnoses can present during the newborn period and can usually be readily diagnosed by clinical manifestations alone; a summary of these eruptions is provided in Table 2. Erythema toxicum neonatorum is the most common pustular eruption in neonates and presents in up to 50% of full-term infants at days 1 to 2 of life. Inflammatory pustules surrounded by characteristic blotchy erythema are displayed on the face, trunk, arms, and legs, usually sparing the palms and soles.3 Erythema toxicum neonatorum typically is a clinical diagnosis; however, it can be confirmed by demonstrating the predominance of eosinophils on Tzanck smear.
Transient neonatal pustular melanosis (TNPM) also presents in full-term infants; usually favors darkly pigmented neonates; and exhibits either pustules with a collarette of scale that lack surrounding erythema or with residual brown macules on the face, genitals, and acral surfaces. Postinflammatory pigmentary alteration on lesion clearance is another clue to diagnosis. Similarly, it is a clinical diagnosis but can be confirmed with a Tzanck smear demonstrating neutrophils as the major cell infiltrate.
In a prospective 1-year multicenter study performed by Reginatto et al,4 2831 neonates born in southern Brazil underwent a skin examination by a dermatologist within 72 hours of birth to characterize the prevalence and demographics of ETN and TNPM. They found a 21.3% (602 cases) prevalence of ETN compared to a 3.4% (97 cases) prevalence of TNPM, but they noted that most patients were white, and thus the diagnosis of TNPM likely is less prevalent in this group, as it favors darkly pigmented individuals. Additional predisposing factors associated with ETN were male gender, an Apgar score of 8 to 10 at 1 minute, non–neonatal intensive care unit (NICU) patients, and lack of gestational risk factors. The TNPM population was much smaller, though the authors were able to conclude that the disease also was correlated with healthy, non-NICU patients. The authors hypothesized that there may be a role of immune system maturity in the pathogenesis of ETN and thus dermatology residents should be aware of the setting of their consultation.4 A NICU consultation for ETN should raise suspicion, as ETN and TNPM favor healthy infants who likely are not residing in the NICU; we are reminded of the target populations for these disease processes.
Additional common causes of vesicular eruptions in neonates can likewise be diagnosed chiefly with clinical inspection. Miliaria presents with tiny superficial crystalline vesicles on the neck and back of newborns due to elevated temperature and resultant obstruction of the eccrine sweat ducts. Reassurance can be provided, as spontaneous resolution occurs with cooling and limitation of occlusive clothing and swaddling.2
Infants at a few weeks of life may present with a noncomedonal pustular eruption on the cheeks, forehead, and scalp commonly known as neonatal acne or neonatal cephalic pustulosis. The driving factor is thought to be an abnormal response to Malassezia and can be treated with ketoconazole cream or expectant management.2
Cutaneous candidiasis is the most common infectious cause of vesicles in the neonate and can present in 2 fashions. Neonatal candidiasis is common, presenting a week after birth and manifesting as oral thrush and red plaques with satellite pustules in the diaper area. Congenital candidiasis is due to infection in utero, presents prior to 1 week of life, exhibits diffuse erythroderma, and requires timely parenteral antifungals.5 Newborns and preterm infants are at higher risk for systemic disease, while full-term infants may experience a mild course of skin-limited lesions.
It is imperative to rule out other infectious etiologies in ill-appearing neonates with vesicles such as herpes simplex virus, bacterial infections, syphilis, and vertically transmitted TORCH (toxoplasmosis, other infections rubella, cytomegalovirus infection, and herpes simplex) diagnoses.6 Herpes simplex virus classically presents with grouped vesicles on an erythematous base; however, such characteristic lesions may be subtle in the newborn. The site of skin involvement usually is the area that first comes into contact with maternal lesions, such as the face for a newborn delivered in a cephalic presentation.2 It is critical to be cognizant of this diagnosis, as a delay in antiviral therapy can result in neurologic consequences due to disseminated disease.
If the clinical picture of vesiculobullous disease in the newborn is not as clear, less common causes must be considered. Infantile acropustulosis presents with recurring crops of pustules on the hands and feet at several months of age. The most common differential diagnosis is scabies; therefore, a mineral oil preparation should be performed to rule out this common mimicker. Potent topical corticosteroids are first-line therapy, and episodes generally resolve with time.
Another mimicker of pustules in neonates includes deficiency of IL-1ra, a rare entity described in 2009.7 Deficiency of IL-1ra is an autoinflammatory syndrome of skin and bone due to unopposed action of IL-1 with life-threatening inflammation; infants present with pustules, lytic bone lesions, elevated erythrocyte sedimentation rate and C-reactive protein, and failure to thrive.8 The characteristic mutation was discovered when the infants dramatically responded to therapy with anakinra, an IL-1ra.
Eosinophilic pustular folliculitis is an additional pustular dermatosis that manifests with lesions predominately in the head and neck area, and unlike the adult population, it usually is self-resolving and not associated with other comorbidities in newborns.2
Incontinentia pigmenti is an X-linked dominant syndrome due to a genetic mutation in NEMO, nuclear factor κβ essential modulator, which protects against apoptosis.3 Incontinentia pigmenti presents in newborn girls shortly after birth with vesicles in a blaschkoid distribution before evolving through 4 unique stages of vesicular lesions, verrucous lesions, hyperpigmentation, and ultimately resolves with residual hypopigmentation in the affected area.
