Image courtesy of P. Eyers

Researchers have found the cancer-associated pseudokinase Tribbles 2 (TRIB2) to be a potential therapeutic target in solid tumors and blood cancers, including acute myeloid leukemia (AML).

Previous research had described TRIB2 as a target of small-molecule protein kinase inhibitors originally designed to interfere with kinase domains of the epidermal growth factor receptor (EGFR) tyrosine kinase family.

Using a thermal shift assay, the team discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS). They then employed a biochemical drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro.

The researchers found that afatinib, which is already approved by the U.S. Food and Drug Administration to treat non-small cell lung cancer, led to rapid TRIB2 degradation in human AML cells.

Patrick A. Eyers, PhD, of the University of Liverpool in the U.K., and his colleagues published their findings in Science Signaling.

The team found afatinib to be relatively specific for EGFR and human epidermal growth factor receptor 2 (HER2) at nanomolar concentrations in cells.

The researchers confirmed that at least two TRIB2 Cys residues interact with afatinib in vitro.

The team also discovered TRIB2 could be destabilized by neratinib and osimertinib in vitro.

“Our data prove that the cellular mechanism by which TRIB2 stability is regulated by compounds is proteasome-based,” the researchers wrote, “and we speculate that an afatinib-induced conformational change might induce TRIB2 ubiquitination.”

The researchers plan to study further TRIB2 small-molecule interactions with dynamic changes in ubiquitination status.

Furthermore, they report their work demonstrates that covalent inhibitors such as afatinib have TRIB2-degrading activity in human cells at micromolar concentrations.

The researchers determined that afatinib has similar efficacy to the TRIB2-destabilizing quinazoline neratinib at similar ranges.

The team believes their data “raise the intriguing possibility that clinical inhibitors might be used as TRIB2-degrading agents in research, and possibly clinical, contexts.”

“A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins,” Dr. Eyers commented. “Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer.”

The TRIB proteins play many diverse roles in cell signaling, development, and cancer. According to a paper in Developmental Dynamics, they were named after the small, round, fictional organisms from the original Star Trek television series. Their major role was to eat and reproduce.

This work was funded by two U.K. Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentships, a Tools and Resources Development Fund award, Royal Society Research Grants, North West Cancer Research grants, and funding from the National Institutes of Health.

The authors disclosed no perceived conflicts of interest, although several authors are affiliated with the Structural Genomics Consortium at the University of North Carolina at Chapel Hill, which receives direct funds from various pharmaceutical companies but remains entirely independent. 

Image courtesy of P. Eyers

Researchers have found the cancer-associated pseudokinase Tribbles 2 (TRIB2) to be a potential therapeutic target in solid tumors and blood cancers, including acute myeloid leukemia (AML).

Previous research had described TRIB2 as a target of small-molecule protein kinase inhibitors originally designed to interfere with kinase domains of the epidermal growth factor receptor (EGFR) tyrosine kinase family.

Using a thermal shift assay, the team discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS). They then employed a biochemical drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro.

The researchers found that afatinib, which is already approved by the U.S. Food and Drug Administration to treat non-small cell lung cancer, led to rapid TRIB2 degradation in human AML cells.

Patrick A. Eyers, PhD, of the University of Liverpool in the U.K., and his colleagues published their findings in Science Signaling.

The team found afatinib to be relatively specific for EGFR and human epidermal growth factor receptor 2 (HER2) at nanomolar concentrations in cells.

The researchers confirmed that at least two TRIB2 Cys residues interact with afatinib in vitro.

The team also discovered TRIB2 could be destabilized by neratinib and osimertinib in vitro.

“Our data prove that the cellular mechanism by which TRIB2 stability is regulated by compounds is proteasome-based,” the researchers wrote, “and we speculate that an afatinib-induced conformational change might induce TRIB2 ubiquitination.”

The researchers plan to study further TRIB2 small-molecule interactions with dynamic changes in ubiquitination status.

Furthermore, they report their work demonstrates that covalent inhibitors such as afatinib have TRIB2-degrading activity in human cells at micromolar concentrations.

The researchers determined that afatinib has similar efficacy to the TRIB2-destabilizing quinazoline neratinib at similar ranges.

The team believes their data “raise the intriguing possibility that clinical inhibitors might be used as TRIB2-degrading agents in research, and possibly clinical, contexts.”

“A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins,” Dr. Eyers commented. “Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer.”

The TRIB proteins play many diverse roles in cell signaling, development, and cancer. According to a paper in Developmental Dynamics, they were named after the small, round, fictional organisms from the original Star Trek television series. Their major role was to eat and reproduce.

This work was funded by two U.K. Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentships, a Tools and Resources Development Fund award, Royal Society Research Grants, North West Cancer Research grants, and funding from the National Institutes of Health.

The authors disclosed no perceived conflicts of interest, although several authors are affiliated with the Structural Genomics Consortium at the University of North Carolina at Chapel Hill, which receives direct funds from various pharmaceutical companies but remains entirely independent. 

Image courtesy of P. Eyers

Researchers have found the cancer-associated pseudokinase Tribbles 2 (TRIB2) to be a potential therapeutic target in solid tumors and blood cancers, including acute myeloid leukemia (AML).

Previous research had described TRIB2 as a target of small-molecule protein kinase inhibitors originally designed to interfere with kinase domains of the epidermal growth factor receptor (EGFR) tyrosine kinase family.

Using a thermal shift assay, the team discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS). They then employed a biochemical drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro.

The researchers found that afatinib, which is already approved by the U.S. Food and Drug Administration to treat non-small cell lung cancer, led to rapid TRIB2 degradation in human AML cells.

Patrick A. Eyers, PhD, of the University of Liverpool in the U.K., and his colleagues published their findings in Science Signaling.

The team found afatinib to be relatively specific for EGFR and human epidermal growth factor receptor 2 (HER2) at nanomolar concentrations in cells.

The researchers confirmed that at least two TRIB2 Cys residues interact with afatinib in vitro.

The team also discovered TRIB2 could be destabilized by neratinib and osimertinib in vitro.

“Our data prove that the cellular mechanism by which TRIB2 stability is regulated by compounds is proteasome-based,” the researchers wrote, “and we speculate that an afatinib-induced conformational change might induce TRIB2 ubiquitination.”

The researchers plan to study further TRIB2 small-molecule interactions with dynamic changes in ubiquitination status.

Furthermore, they report their work demonstrates that covalent inhibitors such as afatinib have TRIB2-degrading activity in human cells at micromolar concentrations.

The researchers determined that afatinib has similar efficacy to the TRIB2-destabilizing quinazoline neratinib at similar ranges.

The team believes their data “raise the intriguing possibility that clinical inhibitors might be used as TRIB2-degrading agents in research, and possibly clinical, contexts.”

“A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins,” Dr. Eyers commented. “Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer.”

The TRIB proteins play many diverse roles in cell signaling, development, and cancer. According to a paper in Developmental Dynamics, they were named after the small, round, fictional organisms from the original Star Trek television series. Their major role was to eat and reproduce.

This work was funded by two U.K. Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentships, a Tools and Resources Development Fund award, Royal Society Research Grants, North West Cancer Research grants, and funding from the National Institutes of Health.

The authors disclosed no perceived conflicts of interest, although several authors are affiliated with the Structural Genomics Consortium at the University of North Carolina at Chapel Hill, which receives direct funds from various pharmaceutical companies but remains entirely independent. 

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Cancer of unknown primary (CUP) represents 3% to 5% of all cancer malignancies in the world.¹ Since 2003, CUP has been divided into 2 subsets – favorable (20% of the cases) and unfavorable (80% of the cases) – based on histopathologic and clinical manifestations.² The impact of locoregional therapies, such as surgery and radiation, in addition to systemic chemotherapy in adenocarcinomas of unknown primary is not well described in the literature. We report here the case of a patient with adenocarcinoma of unknown primary with lymph-node–only metastases who has remained free of tumor progression for 2 years since completion of systemic multiagent chemotherapy followed by consolidation chemoradiotherapy (CRT).

Case presentation and summary

A 37-year-old Bengali woman born and raised in Bangladesh, with a history of gallstones diagnosed in 2010, presented to the emergency department at an outside community hospital in New York in the fall of 2014 with right upper-quadrant pain that was more severe after meals during the previous 3 to 6 months. Her past medical history was significant for hypertension, gastroesophageal reflux disease, and kidney stones. She had no past surgical procedures. On family history, both her parents were deceased, and her mother had been diagnosed with hypertension. Her 4 siblings and 2 daughters had no known medical conditions. She did not smoke or drink alcohol and lived with her husband in Queens, New York. On physical exam, her abdomen was soft, nontender, and with normal bowel sounds. An ultrasound on November 10, 2014, showed a shadowing stone measuring 1.5 x 0.9 cm in the gallbladder fundus. She therefore underwent a cholecystectomy at an outside community hospital in December 2014 and was found to have gallstones and a metastatic adenocarcinoma of a pericholecystic lymph node. No mass was found in the gallbladder. A positron-emission and computed-tomographic (PET-CT) scan in January 2015 showed hypermetabolic activity in the porta hepatis. She was scheduled for an upper endoscopy that was cancelled because the results of her beta human chorionic gonadotropin (hCG) test were elevated.

The patient was frustrated by the lack of diagnosis and extensive work-up and decided to travel to Bangladesh for several months. Upon her return in May 2015, the patient underwent dilation and curettage at an outside tertiary care center because of her persistently elevated beta-hCG levels (>500 mIU/mL; reference range for nonpregnant woman, <5 mIU/mL) that found no products of conception and excluded a malignant process. Endoscopy and colonoscopy at that time failed to reveal a primary tumor.

She was then referred to our institution. Her level of beta-hCG remained elevated, and another transvaginal ultrasound was performed but failed to reveal any masses or evidence of pregnancy. Mammogram and a breast ultrasound showed left breast lesions. Biopsy of the breast lesions was performed, and the pathology demonstrated fibrocystic changes.

Because the lymph node was located near the liver, we also measured the patient’s alpha fetoprotein (AFP), which is a marker for hepatocellular carcinoma. It was found to be elevated at 1,800.7 ng/mL (reference range, 0.0-9.0 ng/mL). Elevated serum AFP occurs in pregnancy, nonseminatous germ cell tumors, hepatocellular carcinoma, and other gastrointestinal tumors. The test for AFP has a low sensitivity, so an elevated AFP is not clinically useful in helping identify the origin of the primary tumor. The patient’s level of lactate dehydrogenase (LDH), a tumor marker for germ cell tumors, was also elevated at 296 U/L (reference range, 100-220 U/L). CA 19-9, CA 125, and carcinoembryonic antigen, tumor markers of gastrointestinal carcinomas, did not demonstrate elevated levels at 19.8 U/mL (reference range, 0.0-35.0 U/mL), 16 U/mL (reference range, 0-35 U/mL), and 0.7 ng/mL (reference range, 0.0-3.0 ng/mL), respectively. No hepatitis serologies were measured at the time of diagnosis.

The results of a PET-CT scan in August 2015 showed a lobulated abdominal mass of 5.7 x 3.7 cm, consisting of multiple periportal necrotic lymph nodes with a standardized uptake value (SUV) of 14 (Figure 1A) and a 2.0-cm hypermetabolic retroperitoneal lymph node at the aortic bifurcation level with an SUV of 8.6. The SUV is a ratio of activity per unit volume of a region of interest to the activity per unit whole body volume. An SUV of 2.5 or higher is generally considered to be indicative of malignant tissue. We conducted a detailed review of the lymph node pathologic specimen. Immunohistochemical (IHC) studies were positive for CK7, CDX2, and EMA; focally positive for PR and mammaglobin; and negative for CK20, ER, TTF-1, and WT-1. Nonspecific staining was seen with BRST2, and there was no staining with GATA3. IHC stain for HER2-NEU was equivocal. Molecular analysis did not detect BRAF, KRAS, NRAS, and PIK3CA mutations, but did find a CTNNB1 mutation. The IHC pattern suggested pancreatobiliary origin of the tumor.³

Discussion

CUP is divided into favorable and unfavorable subsets.¹ The favorable subset includes women with adenocarcinoma involving axillary lymph nodes, women with papillary adenocarcinoma of peritoneal cavity, and adenocarcinoma with a colon profile. The unfavorable subset includes moderate to poorly differentiated adenocarcinomas (64%) and undifferentiated tumors (36%). It involves the liver in 40% to 50% of the cases, followed by lymph nodes (35%), lungs (31%), bones (28%), and the brain (15%).^1,2,6 Although data suggest that CUP with lymph-node–only metastases generally fall into an unfavorable prognosis group, our patient’s survival and progression-free survival have been especially prolonged. Remarkably, our patient is still alive 44 months after the diagnosis.

The combined platinum–paclitaxel-based regimens are the treatment of choice in this unfavorable subset of CUP,^7,8 with patients showing 16% to 38% response rates and median overall survival times of 6.5 to 13 months.⁷ Platinum–gemcitabine combinations can also be used as an alternative first-line regimen, with an overall response rate of 55% and a median survival of 8 months.⁹ The addition of the targeted agents bevacizumab and erlotinib to the carboplatin–paclitaxel combination, followed by bevacizumab and erlotinib maintenance, has been shown to yield a median survival of 12.6 months but was not meaningfully superior to historical studies with chemotherapy alone.¹⁰

We chose the FOLFIRINOX regimen for our patient. Conroy and colleagues reported a notably improved survival of 11.1 months with that combination chemotherapy in patients with metastatic pancreatic cancer compared with 6.8 months with gemcitabine alone.⁵ Given the possible pancreatobiliary site of tumor origin on IHC, the lymph node pattern of spread, and the patient’s young age and robust performance status, we felt that this multiagent systemic therapy would offer the best chance of prolonged survival. FOLFIRINOX includes a platinum agent, oxaliplatin, and platinum agents are recommended to be included in chemotherapy combinations for CUP.^9,10 Although there is no data to suggest the superiority of a triplet regimen over a doublet regimen in a CUP, a triplet chemotherapy regimen may be considered in select cases.

There have been only a few reports showing the effectiveness of radiotherapy in the treatment of adenocarcinomas of unknown primary outside of the head and neck. Kubisch and colleagues have reported a case of a woman with hepatic adenocarcinoma of unknown primary that was treated with chemotherapy and surgery. Upon recurrence, the patient was then treated with selective internal radiation therapy (SIRT). She was still alive 3 years after diagnosis, and there had been no tumor relapse 21 months after SIRT.¹¹ Shiota and colleagues have reported a case of a mediastinal lymph node CUP that was treated with docetaxel and cisplatin with concurrent thoracic radiation therapy.¹² The patient remained free of symptoms without regrowth of the primary site 22 months after disease onset, and exploration of the body with enhanced and PET-CT scan showed no further abnormalities.

Other reports suggest that locoregional therapy such as surgery and radiation may be of benefit to select patients with CUP. A retrospective study by Löffler and colleagues reported that patients with a limited local involvement who received radical surgery had a median overall survival of 52.7 months compared with those who received radiation (median overall survival, 19.4 months) and those who received chemotherapy alone (median overall survival, 16 months).¹³ A case of a metastatic undifferentiated CUP also reported a long-term (>5 years), disease-free survivor after pancreaticoduodenectomy and systemic adjuvant chemotherapy.¹⁴

Our case further demonstrates that a multidisciplinary approach to CUP may lead to excellent clinical outcomes. Chemotherapy followed by chemoradiation in our patient increased local tumor control and survival. Our patient’s 44-month survival was superior to the historic 6.5- to 13-month median survival in CUP patients treated with chemotherapy alone. Consolidation chemoradiation treatment may therefore be a viable and more effective therapy in the treatment of adenocarcinoma of unknown primary, in which anatomical disease concentration is amenable to radiotherapy following control with systemic chemotherapy. Nevertheless, it is difficult to draw conclusions from select cases. Another case of mediastinal adenocarcinoma, favoring a colorectal primary but with no evidence of a primary lesion on endoscopy, had a poorer outcome than did our patient, with the cancer recurring 6 months after completion of chemotherapy, surgical excision, and adjuvant radiotherapy.¹⁵

Adenocarcinomas of unknown primary cases should involve management by a multidisciplinary team. Clinical trials incorporating locoregional therapies for CUP in addition to systemic therapy are warranted.

Cancer of unknown primary (CUP) represents 3% to 5% of all cancer malignancies in the world.¹ Since 2003, CUP has been divided into 2 subsets – favorable (20% of the cases) and unfavorable (80% of the cases) – based on histopathologic and clinical manifestations.² The impact of locoregional therapies, such as surgery and radiation, in addition to systemic chemotherapy in adenocarcinomas of unknown primary is not well described in the literature. We report here the case of a patient with adenocarcinoma of unknown primary with lymph-node–only metastases who has remained free of tumor progression for 2 years since completion of systemic multiagent chemotherapy followed by consolidation chemoradiotherapy (CRT).

Case presentation and summary

A 37-year-old Bengali woman born and raised in Bangladesh, with a history of gallstones diagnosed in 2010, presented to the emergency department at an outside community hospital in New York in the fall of 2014 with right upper-quadrant pain that was more severe after meals during the previous 3 to 6 months. Her past medical history was significant for hypertension, gastroesophageal reflux disease, and kidney stones. She had no past surgical procedures. On family history, both her parents were deceased, and her mother had been diagnosed with hypertension. Her 4 siblings and 2 daughters had no known medical conditions. She did not smoke or drink alcohol and lived with her husband in Queens, New York. On physical exam, her abdomen was soft, nontender, and with normal bowel sounds. An ultrasound on November 10, 2014, showed a shadowing stone measuring 1.5 x 0.9 cm in the gallbladder fundus. She therefore underwent a cholecystectomy at an outside community hospital in December 2014 and was found to have gallstones and a metastatic adenocarcinoma of a pericholecystic lymph node. No mass was found in the gallbladder. A positron-emission and computed-tomographic (PET-CT) scan in January 2015 showed hypermetabolic activity in the porta hepatis. She was scheduled for an upper endoscopy that was cancelled because the results of her beta human chorionic gonadotropin (hCG) test were elevated.

The patient was frustrated by the lack of diagnosis and extensive work-up and decided to travel to Bangladesh for several months. Upon her return in May 2015, the patient underwent dilation and curettage at an outside tertiary care center because of her persistently elevated beta-hCG levels (>500 mIU/mL; reference range for nonpregnant woman, <5 mIU/mL) that found no products of conception and excluded a malignant process. Endoscopy and colonoscopy at that time failed to reveal a primary tumor.

She was then referred to our institution. Her level of beta-hCG remained elevated, and another transvaginal ultrasound was performed but failed to reveal any masses or evidence of pregnancy. Mammogram and a breast ultrasound showed left breast lesions. Biopsy of the breast lesions was performed, and the pathology demonstrated fibrocystic changes.

Because the lymph node was located near the liver, we also measured the patient’s alpha fetoprotein (AFP), which is a marker for hepatocellular carcinoma. It was found to be elevated at 1,800.7 ng/mL (reference range, 0.0-9.0 ng/mL). Elevated serum AFP occurs in pregnancy, nonseminatous germ cell tumors, hepatocellular carcinoma, and other gastrointestinal tumors. The test for AFP has a low sensitivity, so an elevated AFP is not clinically useful in helping identify the origin of the primary tumor. The patient’s level of lactate dehydrogenase (LDH), a tumor marker for germ cell tumors, was also elevated at 296 U/L (reference range, 100-220 U/L). CA 19-9, CA 125, and carcinoembryonic antigen, tumor markers of gastrointestinal carcinomas, did not demonstrate elevated levels at 19.8 U/mL (reference range, 0.0-35.0 U/mL), 16 U/mL (reference range, 0-35 U/mL), and 0.7 ng/mL (reference range, 0.0-3.0 ng/mL), respectively. No hepatitis serologies were measured at the time of diagnosis.