Lastly, neonatal Behçet disease can present with vesicles in the mouth and genital region due to transfer of maternal antibodies. It is self-limiting in nature and would be readily diagnosed with a known maternal history, though judicious screening for infections may be needed in specific settings.2
Conclusion
In summary, a vast array of benign and worrisome dermatoses present in the neonatal period. A thorough history and physical examination, including the temporality of the lesions, the health status of the newborn, and the maternal history, can help delineate the diagnosis. The 5-step method presented can further elucidate the underlying mechanism and reduce an overwhelming differential diagnosis list by reviewing each finding yielded from each step. Dermatology residents should feel comfortable addressing this unique patient population to ameliorate unclear cutaneous diagnoses for pediatricians.
Acknowledgment
A special thank you to Lawrence A. Schachner, MD (Miami, Florida), for his help providing resources and guidance for this topic.
Vesiculobullous eruptions in neonates can readily generate anxiety from parents/guardians and pediatricians over both infectious and noninfectious causes. The role of the dermatology resident is critical to help diminish fear over common vesicular presentations or to escalate care in rarer situations if a more obscure or ominous diagnosis is clouding the patient’s clinical presentation and well-being. This article summarizes both common and uncommon vesiculobullous neonatal diseases to augment precise and efficient diagnoses in this vulnerable patient population.
Steps for Evaluating a Vesiculopustular Eruption
Receiving a consultation for a newborn with widespread vesicles can be a daunting scenario for a dermatology resident. Fear of missing an ominous diagnosis or aggressively treating a newborn for an erroneous infection when the diagnosis is actually a benign presentation can lead to an anxiety-provoking situation. Additionally, performing a procedure on a newborn can cause personal uneasiness. Dr. Lawrence A. Schachner, an eminent pediatric dermatologist at the University of Miami Miller School of Medicine (Miami, Florida), recently lectured on 5 key steps (Table 1) for the evaluation of a vesiculobullous eruption in the newborn to maximize the accuracy of diagnosis and patient care.1
First, draw out the fluid from the vesicle to send for bacterial and viral culture as well as Gram stain. Second, snip the roof of the vesicle to perform potassium hydroxide examination for yeast or fungi and frozen pathology when indicated. Third, use the base of the vesicle to obtain cells for a Tzanck smear to identify the predominant cell infiltrate, such as multinucleated giant cells in herpes simplex virus or eosinophils in erythema toxicum neonatorum (ETN). Fourth, a mineral oil preparation can be performed on several lesions, especially if a burrow is observed, to rule out bullous scabies in the appropriate clinical presentation. Lastly, a perilesional or lesional punch biopsy can be performed if the above steps have not yet clinched the diagnosis.2 By utilizing these steps, the resident efficiently utilizes 1 lesion to narrow down a formidable differential list of bullous disorders in the newborn.
Specific Diagnoses
A number of common diagnoses can present during the newborn period and can usually be readily diagnosed by clinical manifestations alone; a summary of these eruptions is provided in Table 2. Erythema toxicum neonatorum is the most common pustular eruption in neonates and presents in up to 50% of full-term infants at days 1 to 2 of life. Inflammatory pustules surrounded by characteristic blotchy erythema are displayed on the face, trunk, arms, and legs, usually sparing the palms and soles.3 Erythema toxicum neonatorum typically is a clinical diagnosis; however, it can be confirmed by demonstrating the predominance of eosinophils on Tzanck smear.
Transient neonatal pustular melanosis (TNPM) also presents in full-term infants; usually favors darkly pigmented neonates; and exhibits either pustules with a collarette of scale that lack surrounding erythema or with residual brown macules on the face, genitals, and acral surfaces. Postinflammatory pigmentary alteration on lesion clearance is another clue to diagnosis. Similarly, it is a clinical diagnosis but can be confirmed with a Tzanck smear demonstrating neutrophils as the major cell infiltrate.
In a prospective 1-year multicenter study performed by Reginatto et al,4 2831 neonates born in southern Brazil underwent a skin examination by a dermatologist within 72 hours of birth to characterize the prevalence and demographics of ETN and TNPM. They found a 21.3% (602 cases) prevalence of ETN compared to a 3.4% (97 cases) prevalence of TNPM, but they noted that most patients were white, and thus the diagnosis of TNPM likely is less prevalent in this group, as it favors darkly pigmented individuals. Additional predisposing factors associated with ETN were male gender, an Apgar score of 8 to 10 at 1 minute, non–neonatal intensive care unit (NICU) patients, and lack of gestational risk factors. The TNPM population was much smaller, though the authors were able to conclude that the disease also was correlated with healthy, non-NICU patients. The authors hypothesized that there may be a role of immune system maturity in the pathogenesis of ETN and thus dermatology residents should be aware of the setting of their consultation.4 A NICU consultation for ETN should raise suspicion, as ETN and TNPM favor healthy infants who likely are not residing in the NICU; we are reminded of the target populations for these disease processes.