The results of a PET-CT scan in August 2015 showed a lobulated abdominal mass of 5.7 x 3.7 cm, consisting of multiple periportal necrotic lymph nodes with a standardized uptake value (SUV) of 14 (Figure 1A) and a 2.0-cm hypermetabolic retroperitoneal lymph node at the aortic bifurcation level with an SUV of 8.6. The SUV is a ratio of activity per unit volume of a region of interest to the activity per unit whole body volume. An SUV of 2.5 or higher is generally considered to be indicative of malignant tissue. We conducted a detailed review of the lymph node pathologic specimen. Immunohistochemical (IHC) studies were positive for CK7, CDX2, and EMA; focally positive for PR and mammaglobin; and negative for CK20, ER, TTF-1, and WT-1. Nonspecific staining was seen with BRST2, and there was no staining with GATA3. IHC stain for HER2-NEU was equivocal. Molecular analysis did not detect BRAF, KRAS, NRAS, and PIK3CA mutations, but did find a CTNNB1 mutation. The IHC pattern suggested pancreatobiliary origin of the tumor.³

Discussion

CUP is divided into favorable and unfavorable subsets.¹ The favorable subset includes women with adenocarcinoma involving axillary lymph nodes, women with papillary adenocarcinoma of peritoneal cavity, and adenocarcinoma with a colon profile. The unfavorable subset includes moderate to poorly differentiated adenocarcinomas (64%) and undifferentiated tumors (36%). It involves the liver in 40% to 50% of the cases, followed by lymph nodes (35%), lungs (31%), bones (28%), and the brain (15%).^1,2,6 Although data suggest that CUP with lymph-node–only metastases generally fall into an unfavorable prognosis group, our patient’s survival and progression-free survival have been especially prolonged. Remarkably, our patient is still alive 44 months after the diagnosis.

The combined platinum–paclitaxel-based regimens are the treatment of choice in this unfavorable subset of CUP,^7,8 with patients showing 16% to 38% response rates and median overall survival times of 6.5 to 13 months.⁷ Platinum–gemcitabine combinations can also be used as an alternative first-line regimen, with an overall response rate of 55% and a median survival of 8 months.⁹ The addition of the targeted agents bevacizumab and erlotinib to the carboplatin–paclitaxel combination, followed by bevacizumab and erlotinib maintenance, has been shown to yield a median survival of 12.6 months but was not meaningfully superior to historical studies with chemotherapy alone.¹⁰

We chose the FOLFIRINOX regimen for our patient. Conroy and colleagues reported a notably improved survival of 11.1 months with that combination chemotherapy in patients with metastatic pancreatic cancer compared with 6.8 months with gemcitabine alone.⁵ Given the possible pancreatobiliary site of tumor origin on IHC, the lymph node pattern of spread, and the patient’s young age and robust performance status, we felt that this multiagent systemic therapy would offer the best chance of prolonged survival. FOLFIRINOX includes a platinum agent, oxaliplatin, and platinum agents are recommended to be included in chemotherapy combinations for CUP.^9,10 Although there is no data to suggest the superiority of a triplet regimen over a doublet regimen in a CUP, a triplet chemotherapy regimen may be considered in select cases.

There have been only a few reports showing the effectiveness of radiotherapy in the treatment of adenocarcinomas of unknown primary outside of the head and neck. Kubisch and colleagues have reported a case of a woman with hepatic adenocarcinoma of unknown primary that was treated with chemotherapy and surgery. Upon recurrence, the patient was then treated with selective internal radiation therapy (SIRT). She was still alive 3 years after diagnosis, and there had been no tumor relapse 21 months after SIRT.¹¹ Shiota and colleagues have reported a case of a mediastinal lymph node CUP that was treated with docetaxel and cisplatin with concurrent thoracic radiation therapy.¹² The patient remained free of symptoms without regrowth of the primary site 22 months after disease onset, and exploration of the body with enhanced and PET-CT scan showed no further abnormalities.

Other reports suggest that locoregional therapy such as surgery and radiation may be of benefit to select patients with CUP. A retrospective study by Löffler and colleagues reported that patients with a limited local involvement who received radical surgery had a median overall survival of 52.7 months compared with those who received radiation (median overall survival, 19.4 months) and those who received chemotherapy alone (median overall survival, 16 months).¹³ A case of a metastatic undifferentiated CUP also reported a long-term (>5 years), disease-free survivor after pancreaticoduodenectomy and systemic adjuvant chemotherapy.¹⁴

Our case further demonstrates that a multidisciplinary approach to CUP may lead to excellent clinical outcomes. Chemotherapy followed by chemoradiation in our patient increased local tumor control and survival. Our patient’s 44-month survival was superior to the historic 6.5- to 13-month median survival in CUP patients treated with chemotherapy alone. Consolidation chemoradiation treatment may therefore be a viable and more effective therapy in the treatment of adenocarcinoma of unknown primary, in which anatomical disease concentration is amenable to radiotherapy following control with systemic chemotherapy. Nevertheless, it is difficult to draw conclusions from select cases. Another case of mediastinal adenocarcinoma, favoring a colorectal primary but with no evidence of a primary lesion on endoscopy, had a poorer outcome than did our patient, with the cancer recurring 6 months after completion of chemotherapy, surgical excision, and adjuvant radiotherapy.¹⁵

Adenocarcinomas of unknown primary cases should involve management by a multidisciplinary team. Clinical trials incorporating locoregional therapies for CUP in addition to systemic therapy are warranted.

Cancer of unknown primary (CUP) represents 3% to 5% of all cancer malignancies in the world.¹ Since 2003, CUP has been divided into 2 subsets – favorable (20% of the cases) and unfavorable (80% of the cases) – based on histopathologic and clinical manifestations.² The impact of locoregional therapies, such as surgery and radiation, in addition to systemic chemotherapy in adenocarcinomas of unknown primary is not well described in the literature. We report here the case of a patient with adenocarcinoma of unknown primary with lymph-node–only metastases who has remained free of tumor progression for 2 years since completion of systemic multiagent chemotherapy followed by consolidation chemoradiotherapy (CRT).

Case presentation and summary

A 37-year-old Bengali woman born and raised in Bangladesh, with a history of gallstones diagnosed in 2010, presented to the emergency department at an outside community hospital in New York in the fall of 2014 with right upper-quadrant pain that was more severe after meals during the previous 3 to 6 months. Her past medical history was significant for hypertension, gastroesophageal reflux disease, and kidney stones. She had no past surgical procedures. On family history, both her parents were deceased, and her mother had been diagnosed with hypertension. Her 4 siblings and 2 daughters had no known medical conditions. She did not smoke or drink alcohol and lived with her husband in Queens, New York. On physical exam, her abdomen was soft, nontender, and with normal bowel sounds. An ultrasound on November 10, 2014, showed a shadowing stone measuring 1.5 x 0.9 cm in the gallbladder fundus. She therefore underwent a cholecystectomy at an outside community hospital in December 2014 and was found to have gallstones and a metastatic adenocarcinoma of a pericholecystic lymph node. No mass was found in the gallbladder. A positron-emission and computed-tomographic (PET-CT) scan in January 2015 showed hypermetabolic activity in the porta hepatis. She was scheduled for an upper endoscopy that was cancelled because the results of her beta human chorionic gonadotropin (hCG) test were elevated.

The patient was frustrated by the lack of diagnosis and extensive work-up and decided to travel to Bangladesh for several months. Upon her return in May 2015, the patient underwent dilation and curettage at an outside tertiary care center because of her persistently elevated beta-hCG levels (>500 mIU/mL; reference range for nonpregnant woman, <5 mIU/mL) that found no products of conception and excluded a malignant process. Endoscopy and colonoscopy at that time failed to reveal a primary tumor.

She was then referred to our institution. Her level of beta-hCG remained elevated, and another transvaginal ultrasound was performed but failed to reveal any masses or evidence of pregnancy. Mammogram and a breast ultrasound showed left breast lesions. Biopsy of the breast lesions was performed, and the pathology demonstrated fibrocystic changes.

Because the lymph node was located near the liver, we also measured the patient’s alpha fetoprotein (AFP), which is a marker for hepatocellular carcinoma. It was found to be elevated at 1,800.7 ng/mL (reference range, 0.0-9.0 ng/mL). Elevated serum AFP occurs in pregnancy, nonseminatous germ cell tumors, hepatocellular carcinoma, and other gastrointestinal tumors. The test for AFP has a low sensitivity, so an elevated AFP is not clinically useful in helping identify the origin of the primary tumor. The patient’s level of lactate dehydrogenase (LDH), a tumor marker for germ cell tumors, was also elevated at 296 U/L (reference range, 100-220 U/L). CA 19-9, CA 125, and carcinoembryonic antigen, tumor markers of gastrointestinal carcinomas, did not demonstrate elevated levels at 19.8 U/mL (reference range, 0.0-35.0 U/mL), 16 U/mL (reference range, 0-35 U/mL), and 0.7 ng/mL (reference range, 0.0-3.0 ng/mL), respectively. No hepatitis serologies were measured at the time of diagnosis.

The results of a PET-CT scan in August 2015 showed a lobulated abdominal mass of 5.7 x 3.7 cm, consisting of multiple periportal necrotic lymph nodes with a standardized uptake value (SUV) of 14 (Figure 1A) and a 2.0-cm hypermetabolic retroperitoneal lymph node at the aortic bifurcation level with an SUV of 8.6. The SUV is a ratio of activity per unit volume of a region of interest to the activity per unit whole body volume. An SUV of 2.5 or higher is generally considered to be indicative of malignant tissue. We conducted a detailed review of the lymph node pathologic specimen. Immunohistochemical (IHC) studies were positive for CK7, CDX2, and EMA; focally positive for PR and mammaglobin; and negative for CK20, ER, TTF-1, and WT-1. Nonspecific staining was seen with BRST2, and there was no staining with GATA3. IHC stain for HER2-NEU was equivocal. Molecular analysis did not detect BRAF, KRAS, NRAS, and PIK3CA mutations, but did find a CTNNB1 mutation. The IHC pattern suggested pancreatobiliary origin of the tumor.³

Discussion

CUP is divided into favorable and unfavorable subsets.¹ The favorable subset includes women with adenocarcinoma involving axillary lymph nodes, women with papillary adenocarcinoma of peritoneal cavity, and adenocarcinoma with a colon profile. The unfavorable subset includes moderate to poorly differentiated adenocarcinomas (64%) and undifferentiated tumors (36%). It involves the liver in 40% to 50% of the cases, followed by lymph nodes (35%), lungs (31%), bones (28%), and the brain (15%).^1,2,6 Although data suggest that CUP with lymph-node–only metastases generally fall into an unfavorable prognosis group, our patient’s survival and progression-free survival have been especially prolonged. Remarkably, our patient is still alive 44 months after the diagnosis.

The combined platinum–paclitaxel-based regimens are the treatment of choice in this unfavorable subset of CUP,^7,8 with patients showing 16% to 38% response rates and median overall survival times of 6.5 to 13 months.⁷ Platinum–gemcitabine combinations can also be used as an alternative first-line regimen, with an overall response rate of 55% and a median survival of 8 months.⁹ The addition of the targeted agents bevacizumab and erlotinib to the carboplatin–paclitaxel combination, followed by bevacizumab and erlotinib maintenance, has been shown to yield a median survival of 12.6 months but was not meaningfully superior to historical studies with chemotherapy alone.¹⁰

We chose the FOLFIRINOX regimen for our patient. Conroy and colleagues reported a notably improved survival of 11.1 months with that combination chemotherapy in patients with metastatic pancreatic cancer compared with 6.8 months with gemcitabine alone.⁵ Given the possible pancreatobiliary site of tumor origin on IHC, the lymph node pattern of spread, and the patient’s young age and robust performance status, we felt that this multiagent systemic therapy would offer the best chance of prolonged survival. FOLFIRINOX includes a platinum agent, oxaliplatin, and platinum agents are recommended to be included in chemotherapy combinations for CUP.^9,10 Although there is no data to suggest the superiority of a triplet regimen over a doublet regimen in a CUP, a triplet chemotherapy regimen may be considered in select cases.

There have been only a few reports showing the effectiveness of radiotherapy in the treatment of adenocarcinomas of unknown primary outside of the head and neck. Kubisch and colleagues have reported a case of a woman with hepatic adenocarcinoma of unknown primary that was treated with chemotherapy and surgery. Upon recurrence, the patient was then treated with selective internal radiation therapy (SIRT). She was still alive 3 years after diagnosis, and there had been no tumor relapse 21 months after SIRT.¹¹ Shiota and colleagues have reported a case of a mediastinal lymph node CUP that was treated with docetaxel and cisplatin with concurrent thoracic radiation therapy.¹² The patient remained free of symptoms without regrowth of the primary site 22 months after disease onset, and exploration of the body with enhanced and PET-CT scan showed no further abnormalities.

Other reports suggest that locoregional therapy such as surgery and radiation may be of benefit to select patients with CUP. A retrospective study by Löffler and colleagues reported that patients with a limited local involvement who received radical surgery had a median overall survival of 52.7 months compared with those who received radiation (median overall survival, 19.4 months) and those who received chemotherapy alone (median overall survival, 16 months).¹³ A case of a metastatic undifferentiated CUP also reported a long-term (>5 years), disease-free survivor after pancreaticoduodenectomy and systemic adjuvant chemotherapy.¹⁴

Our case further demonstrates that a multidisciplinary approach to CUP may lead to excellent clinical outcomes. Chemotherapy followed by chemoradiation in our patient increased local tumor control and survival. Our patient’s 44-month survival was superior to the historic 6.5- to 13-month median survival in CUP patients treated with chemotherapy alone. Consolidation chemoradiation treatment may therefore be a viable and more effective therapy in the treatment of adenocarcinoma of unknown primary, in which anatomical disease concentration is amenable to radiotherapy following control with systemic chemotherapy. Nevertheless, it is difficult to draw conclusions from select cases. Another case of mediastinal adenocarcinoma, favoring a colorectal primary but with no evidence of a primary lesion on endoscopy, had a poorer outcome than did our patient, with the cancer recurring 6 months after completion of chemotherapy, surgical excision, and adjuvant radiotherapy.¹⁵

Adenocarcinomas of unknown primary cases should involve management by a multidisciplinary team. Clinical trials incorporating locoregional therapies for CUP in addition to systemic therapy are warranted.

BARCELONA – Prenatal exposure to selective serotonin reuptake inhibitors late in pregnancy was associated with a significantly increased risk of anxious and/or depressed behaviors at 5 years of age in the prospective Norwegian Mother and Child Cohort Study.

Bruce Jancin/MDedge News

Other than that specific red flag, however, the outcomes of in utero exposure to maternal SSRIs were reassuringly benign. Prenatal exposure during early- or mid-pregnancy was not associated with increased risk of anxious/depressed behaviors, compared with nonexposure; that adverse effect was restricted to exposure at week 29 of pregnancy or later. Nor did in utero exposure to maternal SSRIs during any time in pregnancy pose an increased risk for pediatric externalizing, emotional, or social problems in this observational study of 8,359 Norwegian mother-child dyads, Josefina Castro-Fornieles, MD, PhD, observed at the annual congress of the European College of Neuropsychopharmacology.

The huge Norwegian study was among what she considers the four most important studies in child/adolescent psychiatry published through the first three quarters of 2018. The others she highlighted were a large longitudinal observational study that demonstrated that persistent maternal postnatal depression was strongly associated with a variety of pediatric behavioral disturbances documented during assessments at ages 3.5, 16, and 18 years; a Philadelphia study showing that multiple traumatic stressful events or any assaultive trauma experienced by children or adolescents were independently associated with significant psychopathology and neurocognitive deficits; and a Dutch brain MRI study that pinpointed a reduction in gray matter volume in the anterior cingulate cortex as a potential key mediator of the neurobiologic aftereffects of childhood sexual abuse.

She selected those studies because they shared a common theme, one that constituted her key take-home message: “When recording antecedents during a clinical assessment, both with adults and children, it is clear that we have to ask in a more detailed way – using validated scales and interviews if possible – about the mother’s prenatal problems, including psychopharmacological treatment. That is something we often don’t do in a sufficiently detailed way in our clinical practice. And it’s also important to ask about life events; abuse during childhood and adolescence can be really important. We can modulate our treatment depending upon whether there is an influence of any of these aspects,” said Dr. Castro-Fornieles, director of the Clinical Institute of Neuroscience at the Hospital Clinic of Barcelona and a recent past-president of the Spanish Society for Child and Adolescent Psychiatry.

The following are her Top 4 studies:

The Norwegian Mother and Child Cohort Study

The increased risk of anxious and/or depressed behaviors in children exposed to selective serotonin reuptake inhibitors (SSRIs) late in pregnancy did not emerge until the year-5 assessment; it wasn’t evident at the 1.5- or 3-year evaluations.

The investigators emphasized a key lesson from their study: The importance of following children with late-pregnancy exposure to maternal SSRI therapy for development of symptoms of anxiety and/or depression (J Am Acad Child Adolesc Psychiatry. 2018 Mar;57[3]:200-8). Dr. Castro-Fornieles strongly endorsed that recommendation. However, she noted what she considers an important limitation to the study: even though the University of Oslo investigators adjusted for numerous potential confounders in their risk models – including maternal body mass index, parity, education, smoking, substance use, breastfeeding, folic acid use, and other medications used during pregnancy – it’s not possible in a study such as this to control for genetic and environmental risk factors, which she suspects also were at work.

The Avon Longitudinal Study of Parents and Children in the United Kingdom

Maternal postnatal depression is common, affecting roughly 10% of mothers. But it is not invariably associated with adverse mental health outcomes in their children. This study of nearly 10,000 mothers and their children sought to identify which children were at most risk. Using the Edinburgh Postnatal Depression Scale, the international team of investigators categorized maternal postnatal depression as moderate, marked, or severe. The affective disorder was deemed persistent if scores on the Edinburgh scale were elevated at both 2 and 8 months after delivery.

Postnatal depression, whether persistent or not, was associated with roughly a 2- to 2.4-fold increase for child behavioral disturbances when assessed at age 3.5 years using the Rutter Total Problems Scale. But postnatal depression that was persistent was the real difference maker: It carried a much higher risk of adverse behavioral outcomes and cognitive deficits than did the nonpersistent version. Indeed, persistent severe postnatal depression was associated a 4.8-fold increased risk of behavioral problems at age 3.5 years, a 2.65-fold greater risk of markedly lower grades in mathematics at age 16 years, and a 7.4-fold increased prevalence of depression at 18 years of age. The investigators advised screening mothers during the first postpartum year in order to identify those with persistent postpartum depression (JAMA Psychiatry. 2018 Mar 1;75[3]:247-53).

Dr. Castro-Fornieles said an important shortcoming of the Avon study was that it did not record paternal data.

“The study didn’t consider depression or other functional measures in the father, his commitment to childrearing, and whether the family was together or divorced. I feel this is an important limitation in many studies. For me, it’s really important to consider what’s happening with the fathers,” she said.

Traumatic stress load, psychopathology, and cognition

An eye-opening report from the Philadelphia Neurodevelopmental Cohort documented a surprisingly high level of lifetime exposure to traumatic events among 9,498 youth aged 8-21 years, and the stepwise manner by which a greater traumatic stress load was associated with increasing severity of psychopathology and cognitive deficits. Notably, the study participants were recruited from general pediatric clinics in the Children’s Hospital of Philadelphia health care network; they were not patients seeking psychiatric help. And yet, extensive structured psychiatric evaluation showed that 23% of them had a history of one traumatic stressful event, 12% had two, and 1% had three or more.

In analyses adjusted for lifetime history of depression or PTSD, a higher traumatic event load was associated with increased risk of externalizing behaviors, mood/anxiety disorders, psychosis spectrum, and fear. Moreover, a high trauma stress load was associated with a 5.3-fold increased risk of suicidal thoughts and a 3.2-fold increased likelihood of cannabis use, compared with youth who had never been exposed to a traumatic event. Increased stress load also was associated with worse cognitive performance on tests of executive functioning, social cognition, and complex reasoning.

A history of assaultive trauma – being badly beaten, threatened with a weapon, or sexually abused – was associated with more severe psychopathology than in subjects with a history of nonassaultive traumatic events (Psychol Med. 2018 Apr 15:1-10).

Session moderator Carmen Moreno, MD, a child and adolescent psychiatrist at Gregorio Marañón University Hospital in Madrid, commented, “It was striking to me that the prevalence of childhood traumatic events was so high in a pediatric community sample. Is the measure the investigators chose the right measure?”

Dr. Castro-Fornieles replied that it was a very sensitive measure, in that an event many would consider part of normal life – for example, seeing a relative’s body on display in a funeral home – was scored as a traumatic exposure.

“Only one exposure is not that important,” she said. “The impact increases as you increase the number of traumatic events. And also the assaultive ones.”