Additional common causes of vesicular eruptions in neonates can likewise be diagnosed chiefly with clinical inspection. Miliaria presents with tiny superficial crystalline vesicles on the neck and back of newborns due to elevated temperature and resultant obstruction of the eccrine sweat ducts. Reassurance can be provided, as spontaneous resolution occurs with cooling and limitation of occlusive clothing and swaddling.2
Infants at a few weeks of life may present with a noncomedonal pustular eruption on the cheeks, forehead, and scalp commonly known as neonatal acne or neonatal cephalic pustulosis. The driving factor is thought to be an abnormal response to Malassezia and can be treated with ketoconazole cream or expectant management.2
Cutaneous candidiasis is the most common infectious cause of vesicles in the neonate and can present in 2 fashions. Neonatal candidiasis is common, presenting a week after birth and manifesting as oral thrush and red plaques with satellite pustules in the diaper area. Congenital candidiasis is due to infection in utero, presents prior to 1 week of life, exhibits diffuse erythroderma, and requires timely parenteral antifungals.5 Newborns and preterm infants are at higher risk for systemic disease, while full-term infants may experience a mild course of skin-limited lesions.
It is imperative to rule out other infectious etiologies in ill-appearing neonates with vesicles such as herpes simplex virus, bacterial infections, syphilis, and vertically transmitted TORCH (toxoplasmosis, other infections rubella, cytomegalovirus infection, and herpes simplex) diagnoses.6 Herpes simplex virus classically presents with grouped vesicles on an erythematous base; however, such characteristic lesions may be subtle in the newborn. The site of skin involvement usually is the area that first comes into contact with maternal lesions, such as the face for a newborn delivered in a cephalic presentation.2 It is critical to be cognizant of this diagnosis, as a delay in antiviral therapy can result in neurologic consequences due to disseminated disease.
If the clinical picture of vesiculobullous disease in the newborn is not as clear, less common causes must be considered. Infantile acropustulosis presents with recurring crops of pustules on the hands and feet at several months of age. The most common differential diagnosis is scabies; therefore, a mineral oil preparation should be performed to rule out this common mimicker. Potent topical corticosteroids are first-line therapy, and episodes generally resolve with time.
Another mimicker of pustules in neonates includes deficiency of IL-1ra, a rare entity described in 2009.7 Deficiency of IL-1ra is an autoinflammatory syndrome of skin and bone due to unopposed action of IL-1 with life-threatening inflammation; infants present with pustules, lytic bone lesions, elevated erythrocyte sedimentation rate and C-reactive protein, and failure to thrive.8 The characteristic mutation was discovered when the infants dramatically responded to therapy with anakinra, an IL-1ra.
Eosinophilic pustular folliculitis is an additional pustular dermatosis that manifests with lesions predominately in the head and neck area, and unlike the adult population, it usually is self-resolving and not associated with other comorbidities in newborns.2
Incontinentia pigmenti is an X-linked dominant syndrome due to a genetic mutation in NEMO, nuclear factor κβ essential modulator, which protects against apoptosis.3 Incontinentia pigmenti presents in newborn girls shortly after birth with vesicles in a blaschkoid distribution before evolving through 4 unique stages of vesicular lesions, verrucous lesions, hyperpigmentation, and ultimately resolves with residual hypopigmentation in the affected area.
Lastly, neonatal Behçet disease can present with vesicles in the mouth and genital region due to transfer of maternal antibodies. It is self-limiting in nature and would be readily diagnosed with a known maternal history, though judicious screening for infections may be needed in specific settings.2
Conclusion
In summary, a vast array of benign and worrisome dermatoses present in the neonatal period. A thorough history and physical examination, including the temporality of the lesions, the health status of the newborn, and the maternal history, can help delineate the diagnosis. The 5-step method presented can further elucidate the underlying mechanism and reduce an overwhelming differential diagnosis list by reviewing each finding yielded from each step. Dermatology residents should feel comfortable addressing this unique patient population to ameliorate unclear cutaneous diagnoses for pediatricians.
Acknowledgment
A special thank you to Lawrence A. Schachner, MD (Miami, Florida), for his help providing resources and guidance for this topic.
- Schachner L. Vesiculopustular dermatosis in neonates and infants. Lecture presented at: University of Miami Department of Dermatology & Cutaneous Surgery Grand Rounds; August 23, 2017; Miami, Florida.
- Eichenfield LF, Lee PW, Larraide M, et al. Neonatal skin and skin disorders. In: Schachner LA, Hansen RC, eds. Pediatric Dermatology. 4th ed. Philadelphia, PA: Elsevier Mosby; 2011:299-373.
- Goddard DS, Gilliam AE, Frieden IJ. Vesiculobullous and erosive diseases in the newborn. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:523-537.
- Reginatto FP, Muller FM, Peruzzo J, et al. Epidemiology and predisposing factors for erythema toxicum neonatorum and transient neonatal pustular melanosis: a multicenter study [published online May 25, 2017]. Pediatr Dermatol. 2017;34:422-426.
- Aruna C, Seetharam K. Congenital candidiasis. Indian Dermatol Online J. 2014;5(suppl 1):S44-S47.
- O’Connor NR, McLaughlin MR, Ham P. Newborn skin: part I. common rashes. Am Fam Physician. 2008;77:47-52.
- Reddy S, Jia S, Geoffrey R, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360:2438-2444.
- Minkis K, Aksentijevich I, Goldbach-Mansky R, et al. Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis. Arch Dermatol. 2012;148:747-752.
- Schachner L. Vesiculopustular dermatosis in neonates and infants. Lecture presented at: University of Miami Department of Dermatology & Cutaneous Surgery Grand Rounds; August 23, 2017; Miami, Florida.
- Eichenfield LF, Lee PW, Larraide M, et al. Neonatal skin and skin disorders. In: Schachner LA, Hansen RC, eds. Pediatric Dermatology. 4th ed. Philadelphia, PA: Elsevier Mosby; 2011:299-373.
- Goddard DS, Gilliam AE, Frieden IJ. Vesiculobullous and erosive diseases in the newborn. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:523-537.
- Reginatto FP, Muller FM, Peruzzo J, et al. Epidemiology and predisposing factors for erythema toxicum neonatorum and transient neonatal pustular melanosis: a multicenter study [published online May 25, 2017]. Pediatr Dermatol. 2017;34:422-426.
- Aruna C, Seetharam K. Congenital candidiasis. Indian Dermatol Online J. 2014;5(suppl 1):S44-S47.
- O’Connor NR, McLaughlin MR, Ham P. Newborn skin: part I. common rashes. Am Fam Physician. 2008;77:47-52.
- Reddy S, Jia S, Geoffrey R, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360:2438-2444.
- Minkis K, Aksentijevich I, Goldbach-Mansky R, et al. Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis. Arch Dermatol. 2012;148:747-752.
Early evidence shows that surgery can alter gut microbiome
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
EXPERT ANALYSIS FROM THE ACS CLINICAL CONGRESS
Guselkumab tops adalimumab for psychiatric comorbidities in psoriasis
GENEVA – Guselkumab for treatment of moderate to severe plaque psoriasis generated significantly greater improvement in comorbid anxiety and depression than adalimumab in the head-to-head VOYAGE 2 randomized trial, Kenneth B. Gordon, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The population enrolled in VOYAGE 2, which did not preselect to enrich the study population for anxiety and depression, reflected how common these mental health problems are among psoriasis patients. Fully 38.6% of the 992 randomized patients had a baseline Hospital Anxiety and Depression Score-Anxiety (HADS-A) of 8 or more (considered clinically important anxiety) on the 0-21 scale, and 27.7% had a HADS-D score of at least 8 (indicative of clinically meaningful depression), noted Dr. Gordon, professor and chair of dermatology at the Medical College of Wisconsin, Milwaukee.
The on-treatment reductions in psychiatric symptoms in VOYAGE 2 correlated closely with greater improvement in psoriasis, he added. For example, regardless of which drug they were on, patients with a baseline HADS-D of 8 or more averaged a 3.6-point reduction in HADS-D at week 24 if, at that point, they had a Psoriasis Area Severity Index (PASI) response of 75-89, a 4.0-point improvement if they had a PASI 90-99 response, and a 5.2-point reduction in HADS-D if they had a PASI 100 response.
VOYAGE 2 was a phase 3, double-blind, multicenter, placebo-controlled comparison of guselkumab (Tremfya), a human monoclonal antibody targeting the interleukin-23 p 19 subunit, and the tumor necrosis factor-alpha inhibitor adalimumab (Humira) in their standard dosing. Participants were randomized 2:1:1 to guselkumab, adalimumab, or placebo. The study’s primary outcomes have previously been reported (J Am Acad Dermatol. 2017 Mar;76[3]:418-31). For example, at week 24 the guselkumab group demonstrated PASI 75, 90, and 100 responses of 89.1%, 75.2%, and 44.2%, respectively, compared with adalimumab, with PASI 75, 90, and 100 responses of 71%, 54.8%, and 26.6%.
Serial measurement of anxiety and depression symptoms using the HADS-A and HADS-D were part of the study protocol. The mean baseline HADS-A and HADS-D scores were 6.8 and 5.3. At week 24, the mean reduction in the HADS-A score was 2.0 points in the guselkumab group, compared with 1.0 point in the adalimumab arm. HADS-D scores improved by 1.7 and 1.1 points, respectively, in the overall guselkumab and adalimumab groups.
More importantly, among patients with a baseline HADS-A of 8 or higher, by week 16 of the trial, the HADS-A score had dropped below 8 in 51.4% of those on guselkumab, compared with 44.9% of patients on adalimumab and 25.9% on placebo, Dr. Gordon reported. Similarly, 59.2% of guselkumab-treated patients with a high baseline HADS-D improved to a score below 8 at week 16, compared with 54.3% on adalimumab and 27% on placebo.
At week 24, 58.4% of guselkumab-treated patients with a high baseline HADS-A and 59.4% of those with a high HADS-D had scores below 8. Again, these responses were significantly better than the 42.9% and 46.4% rates, respectively, in the adalimumab arm.
VOYAGE 2 was sponsored by Janssen, which markets guselkumab, approved by the Food and Drug Administration in July 2017 for treating adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Dr. Gordon reported receiving research support from and serving as a consultant to Janssen and numerous other pharmaceutical companies.
GENEVA – Guselkumab for treatment of moderate to severe plaque psoriasis generated significantly greater improvement in comorbid anxiety and depression than adalimumab in the head-to-head VOYAGE 2 randomized trial, Kenneth B. Gordon, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The population enrolled in VOYAGE 2, which did not preselect to enrich the study population for anxiety and depression, reflected how common these mental health problems are among psoriasis patients. Fully 38.6% of the 992 randomized patients had a baseline Hospital Anxiety and Depression Score-Anxiety (HADS-A) of 8 or more (considered clinically important anxiety) on the 0-21 scale, and 27.7% had a HADS-D score of at least 8 (indicative of clinically meaningful depression), noted Dr. Gordon, professor and chair of dermatology at the Medical College of Wisconsin, Milwaukee.