Sexual abuse leaves a fingerprint

Investigators at Leiden (the Netherlands) University performed neuroimaging that looked at numerous brain regions of interest in 21 adolescents with childhood sexual abuse–related PTSD and 25 matched healthy controls. The standout finding was that the dorsal gray matter volume of the anterior cingulate cortex was significantly smaller in the teens with PTSD and a history of childhood sexual abuse (Eur Neuropsychopharmacol. 2017 Nov;27[11]:1163-71).

The investigators wanted a pure sample of patients with PTSD after childhood sexual abuse, so they excluded individuals who had experienced childhood sexual abuse and had a diagnosis of attention-deficit/hyperactivity disorder, oppositional defiant disorder, obsessive-compulsive disorder, conduct disorder, pervasive developmental disorder, bipolar disorder, or a psychotic disorder. That is both a strength and a limitation of the study, in Dr. Castro-Fornieles’ view.

“To me, that excludes too many of the children we see in our clinical settings. This work needs to be corroborated in a bigger sample, including patients with other diagnoses,” she said.

She reported having no financial conflicts regarding her presentation.
 

bjancin@mdedge.com

BARCELONA – Prenatal exposure to selective serotonin reuptake inhibitors late in pregnancy was associated with a significantly increased risk of anxious and/or depressed behaviors at 5 years of age in the prospective Norwegian Mother and Child Cohort Study.

Bruce Jancin/MDedge News

Other than that specific red flag, however, the outcomes of in utero exposure to maternal SSRIs were reassuringly benign. Prenatal exposure during early- or mid-pregnancy was not associated with increased risk of anxious/depressed behaviors, compared with nonexposure; that adverse effect was restricted to exposure at week 29 of pregnancy or later. Nor did in utero exposure to maternal SSRIs during any time in pregnancy pose an increased risk for pediatric externalizing, emotional, or social problems in this observational study of 8,359 Norwegian mother-child dyads, Josefina Castro-Fornieles, MD, PhD, observed at the annual congress of the European College of Neuropsychopharmacology.

The huge Norwegian study was among what she considers the four most important studies in child/adolescent psychiatry published through the first three quarters of 2018. The others she highlighted were a large longitudinal observational study that demonstrated that persistent maternal postnatal depression was strongly associated with a variety of pediatric behavioral disturbances documented during assessments at ages 3.5, 16, and 18 years; a Philadelphia study showing that multiple traumatic stressful events or any assaultive trauma experienced by children or adolescents were independently associated with significant psychopathology and neurocognitive deficits; and a Dutch brain MRI study that pinpointed a reduction in gray matter volume in the anterior cingulate cortex as a potential key mediator of the neurobiologic aftereffects of childhood sexual abuse.

She selected those studies because they shared a common theme, one that constituted her key take-home message: “When recording antecedents during a clinical assessment, both with adults and children, it is clear that we have to ask in a more detailed way – using validated scales and interviews if possible – about the mother’s prenatal problems, including psychopharmacological treatment. That is something we often don’t do in a sufficiently detailed way in our clinical practice. And it’s also important to ask about life events; abuse during childhood and adolescence can be really important. We can modulate our treatment depending upon whether there is an influence of any of these aspects,” said Dr. Castro-Fornieles, director of the Clinical Institute of Neuroscience at the Hospital Clinic of Barcelona and a recent past-president of the Spanish Society for Child and Adolescent Psychiatry.

The following are her Top 4 studies:

The Norwegian Mother and Child Cohort Study

The increased risk of anxious and/or depressed behaviors in children exposed to selective serotonin reuptake inhibitors (SSRIs) late in pregnancy did not emerge until the year-5 assessment; it wasn’t evident at the 1.5- or 3-year evaluations.

The investigators emphasized a key lesson from their study: The importance of following children with late-pregnancy exposure to maternal SSRI therapy for development of symptoms of anxiety and/or depression (J Am Acad Child Adolesc Psychiatry. 2018 Mar;57[3]:200-8). Dr. Castro-Fornieles strongly endorsed that recommendation. However, she noted what she considers an important limitation to the study: even though the University of Oslo investigators adjusted for numerous potential confounders in their risk models – including maternal body mass index, parity, education, smoking, substance use, breastfeeding, folic acid use, and other medications used during pregnancy – it’s not possible in a study such as this to control for genetic and environmental risk factors, which she suspects also were at work.

The Avon Longitudinal Study of Parents and Children in the United Kingdom

Maternal postnatal depression is common, affecting roughly 10% of mothers. But it is not invariably associated with adverse mental health outcomes in their children. This study of nearly 10,000 mothers and their children sought to identify which children were at most risk. Using the Edinburgh Postnatal Depression Scale, the international team of investigators categorized maternal postnatal depression as moderate, marked, or severe. The affective disorder was deemed persistent if scores on the Edinburgh scale were elevated at both 2 and 8 months after delivery.

Postnatal depression, whether persistent or not, was associated with roughly a 2- to 2.4-fold increase for child behavioral disturbances when assessed at age 3.5 years using the Rutter Total Problems Scale. But postnatal depression that was persistent was the real difference maker: It carried a much higher risk of adverse behavioral outcomes and cognitive deficits than did the nonpersistent version. Indeed, persistent severe postnatal depression was associated a 4.8-fold increased risk of behavioral problems at age 3.5 years, a 2.65-fold greater risk of markedly lower grades in mathematics at age 16 years, and a 7.4-fold increased prevalence of depression at 18 years of age. The investigators advised screening mothers during the first postpartum year in order to identify those with persistent postpartum depression (JAMA Psychiatry. 2018 Mar 1;75[3]:247-53).

Dr. Castro-Fornieles said an important shortcoming of the Avon study was that it did not record paternal data.

“The study didn’t consider depression or other functional measures in the father, his commitment to childrearing, and whether the family was together or divorced. I feel this is an important limitation in many studies. For me, it’s really important to consider what’s happening with the fathers,” she said.

Traumatic stress load, psychopathology, and cognition

An eye-opening report from the Philadelphia Neurodevelopmental Cohort documented a surprisingly high level of lifetime exposure to traumatic events among 9,498 youth aged 8-21 years, and the stepwise manner by which a greater traumatic stress load was associated with increasing severity of psychopathology and cognitive deficits. Notably, the study participants were recruited from general pediatric clinics in the Children’s Hospital of Philadelphia health care network; they were not patients seeking psychiatric help. And yet, extensive structured psychiatric evaluation showed that 23% of them had a history of one traumatic stressful event, 12% had two, and 1% had three or more.

In analyses adjusted for lifetime history of depression or PTSD, a higher traumatic event load was associated with increased risk of externalizing behaviors, mood/anxiety disorders, psychosis spectrum, and fear. Moreover, a high trauma stress load was associated with a 5.3-fold increased risk of suicidal thoughts and a 3.2-fold increased likelihood of cannabis use, compared with youth who had never been exposed to a traumatic event. Increased stress load also was associated with worse cognitive performance on tests of executive functioning, social cognition, and complex reasoning.

A history of assaultive trauma – being badly beaten, threatened with a weapon, or sexually abused – was associated with more severe psychopathology than in subjects with a history of nonassaultive traumatic events (Psychol Med. 2018 Apr 15:1-10).

Session moderator Carmen Moreno, MD, a child and adolescent psychiatrist at Gregorio Marañón University Hospital in Madrid, commented, “It was striking to me that the prevalence of childhood traumatic events was so high in a pediatric community sample. Is the measure the investigators chose the right measure?”

Dr. Castro-Fornieles replied that it was a very sensitive measure, in that an event many would consider part of normal life – for example, seeing a relative’s body on display in a funeral home – was scored as a traumatic exposure.

“Only one exposure is not that important,” she said. “The impact increases as you increase the number of traumatic events. And also the assaultive ones.”

Sexual abuse leaves a fingerprint

Investigators at Leiden (the Netherlands) University performed neuroimaging that looked at numerous brain regions of interest in 21 adolescents with childhood sexual abuse–related PTSD and 25 matched healthy controls. The standout finding was that the dorsal gray matter volume of the anterior cingulate cortex was significantly smaller in the teens with PTSD and a history of childhood sexual abuse (Eur Neuropsychopharmacol. 2017 Nov;27[11]:1163-71).

The investigators wanted a pure sample of patients with PTSD after childhood sexual abuse, so they excluded individuals who had experienced childhood sexual abuse and had a diagnosis of attention-deficit/hyperactivity disorder, oppositional defiant disorder, obsessive-compulsive disorder, conduct disorder, pervasive developmental disorder, bipolar disorder, or a psychotic disorder. That is both a strength and a limitation of the study, in Dr. Castro-Fornieles’ view.

“To me, that excludes too many of the children we see in our clinical settings. This work needs to be corroborated in a bigger sample, including patients with other diagnoses,” she said.

She reported having no financial conflicts regarding her presentation.
 

bjancin@mdedge.com

BARCELONA – Prenatal exposure to selective serotonin reuptake inhibitors late in pregnancy was associated with a significantly increased risk of anxious and/or depressed behaviors at 5 years of age in the prospective Norwegian Mother and Child Cohort Study.

Bruce Jancin/MDedge News

Other than that specific red flag, however, the outcomes of in utero exposure to maternal SSRIs were reassuringly benign. Prenatal exposure during early- or mid-pregnancy was not associated with increased risk of anxious/depressed behaviors, compared with nonexposure; that adverse effect was restricted to exposure at week 29 of pregnancy or later. Nor did in utero exposure to maternal SSRIs during any time in pregnancy pose an increased risk for pediatric externalizing, emotional, or social problems in this observational study of 8,359 Norwegian mother-child dyads, Josefina Castro-Fornieles, MD, PhD, observed at the annual congress of the European College of Neuropsychopharmacology.

The huge Norwegian study was among what she considers the four most important studies in child/adolescent psychiatry published through the first three quarters of 2018. The others she highlighted were a large longitudinal observational study that demonstrated that persistent maternal postnatal depression was strongly associated with a variety of pediatric behavioral disturbances documented during assessments at ages 3.5, 16, and 18 years; a Philadelphia study showing that multiple traumatic stressful events or any assaultive trauma experienced by children or adolescents were independently associated with significant psychopathology and neurocognitive deficits; and a Dutch brain MRI study that pinpointed a reduction in gray matter volume in the anterior cingulate cortex as a potential key mediator of the neurobiologic aftereffects of childhood sexual abuse.