The on-treatment reductions in psychiatric symptoms in VOYAGE 2 correlated closely with greater improvement in psoriasis, he added. For example, regardless of which drug they were on, patients with a baseline HADS-D of 8 or more averaged a 3.6-point reduction in HADS-D at week 24 if, at that point, they had a Psoriasis Area Severity Index (PASI) response of 75-89, a 4.0-point improvement if they had a PASI 90-99 response, and a 5.2-point reduction in HADS-D if they had a PASI 100 response.
VOYAGE 2 was a phase 3, double-blind, multicenter, placebo-controlled comparison of guselkumab (Tremfya), a human monoclonal antibody targeting the interleukin-23 p 19 subunit, and the tumor necrosis factor-alpha inhibitor adalimumab (Humira) in their standard dosing. Participants were randomized 2:1:1 to guselkumab, adalimumab, or placebo. The study’s primary outcomes have previously been reported (J Am Acad Dermatol. 2017 Mar;76[3]:418-31). For example, at week 24 the guselkumab group demonstrated PASI 75, 90, and 100 responses of 89.1%, 75.2%, and 44.2%, respectively, compared with adalimumab, with PASI 75, 90, and 100 responses of 71%, 54.8%, and 26.6%.
Serial measurement of anxiety and depression symptoms using the HADS-A and HADS-D were part of the study protocol. The mean baseline HADS-A and HADS-D scores were 6.8 and 5.3. At week 24, the mean reduction in the HADS-A score was 2.0 points in the guselkumab group, compared with 1.0 point in the adalimumab arm. HADS-D scores improved by 1.7 and 1.1 points, respectively, in the overall guselkumab and adalimumab groups.
More importantly, among patients with a baseline HADS-A of 8 or higher, by week 16 of the trial, the HADS-A score had dropped below 8 in 51.4% of those on guselkumab, compared with 44.9% of patients on adalimumab and 25.9% on placebo, Dr. Gordon reported. Similarly, 59.2% of guselkumab-treated patients with a high baseline HADS-D improved to a score below 8 at week 16, compared with 54.3% on adalimumab and 27% on placebo.
At week 24, 58.4% of guselkumab-treated patients with a high baseline HADS-A and 59.4% of those with a high HADS-D had scores below 8. Again, these responses were significantly better than the 42.9% and 46.4% rates, respectively, in the adalimumab arm.
VOYAGE 2 was sponsored by Janssen, which markets guselkumab, approved by the Food and Drug Administration in July 2017 for treating adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Dr. Gordon reported receiving research support from and serving as a consultant to Janssen and numerous other pharmaceutical companies.
GENEVA – Guselkumab for treatment of moderate to severe plaque psoriasis generated significantly greater improvement in comorbid anxiety and depression than adalimumab in the head-to-head VOYAGE 2 randomized trial, Kenneth B. Gordon, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The population enrolled in VOYAGE 2, which did not preselect to enrich the study population for anxiety and depression, reflected how common these mental health problems are among psoriasis patients. Fully 38.6% of the 992 randomized patients had a baseline Hospital Anxiety and Depression Score-Anxiety (HADS-A) of 8 or more (considered clinically important anxiety) on the 0-21 scale, and 27.7% had a HADS-D score of at least 8 (indicative of clinically meaningful depression), noted Dr. Gordon, professor and chair of dermatology at the Medical College of Wisconsin, Milwaukee.
The on-treatment reductions in psychiatric symptoms in VOYAGE 2 correlated closely with greater improvement in psoriasis, he added. For example, regardless of which drug they were on, patients with a baseline HADS-D of 8 or more averaged a 3.6-point reduction in HADS-D at week 24 if, at that point, they had a Psoriasis Area Severity Index (PASI) response of 75-89, a 4.0-point improvement if they had a PASI 90-99 response, and a 5.2-point reduction in HADS-D if they had a PASI 100 response.
VOYAGE 2 was a phase 3, double-blind, multicenter, placebo-controlled comparison of guselkumab (Tremfya), a human monoclonal antibody targeting the interleukin-23 p 19 subunit, and the tumor necrosis factor-alpha inhibitor adalimumab (Humira) in their standard dosing. Participants were randomized 2:1:1 to guselkumab, adalimumab, or placebo. The study’s primary outcomes have previously been reported (J Am Acad Dermatol. 2017 Mar;76[3]:418-31). For example, at week 24 the guselkumab group demonstrated PASI 75, 90, and 100 responses of 89.1%, 75.2%, and 44.2%, respectively, compared with adalimumab, with PASI 75, 90, and 100 responses of 71%, 54.8%, and 26.6%.
Serial measurement of anxiety and depression symptoms using the HADS-A and HADS-D were part of the study protocol. The mean baseline HADS-A and HADS-D scores were 6.8 and 5.3. At week 24, the mean reduction in the HADS-A score was 2.0 points in the guselkumab group, compared with 1.0 point in the adalimumab arm. HADS-D scores improved by 1.7 and 1.1 points, respectively, in the overall guselkumab and adalimumab groups.
More importantly, among patients with a baseline HADS-A of 8 or higher, by week 16 of the trial, the HADS-A score had dropped below 8 in 51.4% of those on guselkumab, compared with 44.9% of patients on adalimumab and 25.9% on placebo, Dr. Gordon reported. Similarly, 59.2% of guselkumab-treated patients with a high baseline HADS-D improved to a score below 8 at week 16, compared with 54.3% on adalimumab and 27% on placebo.
At week 24, 58.4% of guselkumab-treated patients with a high baseline HADS-A and 59.4% of those with a high HADS-D had scores below 8. Again, these responses were significantly better than the 42.9% and 46.4% rates, respectively, in the adalimumab arm.
VOYAGE 2 was sponsored by Janssen, which markets guselkumab, approved by the Food and Drug Administration in July 2017 for treating adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Dr. Gordon reported receiving research support from and serving as a consultant to Janssen and numerous other pharmaceutical companies.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Fifty-nine percent of gesulkumab-treated patients with moderate to severe psoriasis and clinically significant depression at baseline were below the depression threshold at week 24, compared with 46% of adalimumab-treated patients.
Data source: A phase 3, double-blind, multicenter, placebo-controlled comparison of guselkumab and adalimumab in 992 randomized patients with moderate to severe psoriasis.
Disclosures: VOYAGE 2 was sponsored by Janssen, which markets guselkumab. The presenter reported receiving research support from and serving as a consultant to Janssen and numerous other pharmaceutical companies.
Statement Offers Guidance for Management of Brain AVMs
Recent studies have helped clarify the natural history risks of intracranial hemorrhage (ICH) and seizure in patients with unruptured brain arteriovenous malformations (AVMs). In addition, researchers have completed the first randomized trial of interventional therapy versus conservative management for unruptured brain AVMs. Nevertheless, data to guide treatment decisions remain limited, and “considerable uncertainties … face physicians managing patients with ruptured and unruptured brain AVMs,” according to a scientific statement for healthcare professionals from the American Heart Association (AHA) and American Stroke Association (ASA). Optimal management of unruptured brain AVMs is a subject of debate, and discussion of treatment options should include careful consideration of natural history risks, the relative risks of intervention strategies, and patients’ life expectancy, the authors said.
The scientific statement on the management of brain AVMs was published in the August issue of Stroke. It updates the American Heart Association’s 2001 statement on this topic. The report reviews epidemiology, diagnosis, natural history, treatment, and management of ruptured and unruptured brain AVMs, as well as areas requiring more evidence. The American Academy of Neurology affirmed the value of the statement as an educational tool for neurologists. The Society of NeuroInterventional Surgery endorsed it, and the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Cerebrovascular Section affirmed its educational benefit.
An Uncommon Lesion
Brain AVMs are uncommon, may present with spontaneous ICH, seizures, or headache, and typically present in young adults. Neurologists may identify incidental asymptomatic AVMs when patients undergo brain imaging for other reasons. The primary goal of treatment is prevention of hemorrhagic stroke. 
Colin P. Derdeyn, MD, Professor of Neurology and Radiology at the University of Iowa in Iowa City and chair of the group that wrote the scientific statement, and colleagues searched all English-language articles on brain AVMs in humans that had been published following the 2001 statement. “Advances … include the accumulation of new data related to epidemiology, biology, imaging, outcomes with treatment, and introduction of new embolic agents,” the authors said. “Most notable of these data are the results of the first randomized trial of intervention for unruptured brain AVMs, the ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformations).”
ARUBA enrolled 226 adult patients with unruptured brain AVMs between 2007 and 2013. Patients were randomized to receive medical management alone or medical management with interventional therapy (eg, resection, embolization, or stereotactic radiosurgery alone or in combination).
A preplanned interim analysis found that after a mean follow-up of 33 months, the risk of stroke or death was more than three times higher in the intervention group (30.7%) than in the medical management group (10.1%). The analysis included data from 224 participants at 39 sites worldwide. On the recommendation of the ARUBA Data and Safety Monitoring Board, the National Institute of Neurological Disorders and Stroke stopped enrollment and stated that “under the experimental conditions in this trial, the interim analysis … shows that medical management is superior to intervention in patients with unruptured brain AVMs.”
Although ARUBA and an observational study by Al-Shahi Salman et al support a conservative approach to management, the studies had relatively short follow-up, considering the long duration of hemorrhage risk for patients with untreated brain AVMs. Furthermore, complication rates in the treatment arms in ARUBA were much higher than expected, the authors said. “The primary end points of ARUBA [ie, stroke or death] in the intervention group for Spetzler-Martin (SM) grade I (14.3%), II (43.3%), and III (57.1%) AVMs are higher than would have been expected in contemporary series, particularly for surgery or radiosurgery performed alone,” the authors said.
Additional studies are needed to better define long-term risks of stroke and seizure and to identify specific predictors of hemorrhagic stroke. “Long-term follow-up of participants in the ARUBA trial will be valuable for determining whether the superiority of conservative management over intervention observed in that study persists in the long term,” they said. “Further randomized controlled trials are justified to investigate the reproducibility of the findings of ARUBA and to investigate whether the balance of risk between conservative management and intervention is different in specific groups (eg, patients with SM grade I brain AVM).”