She selected those studies because they shared a common theme, one that constituted her key take-home message: “When recording antecedents during a clinical assessment, both with adults and children, it is clear that we have to ask in a more detailed way – using validated scales and interviews if possible – about the mother’s prenatal problems, including psychopharmacological treatment. That is something we often don’t do in a sufficiently detailed way in our clinical practice. And it’s also important to ask about life events; abuse during childhood and adolescence can be really important. We can modulate our treatment depending upon whether there is an influence of any of these aspects,” said Dr. Castro-Fornieles, director of the Clinical Institute of Neuroscience at the Hospital Clinic of Barcelona and a recent past-president of the Spanish Society for Child and Adolescent Psychiatry.

The following are her Top 4 studies:

The Norwegian Mother and Child Cohort Study

The increased risk of anxious and/or depressed behaviors in children exposed to selective serotonin reuptake inhibitors (SSRIs) late in pregnancy did not emerge until the year-5 assessment; it wasn’t evident at the 1.5- or 3-year evaluations.

The investigators emphasized a key lesson from their study: The importance of following children with late-pregnancy exposure to maternal SSRI therapy for development of symptoms of anxiety and/or depression (J Am Acad Child Adolesc Psychiatry. 2018 Mar;57[3]:200-8). Dr. Castro-Fornieles strongly endorsed that recommendation. However, she noted what she considers an important limitation to the study: even though the University of Oslo investigators adjusted for numerous potential confounders in their risk models – including maternal body mass index, parity, education, smoking, substance use, breastfeeding, folic acid use, and other medications used during pregnancy – it’s not possible in a study such as this to control for genetic and environmental risk factors, which she suspects also were at work.

The Avon Longitudinal Study of Parents and Children in the United Kingdom

Maternal postnatal depression is common, affecting roughly 10% of mothers. But it is not invariably associated with adverse mental health outcomes in their children. This study of nearly 10,000 mothers and their children sought to identify which children were at most risk. Using the Edinburgh Postnatal Depression Scale, the international team of investigators categorized maternal postnatal depression as moderate, marked, or severe. The affective disorder was deemed persistent if scores on the Edinburgh scale were elevated at both 2 and 8 months after delivery.

Postnatal depression, whether persistent or not, was associated with roughly a 2- to 2.4-fold increase for child behavioral disturbances when assessed at age 3.5 years using the Rutter Total Problems Scale. But postnatal depression that was persistent was the real difference maker: It carried a much higher risk of adverse behavioral outcomes and cognitive deficits than did the nonpersistent version. Indeed, persistent severe postnatal depression was associated a 4.8-fold increased risk of behavioral problems at age 3.5 years, a 2.65-fold greater risk of markedly lower grades in mathematics at age 16 years, and a 7.4-fold increased prevalence of depression at 18 years of age. The investigators advised screening mothers during the first postpartum year in order to identify those with persistent postpartum depression (JAMA Psychiatry. 2018 Mar 1;75[3]:247-53).

Dr. Castro-Fornieles said an important shortcoming of the Avon study was that it did not record paternal data.

“The study didn’t consider depression or other functional measures in the father, his commitment to childrearing, and whether the family was together or divorced. I feel this is an important limitation in many studies. For me, it’s really important to consider what’s happening with the fathers,” she said.

Traumatic stress load, psychopathology, and cognition

An eye-opening report from the Philadelphia Neurodevelopmental Cohort documented a surprisingly high level of lifetime exposure to traumatic events among 9,498 youth aged 8-21 years, and the stepwise manner by which a greater traumatic stress load was associated with increasing severity of psychopathology and cognitive deficits. Notably, the study participants were recruited from general pediatric clinics in the Children’s Hospital of Philadelphia health care network; they were not patients seeking psychiatric help. And yet, extensive structured psychiatric evaluation showed that 23% of them had a history of one traumatic stressful event, 12% had two, and 1% had three or more.

In analyses adjusted for lifetime history of depression or PTSD, a higher traumatic event load was associated with increased risk of externalizing behaviors, mood/anxiety disorders, psychosis spectrum, and fear. Moreover, a high trauma stress load was associated with a 5.3-fold increased risk of suicidal thoughts and a 3.2-fold increased likelihood of cannabis use, compared with youth who had never been exposed to a traumatic event. Increased stress load also was associated with worse cognitive performance on tests of executive functioning, social cognition, and complex reasoning.

A history of assaultive trauma – being badly beaten, threatened with a weapon, or sexually abused – was associated with more severe psychopathology than in subjects with a history of nonassaultive traumatic events (Psychol Med. 2018 Apr 15:1-10).

Session moderator Carmen Moreno, MD, a child and adolescent psychiatrist at Gregorio Marañón University Hospital in Madrid, commented, “It was striking to me that the prevalence of childhood traumatic events was so high in a pediatric community sample. Is the measure the investigators chose the right measure?”

Dr. Castro-Fornieles replied that it was a very sensitive measure, in that an event many would consider part of normal life – for example, seeing a relative’s body on display in a funeral home – was scored as a traumatic exposure.

“Only one exposure is not that important,” she said. “The impact increases as you increase the number of traumatic events. And also the assaultive ones.”

Sexual abuse leaves a fingerprint

Investigators at Leiden (the Netherlands) University performed neuroimaging that looked at numerous brain regions of interest in 21 adolescents with childhood sexual abuse–related PTSD and 25 matched healthy controls. The standout finding was that the dorsal gray matter volume of the anterior cingulate cortex was significantly smaller in the teens with PTSD and a history of childhood sexual abuse (Eur Neuropsychopharmacol. 2017 Nov;27[11]:1163-71).

The investigators wanted a pure sample of patients with PTSD after childhood sexual abuse, so they excluded individuals who had experienced childhood sexual abuse and had a diagnosis of attention-deficit/hyperactivity disorder, oppositional defiant disorder, obsessive-compulsive disorder, conduct disorder, pervasive developmental disorder, bipolar disorder, or a psychotic disorder. That is both a strength and a limitation of the study, in Dr. Castro-Fornieles’ view.

“To me, that excludes too many of the children we see in our clinical settings. This work needs to be corroborated in a bigger sample, including patients with other diagnoses,” she said.

She reported having no financial conflicts regarding her presentation.
 

bjancin@mdedge.com

MONTEREY, CALIF. – “Consort dermatitis” – when a patient is allergic to his or her partner. “Lime dermatitis” – when gin and tonics are the culprit. And “sample dermatitis” – when an unprescribed drug sample turns out to be the cause of a mysterious reaction.

Pcholik/getty images

Dermatologist Vincent DeLeo, MD, of the University of Southern California, Los Angeles, has seen them all. He provided insight about how to diagnose these unusual conditions at the Coastal Dermatology Symposium.

The following are a few unusual causes of dermatitis that he discussed:

• Romantic partners. A patient’s partner can be the cause of a reaction, as in the case of a 25-year-old woman who turned out to be allergic to her boyfriend’s cologne. In another case, a 50-year-old man had a 3-year history of recurrent dermatitis on his left arm and the left side of his chest. The cause was a mystery until it became clear that it was caused by exposure to hair dye, but not his. “He didn’t color his hair, but his wife did, and she always slept on that side of him,” Dr. DeLeo recalled. “When she stopped coloring her hair, his disease cleared.”
• Black henna. The dye known as “black henna,” or just “henna,” can cause reactions in adults (who use it as a hair dye or to decorate the skin) and children (who can be exposed to it with temporary tattoos). “Because henna typically produces a brown, orange-brown, or reddish-brown tint, other ingredients must be added to produce other colors, such as those marketed as ‘black henna’ and ‘blue henna,’ ” according to a Food and Drug Administration statement. “Even brown shades of products marketed as henna may contain other ingredients intended to make them darker or make the stain last longer on the skin. The problem? “The extra ingredient used to blacken henna is often a coal-tar hair dye containing p-Phenylenediamine, an ingredient that can cause dangerous skin reactions in some people,” the statement says. Dr. DeLeo said that one good rule of thumb is to consider a reaction to black henna if a patient acknowledges using a henna dye and their hair is any color but red. That’s a sign, he said, that they’re actually using black henna.
• Makeup applicators. Dr. DeLeo has seen two cases of patients with facial dermatitis who turned out to be allergic to thiuram, a component of rubber. Their skin was reacting to the rubber in some sponges used to apply makeup.
• Lime and sun exposure. Patients are impressed when Dr. DeLeo correctly guesses what they were drinking the previous weekend, because of their telltale blisters indicating a lime allergy. Noninflammatory blisters on the fingers or hyperpigmentation can be caused by touching the skin of a lime and then having subsequent exposure to ultraviolet light. It may take days for the blisters to appear, he noted. A weekend after mixing gin and tonics with lime, for example, a patient “may show up on Tuesday of the following week. The patient doesn’t always think of what they did over the weekend.”
• Liquid detergents. As a general rule, laundry detergents do not cause dermatitis, Dr. DeLeo said. “By the time that clothing is rinsed in your washer, there’s not enough left of anything on the clothing to cause a problem.” But there’s an exception: When people hand wash clothing with liquid detergents, such as Woolite. “It’s not the fragrance,” he said. “It’s the preservative in the detergent.”
• Unexpected nickel. Skin allergy to nickel is common, and the metal can lurk in unexpected places, as he discovered when he treated a Columbia University student who was “allergic to his tuba.” The tuba was made of brass, not nickel. But “the little things connecting the tubes to each other are alloy metals,” he said, including nickel.
• Drug samples. Dr. DeLeo recalled the case of a dermatology office administrator with a recurrent neck rash. Dermatologist after dermatologist failed to find the cause. Patch and photopatch testing turned up nothing. Then Dr. DeLeo asked her to bring in every skin product she was using. She returned with a large bag full of dermatologic samples, including Drithocreme (anthralin), which can be an irritant. None of the drugs were prescribed. “This is case of sample dermatitis,” which may occur among employees and family members of dermatologists, he said. “Always think of having patients bring in what they’re using,” he added, “because you can be surprised.”

The Coastal Dermatology Symposium is jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

Dr. DeLeo disclosed consulting work for Estée Lauder.