Recommendations for Management
Neurologists can inform patients about natural history risks, which are reliably quantified over approximately 10 years for ICH and approximately five years for epileptic seizure, the authors said. The annual risk of a first-ever ICH from an unruptured brain AVM is approximately 1%. The five-year risk of developing a first seizure is approximately 8%, and the five-year risk of developing epilepsy after a first seizure is approximately 58%.
Discussion of treatment options should consider natural history risks “weighed carefully against the relative risks of different intervention strategies and life expectancy,” the authors said. The SM grading scale is useful for predicting the risk of surgical resection.
For the management of patients with ruptured brain AVMs, the authors recommend that the evaluation of underlying brain AVMs and management of an initial hemorrhage follow the AHA and ASA’s 2015 spontaneous ICH management guidelines. The annual risk of recurrent ICH from a ruptured brain AVM is approximately 5%, and increasing age, deep venous drainage, arterial aneurysms, and female sex may increase the risk.
—Jake Remaly
Suggested Reading
Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):1661-1669.
Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48(8):e200-e224.
Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032-2060.
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614-621.
Recent studies have helped clarify the natural history risks of intracranial hemorrhage (ICH) and seizure in patients with unruptured brain arteriovenous malformations (AVMs). In addition, researchers have completed the first randomized trial of interventional therapy versus conservative management for unruptured brain AVMs. Nevertheless, data to guide treatment decisions remain limited, and “considerable uncertainties … face physicians managing patients with ruptured and unruptured brain AVMs,” according to a scientific statement for healthcare professionals from the American Heart Association (AHA) and American Stroke Association (ASA). Optimal management of unruptured brain AVMs is a subject of debate, and discussion of treatment options should include careful consideration of natural history risks, the relative risks of intervention strategies, and patients’ life expectancy, the authors said.
The scientific statement on the management of brain AVMs was published in the August issue of Stroke. It updates the American Heart Association’s 2001 statement on this topic. The report reviews epidemiology, diagnosis, natural history, treatment, and management of ruptured and unruptured brain AVMs, as well as areas requiring more evidence. The American Academy of Neurology affirmed the value of the statement as an educational tool for neurologists. The Society of NeuroInterventional Surgery endorsed it, and the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Cerebrovascular Section affirmed its educational benefit.
An Uncommon Lesion
Brain AVMs are uncommon, may present with spontaneous ICH, seizures, or headache, and typically present in young adults. Neurologists may identify incidental asymptomatic AVMs when patients undergo brain imaging for other reasons. The primary goal of treatment is prevention of hemorrhagic stroke.
Colin P. Derdeyn, MD, Professor of Neurology and Radiology at the University of Iowa in Iowa City and chair of the group that wrote the scientific statement, and colleagues searched all English-language articles on brain AVMs in humans that had been published following the 2001 statement. “Advances … include the accumulation of new data related to epidemiology, biology, imaging, outcomes with treatment, and introduction of new embolic agents,” the authors said. “Most notable of these data are the results of the first randomized trial of intervention for unruptured brain AVMs, the ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformations).”
ARUBA enrolled 226 adult patients with unruptured brain AVMs between 2007 and 2013. Patients were randomized to receive medical management alone or medical management with interventional therapy (eg, resection, embolization, or stereotactic radiosurgery alone or in combination).
A preplanned interim analysis found that after a mean follow-up of 33 months, the risk of stroke or death was more than three times higher in the intervention group (30.7%) than in the medical management group (10.1%). The analysis included data from 224 participants at 39 sites worldwide. On the recommendation of the ARUBA Data and Safety Monitoring Board, the National Institute of Neurological Disorders and Stroke stopped enrollment and stated that “under the experimental conditions in this trial, the interim analysis … shows that medical management is superior to intervention in patients with unruptured brain AVMs.”
Although ARUBA and an observational study by Al-Shahi Salman et al support a conservative approach to management, the studies had relatively short follow-up, considering the long duration of hemorrhage risk for patients with untreated brain AVMs. Furthermore, complication rates in the treatment arms in ARUBA were much higher than expected, the authors said. “The primary end points of ARUBA [ie, stroke or death] in the intervention group for Spetzler-Martin (SM) grade I (14.3%), II (43.3%), and III (57.1%) AVMs are higher than would have been expected in contemporary series, particularly for surgery or radiosurgery performed alone,” the authors said.
Additional studies are needed to better define long-term risks of stroke and seizure and to identify specific predictors of hemorrhagic stroke. “Long-term follow-up of participants in the ARUBA trial will be valuable for determining whether the superiority of conservative management over intervention observed in that study persists in the long term,” they said. “Further randomized controlled trials are justified to investigate the reproducibility of the findings of ARUBA and to investigate whether the balance of risk between conservative management and intervention is different in specific groups (eg, patients with SM grade I brain AVM).”
Recommendations for Management
Neurologists can inform patients about natural history risks, which are reliably quantified over approximately 10 years for ICH and approximately five years for epileptic seizure, the authors said. The annual risk of a first-ever ICH from an unruptured brain AVM is approximately 1%. The five-year risk of developing a first seizure is approximately 8%, and the five-year risk of developing epilepsy after a first seizure is approximately 58%.
Discussion of treatment options should consider natural history risks “weighed carefully against the relative risks of different intervention strategies and life expectancy,” the authors said. The SM grading scale is useful for predicting the risk of surgical resection.
For the management of patients with ruptured brain AVMs, the authors recommend that the evaluation of underlying brain AVMs and management of an initial hemorrhage follow the AHA and ASA’s 2015 spontaneous ICH management guidelines. The annual risk of recurrent ICH from a ruptured brain AVM is approximately 5%, and increasing age, deep venous drainage, arterial aneurysms, and female sex may increase the risk.
—Jake Remaly
Suggested Reading
Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):1661-1669.
Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48(8):e200-e224.
Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032-2060.
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614-621.
Recent studies have helped clarify the natural history risks of intracranial hemorrhage (ICH) and seizure in patients with unruptured brain arteriovenous malformations (AVMs). In addition, researchers have completed the first randomized trial of interventional therapy versus conservative management for unruptured brain AVMs. Nevertheless, data to guide treatment decisions remain limited, and “considerable uncertainties … face physicians managing patients with ruptured and unruptured brain AVMs,” according to a scientific statement for healthcare professionals from the American Heart Association (AHA) and American Stroke Association (ASA). Optimal management of unruptured brain AVMs is a subject of debate, and discussion of treatment options should include careful consideration of natural history risks, the relative risks of intervention strategies, and patients’ life expectancy, the authors said.
The scientific statement on the management of brain AVMs was published in the August issue of Stroke. It updates the American Heart Association’s 2001 statement on this topic. The report reviews epidemiology, diagnosis, natural history, treatment, and management of ruptured and unruptured brain AVMs, as well as areas requiring more evidence. The American Academy of Neurology affirmed the value of the statement as an educational tool for neurologists. The Society of NeuroInterventional Surgery endorsed it, and the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Cerebrovascular Section affirmed its educational benefit.
An Uncommon Lesion
Brain AVMs are uncommon, may present with spontaneous ICH, seizures, or headache, and typically present in young adults. Neurologists may identify incidental asymptomatic AVMs when patients undergo brain imaging for other reasons. The primary goal of treatment is prevention of hemorrhagic stroke.
Colin P. Derdeyn, MD, Professor of Neurology and Radiology at the University of Iowa in Iowa City and chair of the group that wrote the scientific statement, and colleagues searched all English-language articles on brain AVMs in humans that had been published following the 2001 statement. “Advances … include the accumulation of new data related to epidemiology, biology, imaging, outcomes with treatment, and introduction of new embolic agents,” the authors said. “Most notable of these data are the results of the first randomized trial of intervention for unruptured brain AVMs, the ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformations).”
ARUBA enrolled 226 adult patients with unruptured brain AVMs between 2007 and 2013. Patients were randomized to receive medical management alone or medical management with interventional therapy (eg, resection, embolization, or stereotactic radiosurgery alone or in combination).
A preplanned interim analysis found that after a mean follow-up of 33 months, the risk of stroke or death was more than three times higher in the intervention group (30.7%) than in the medical management group (10.1%). The analysis included data from 224 participants at 39 sites worldwide. On the recommendation of the ARUBA Data and Safety Monitoring Board, the National Institute of Neurological Disorders and Stroke stopped enrollment and stated that “under the experimental conditions in this trial, the interim analysis … shows that medical management is superior to intervention in patients with unruptured brain AVMs.”
Although ARUBA and an observational study by Al-Shahi Salman et al support a conservative approach to management, the studies had relatively short follow-up, considering the long duration of hemorrhage risk for patients with untreated brain AVMs. Furthermore, complication rates in the treatment arms in ARUBA were much higher than expected, the authors said. “The primary end points of ARUBA [ie, stroke or death] in the intervention group for Spetzler-Martin (SM) grade I (14.3%), II (43.3%), and III (57.1%) AVMs are higher than would have been expected in contemporary series, particularly for surgery or radiosurgery performed alone,” the authors said.
Additional studies are needed to better define long-term risks of stroke and seizure and to identify specific predictors of hemorrhagic stroke. “Long-term follow-up of participants in the ARUBA trial will be valuable for determining whether the superiority of conservative management over intervention observed in that study persists in the long term,” they said. “Further randomized controlled trials are justified to investigate the reproducibility of the findings of ARUBA and to investigate whether the balance of risk between conservative management and intervention is different in specific groups (eg, patients with SM grade I brain AVM).”
Recommendations for Management
Neurologists can inform patients about natural history risks, which are reliably quantified over approximately 10 years for ICH and approximately five years for epileptic seizure, the authors said. The annual risk of a first-ever ICH from an unruptured brain AVM is approximately 1%. The five-year risk of developing a first seizure is approximately 8%, and the five-year risk of developing epilepsy after a first seizure is approximately 58%.
Discussion of treatment options should consider natural history risks “weighed carefully against the relative risks of different intervention strategies and life expectancy,” the authors said. The SM grading scale is useful for predicting the risk of surgical resection.
For the management of patients with ruptured brain AVMs, the authors recommend that the evaluation of underlying brain AVMs and management of an initial hemorrhage follow the AHA and ASA’s 2015 spontaneous ICH management guidelines. The annual risk of recurrent ICH from a ruptured brain AVM is approximately 5%, and increasing age, deep venous drainage, arterial aneurysms, and female sex may increase the risk.
—Jake Remaly
Suggested Reading
Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):1661-1669.
Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48(8):e200-e224.
Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032-2060.
Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614-621.