MONTEREY, CALIF. – “Consort dermatitis” – when a patient is allergic to his or her partner. “Lime dermatitis” – when gin and tonics are the culprit. And “sample dermatitis” – when an unprescribed drug sample turns out to be the cause of a mysterious reaction.

Pcholik/getty images

Dermatologist Vincent DeLeo, MD, of the University of Southern California, Los Angeles, has seen them all. He provided insight about how to diagnose these unusual conditions at the Coastal Dermatology Symposium.

The following are a few unusual causes of dermatitis that he discussed:

• Romantic partners. A patient’s partner can be the cause of a reaction, as in the case of a 25-year-old woman who turned out to be allergic to her boyfriend’s cologne. In another case, a 50-year-old man had a 3-year history of recurrent dermatitis on his left arm and the left side of his chest. The cause was a mystery until it became clear that it was caused by exposure to hair dye, but not his. “He didn’t color his hair, but his wife did, and she always slept on that side of him,” Dr. DeLeo recalled. “When she stopped coloring her hair, his disease cleared.”
• Black henna. The dye known as “black henna,” or just “henna,” can cause reactions in adults (who use it as a hair dye or to decorate the skin) and children (who can be exposed to it with temporary tattoos). “Because henna typically produces a brown, orange-brown, or reddish-brown tint, other ingredients must be added to produce other colors, such as those marketed as ‘black henna’ and ‘blue henna,’ ” according to a Food and Drug Administration statement. “Even brown shades of products marketed as henna may contain other ingredients intended to make them darker or make the stain last longer on the skin. The problem? “The extra ingredient used to blacken henna is often a coal-tar hair dye containing p-Phenylenediamine, an ingredient that can cause dangerous skin reactions in some people,” the statement says. Dr. DeLeo said that one good rule of thumb is to consider a reaction to black henna if a patient acknowledges using a henna dye and their hair is any color but red. That’s a sign, he said, that they’re actually using black henna.
• Makeup applicators. Dr. DeLeo has seen two cases of patients with facial dermatitis who turned out to be allergic to thiuram, a component of rubber. Their skin was reacting to the rubber in some sponges used to apply makeup.
• Lime and sun exposure. Patients are impressed when Dr. DeLeo correctly guesses what they were drinking the previous weekend, because of their telltale blisters indicating a lime allergy. Noninflammatory blisters on the fingers or hyperpigmentation can be caused by touching the skin of a lime and then having subsequent exposure to ultraviolet light. It may take days for the blisters to appear, he noted. A weekend after mixing gin and tonics with lime, for example, a patient “may show up on Tuesday of the following week. The patient doesn’t always think of what they did over the weekend.”
• Liquid detergents. As a general rule, laundry detergents do not cause dermatitis, Dr. DeLeo said. “By the time that clothing is rinsed in your washer, there’s not enough left of anything on the clothing to cause a problem.” But there’s an exception: When people hand wash clothing with liquid detergents, such as Woolite. “It’s not the fragrance,” he said. “It’s the preservative in the detergent.”
• Unexpected nickel. Skin allergy to nickel is common, and the metal can lurk in unexpected places, as he discovered when he treated a Columbia University student who was “allergic to his tuba.” The tuba was made of brass, not nickel. But “the little things connecting the tubes to each other are alloy metals,” he said, including nickel.
• Drug samples. Dr. DeLeo recalled the case of a dermatology office administrator with a recurrent neck rash. Dermatologist after dermatologist failed to find the cause. Patch and photopatch testing turned up nothing. Then Dr. DeLeo asked her to bring in every skin product she was using. She returned with a large bag full of dermatologic samples, including Drithocreme (anthralin), which can be an irritant. None of the drugs were prescribed. “This is case of sample dermatitis,” which may occur among employees and family members of dermatologists, he said. “Always think of having patients bring in what they’re using,” he added, “because you can be surprised.”

The Coastal Dermatology Symposium is jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

Dr. DeLeo disclosed consulting work for Estée Lauder.

MONTEREY, CALIF. – “Consort dermatitis” – when a patient is allergic to his or her partner. “Lime dermatitis” – when gin and tonics are the culprit. And “sample dermatitis” – when an unprescribed drug sample turns out to be the cause of a mysterious reaction.

Pcholik/getty images

Dermatologist Vincent DeLeo, MD, of the University of Southern California, Los Angeles, has seen them all. He provided insight about how to diagnose these unusual conditions at the Coastal Dermatology Symposium.

The following are a few unusual causes of dermatitis that he discussed:

• Romantic partners. A patient’s partner can be the cause of a reaction, as in the case of a 25-year-old woman who turned out to be allergic to her boyfriend’s cologne. In another case, a 50-year-old man had a 3-year history of recurrent dermatitis on his left arm and the left side of his chest. The cause was a mystery until it became clear that it was caused by exposure to hair dye, but not his. “He didn’t color his hair, but his wife did, and she always slept on that side of him,” Dr. DeLeo recalled. “When she stopped coloring her hair, his disease cleared.”
• Black henna. The dye known as “black henna,” or just “henna,” can cause reactions in adults (who use it as a hair dye or to decorate the skin) and children (who can be exposed to it with temporary tattoos). “Because henna typically produces a brown, orange-brown, or reddish-brown tint, other ingredients must be added to produce other colors, such as those marketed as ‘black henna’ and ‘blue henna,’ ” according to a Food and Drug Administration statement. “Even brown shades of products marketed as henna may contain other ingredients intended to make them darker or make the stain last longer on the skin. The problem? “The extra ingredient used to blacken henna is often a coal-tar hair dye containing p-Phenylenediamine, an ingredient that can cause dangerous skin reactions in some people,” the statement says. Dr. DeLeo said that one good rule of thumb is to consider a reaction to black henna if a patient acknowledges using a henna dye and their hair is any color but red. That’s a sign, he said, that they’re actually using black henna.
• Makeup applicators. Dr. DeLeo has seen two cases of patients with facial dermatitis who turned out to be allergic to thiuram, a component of rubber. Their skin was reacting to the rubber in some sponges used to apply makeup.
• Lime and sun exposure. Patients are impressed when Dr. DeLeo correctly guesses what they were drinking the previous weekend, because of their telltale blisters indicating a lime allergy. Noninflammatory blisters on the fingers or hyperpigmentation can be caused by touching the skin of a lime and then having subsequent exposure to ultraviolet light. It may take days for the blisters to appear, he noted. A weekend after mixing gin and tonics with lime, for example, a patient “may show up on Tuesday of the following week. The patient doesn’t always think of what they did over the weekend.”
• Liquid detergents. As a general rule, laundry detergents do not cause dermatitis, Dr. DeLeo said. “By the time that clothing is rinsed in your washer, there’s not enough left of anything on the clothing to cause a problem.” But there’s an exception: When people hand wash clothing with liquid detergents, such as Woolite. “It’s not the fragrance,” he said. “It’s the preservative in the detergent.”
• Unexpected nickel. Skin allergy to nickel is common, and the metal can lurk in unexpected places, as he discovered when he treated a Columbia University student who was “allergic to his tuba.” The tuba was made of brass, not nickel. But “the little things connecting the tubes to each other are alloy metals,” he said, including nickel.
• Drug samples. Dr. DeLeo recalled the case of a dermatology office administrator with a recurrent neck rash. Dermatologist after dermatologist failed to find the cause. Patch and photopatch testing turned up nothing. Then Dr. DeLeo asked her to bring in every skin product she was using. She returned with a large bag full of dermatologic samples, including Drithocreme (anthralin), which can be an irritant. None of the drugs were prescribed. “This is case of sample dermatitis,” which may occur among employees and family members of dermatologists, he said. “Always think of having patients bring in what they’re using,” he added, “because you can be surprised.”

The Coastal Dermatology Symposium is jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

Dr. DeLeo disclosed consulting work for Estée Lauder.

Editors’ Note: Herbert D. Kleber, MD, a pioneer in the field of addiction medicine, died Oct. 5, at the age of 84. At the time of his death, Dr. Kleber was professor of psychiatry and emeritus director of the division on substance use disorders at Columbia University in New York.

I met Herb Kleber in the fall of 1967, when my center at National Institute of Mental Health funded six new programs to treat opiate addiction in selected cities across the United States. Fifty-one years later, only one still survives – in New Haven, Conn.

Herb began his work at Yale University in an academic/psychoanalytic environment that, with few exceptions, had too little respect for, or understanding of, his work; with a state mental health administration that placed addiction treatment at the very bottom of its priorities; and, in a racially polarized community reeling from a murder and a highly politicized jury trial.

It was Herb’s creative genius that led to the formation and maintenance of the APT Foundation with a laserlike focus on successive waves of heroin, crack cocaine, and other drug epidemics. The board structure, the clientele, and the challenges of building and maintaining a program that supported cutting-edge treatment, education, and research could have made him feel like the principal character in a book by Mario Puzo. But Herb generated loyalty in those who worked for and with him not by fear, but by his generosity of spirit, his crediting the work of others, his supporting the advancement of junior colleagues, and by his deep respect and appreciation for everyone on the team. When I last checked, Roz (his dedicated administrator) was still on the job – and the program was still being led by people whom he trained.

Most importantly, in spite of his very busy work schedule, his top priority was his family.

In 1977, I became chairman of the department of psychiatry at the University of Connecticut. In 1978, my group received a 4-year center grant from the National Institute on Alcohol Abuse and Alcoholism. By 1982, we had recruited three full professors and a talented assistant professor to our affiliated Veterans Affairs hospital. But in 1985, unfavorable changes at the Newington VA hospital led to the departure of those key faculty. Herb generously agreed to my request that we try to build collaborative bridges between our center and his programs in New Haven. This made it possible for Hank Kranzler at UConn and Stephanie O’Malley at Yale to launch their careers in clinical trials research. The collaboration that Herb generously provided likely saved our alcohol center. On a personal level, Herb and I began to have lunches halfway between New Haven and Farmington. We looked for ways to strengthen each other’s programs – but in 1989, Herb accepted an offer from President George H.W. Bush to join with William Bennett to launch a new White House Office of National Drug Control Policy.

On a trip to Washington, I visited Herb in his White House office. I watched as he mentored young staff about the intricacies of federal drug policy, and he proudly showed off the first draft of the national action plan. When Bill Bennett decided to move on, Herb and his wife, Marian Fischman, got an offer from Herb Pardes (then chair of psychiatry and dean of the College of Medicine at Columbia) to create a dedicated addiction research center at that institution. Their success at Columbia was unprecedented in an environment that had no previous commitment to addiction treatment and research. The result has been a research program that spans neuroscience, clinical trials, and clinical quality improvement. Herb enabled the research careers of a whole new generation of leaders. Combining his years at Yale and Columbia, there has been no one in this field, or (I believe) in the rest of psychiatry, who comes close to being his equal in terms of the consequences of his mentorship: in the numbers, diversity, and success of his mentees.

In 1993, my wife and I moved to Washington. Despite the distance between New York and Washington, Herb and I remained good friends. Herb and Marian attended our daughter’s wedding. When Marian became ill, we feared the worst. After she died, we felt the depth of Herb’s loss. When, several years later, we met Annie Burlock Lawver, we felt profound joy. We were honored to be present at their wedding – and we truly enjoyed traveling together with them in Colombia, Spain, and Iceland.

Herb and Annie were on vacation in Greece with his son and daughter-in-law when he died suddenly of a heart attack while on the island of Santorini. When Annie called from Athens to tell us of Herb’s death, I felt a powerful unease – a sense that the world suddenly seemed more vulnerable. Especially in the age of Trump, Herb’s honesty, integrity, humility, and effectiveness served as an essential counterweight to frustration and despair.

To those who knew his love (like Annie, his children, grandchildren, and great granddaughter, and his dog Sparky), it was total and unconditional. He brought this boundless caring to mentorship and to friendship. His humor could light up a room. His generosity of spirit is matched by too few leaders in academia. It was my privilege to be counted among his friends. He was one of a kind, and I will miss him.
 

Dr. Meyer is former chair of psychiatry at the University of Connecticut, New Haven. He also served as principal investigator of the Alcohol Research Center and executive dean at UConn. In addition, Dr. Meyer is former vice president of health affairs at George Washington University in Washington, former CEO of Best Practice Project Management (a consulting company), and former professor of psychiatry at Pennsylvania State University, Hershey.

Editors’ Note: Herbert D. Kleber, MD, a pioneer in the field of addiction medicine, died Oct. 5, at the age of 84. At the time of his death, Dr. Kleber was professor of psychiatry and emeritus director of the division on substance use disorders at Columbia University in New York.

I met Herb Kleber in the fall of 1967, when my center at National Institute of Mental Health funded six new programs to treat opiate addiction in selected cities across the United States. Fifty-one years later, only one still survives – in New Haven, Conn.

Herb began his work at Yale University in an academic/psychoanalytic environment that, with few exceptions, had too little respect for, or understanding of, his work; with a state mental health administration that placed addiction treatment at the very bottom of its priorities; and, in a racially polarized community reeling from a murder and a highly politicized jury trial.

It was Herb’s creative genius that led to the formation and maintenance of the APT Foundation with a laserlike focus on successive waves of heroin, crack cocaine, and other drug epidemics. The board structure, the clientele, and the challenges of building and maintaining a program that supported cutting-edge treatment, education, and research could have made him feel like the principal character in a book by Mario Puzo. But Herb generated loyalty in those who worked for and with him not by fear, but by his generosity of spirit, his crediting the work of others, his supporting the advancement of junior colleagues, and by his deep respect and appreciation for everyone on the team. When I last checked, Roz (his dedicated administrator) was still on the job – and the program was still being led by people whom he trained.

Most importantly, in spite of his very busy work schedule, his top priority was his family.

In 1977, I became chairman of the department of psychiatry at the University of Connecticut. In 1978, my group received a 4-year center grant from the National Institute on Alcohol Abuse and Alcoholism. By 1982, we had recruited three full professors and a talented assistant professor to our affiliated Veterans Affairs hospital. But in 1985, unfavorable changes at the Newington VA hospital led to the departure of those key faculty. Herb generously agreed to my request that we try to build collaborative bridges between our center and his programs in New Haven. This made it possible for Hank Kranzler at UConn and Stephanie O’Malley at Yale to launch their careers in clinical trials research. The collaboration that Herb generously provided likely saved our alcohol center. On a personal level, Herb and I began to have lunches halfway between New Haven and Farmington. We looked for ways to strengthen each other’s programs – but in 1989, Herb accepted an offer from President George H.W. Bush to join with William Bennett to launch a new White House Office of National Drug Control Policy.

On a trip to Washington, I visited Herb in his White House office. I watched as he mentored young staff about the intricacies of federal drug policy, and he proudly showed off the first draft of the national action plan. When Bill Bennett decided to move on, Herb and his wife, Marian Fischman, got an offer from Herb Pardes (then chair of psychiatry and dean of the College of Medicine at Columbia) to create a dedicated addiction research center at that institution. Their success at Columbia was unprecedented in an environment that had no previous commitment to addiction treatment and research. The result has been a research program that spans neuroscience, clinical trials, and clinical quality improvement. Herb enabled the research careers of a whole new generation of leaders. Combining his years at Yale and Columbia, there has been no one in this field, or (I believe) in the rest of psychiatry, who comes close to being his equal in terms of the consequences of his mentorship: in the numbers, diversity, and success of his mentees.

In 1993, my wife and I moved to Washington. Despite the distance between New York and Washington, Herb and I remained good friends. Herb and Marian attended our daughter’s wedding. When Marian became ill, we feared the worst. After she died, we felt the depth of Herb’s loss. When, several years later, we met Annie Burlock Lawver, we felt profound joy. We were honored to be present at their wedding – and we truly enjoyed traveling together with them in Colombia, Spain, and Iceland.

Herb and Annie were on vacation in Greece with his son and daughter-in-law when he died suddenly of a heart attack while on the island of Santorini. When Annie called from Athens to tell us of Herb’s death, I felt a powerful unease – a sense that the world suddenly seemed more vulnerable. Especially in the age of Trump, Herb’s honesty, integrity, humility, and effectiveness served as an essential counterweight to frustration and despair.

To those who knew his love (like Annie, his children, grandchildren, and great granddaughter, and his dog Sparky), it was total and unconditional. He brought this boundless caring to mentorship and to friendship. His humor could light up a room. His generosity of spirit is matched by too few leaders in academia. It was my privilege to be counted among his friends. He was one of a kind, and I will miss him.
 

Dr. Meyer is former chair of psychiatry at the University of Connecticut, New Haven. He also served as principal investigator of the Alcohol Research Center and executive dean at UConn. In addition, Dr. Meyer is former vice president of health affairs at George Washington University in Washington, former CEO of Best Practice Project Management (a consulting company), and former professor of psychiatry at Pennsylvania State University, Hershey.

Editors’ Note: Herbert D. Kleber, MD, a pioneer in the field of addiction medicine, died Oct. 5, at the age of 84. At the time of his death, Dr. Kleber was professor of psychiatry and emeritus director of the division on substance use disorders at Columbia University in New York.

I met Herb Kleber in the fall of 1967, when my center at National Institute of Mental Health funded six new programs to treat opiate addiction in selected cities across the United States. Fifty-one years later, only one still survives – in New Haven, Conn.

Herb began his work at Yale University in an academic/psychoanalytic environment that, with few exceptions, had too little respect for, or understanding of, his work; with a state mental health administration that placed addiction treatment at the very bottom of its priorities; and, in a racially polarized community reeling from a murder and a highly politicized jury trial.

It was Herb’s creative genius that led to the formation and maintenance of the APT Foundation with a laserlike focus on successive waves of heroin, crack cocaine, and other drug epidemics. The board structure, the clientele, and the challenges of building and maintaining a program that supported cutting-edge treatment, education, and research could have made him feel like the principal character in a book by Mario Puzo. But Herb generated loyalty in those who worked for and with him not by fear, but by his generosity of spirit, his crediting the work of others, his supporting the advancement of junior colleagues, and by his deep respect and appreciation for everyone on the team. When I last checked, Roz (his dedicated administrator) was still on the job – and the program was still being led by people whom he trained.

Most importantly, in spite of his very busy work schedule, his top priority was his family.

In 1977, I became chairman of the department of psychiatry at the University of Connecticut. In 1978, my group received a 4-year center grant from the National Institute on Alcohol Abuse and Alcoholism. By 1982, we had recruited three full professors and a talented assistant professor to our affiliated Veterans Affairs hospital. But in 1985, unfavorable changes at the Newington VA hospital led to the departure of those key faculty. Herb generously agreed to my request that we try to build collaborative bridges between our center and his programs in New Haven. This made it possible for Hank Kranzler at UConn and Stephanie O’Malley at Yale to launch their careers in clinical trials research. The collaboration that Herb generously provided likely saved our alcohol center. On a personal level, Herb and I began to have lunches halfway between New Haven and Farmington. We looked for ways to strengthen each other’s programs – but in 1989, Herb accepted an offer from President George H.W. Bush to join with William Bennett to launch a new White House Office of National Drug Control Policy.

On a trip to Washington, I visited Herb in his White House office. I watched as he mentored young staff about the intricacies of federal drug policy, and he proudly showed off the first draft of the national action plan. When Bill Bennett decided to move on, Herb and his wife, Marian Fischman, got an offer from Herb Pardes (then chair of psychiatry and dean of the College of Medicine at Columbia) to create a dedicated addiction research center at that institution. Their success at Columbia was unprecedented in an environment that had no previous commitment to addiction treatment and research. The result has been a research program that spans neuroscience, clinical trials, and clinical quality improvement. Herb enabled the research careers of a whole new generation of leaders. Combining his years at Yale and Columbia, there has been no one in this field, or (I believe) in the rest of psychiatry, who comes close to being his equal in terms of the consequences of his mentorship: in the numbers, diversity, and success of his mentees.

In 1993, my wife and I moved to Washington. Despite the distance between New York and Washington, Herb and I remained good friends. Herb and Marian attended our daughter’s wedding. When Marian became ill, we feared the worst. After she died, we felt the depth of Herb’s loss. When, several years later, we met Annie Burlock Lawver, we felt profound joy. We were honored to be present at their wedding – and we truly enjoyed traveling together with them in Colombia, Spain, and Iceland.

Herb and Annie were on vacation in Greece with his son and daughter-in-law when he died suddenly of a heart attack while on the island of Santorini. When Annie called from Athens to tell us of Herb’s death, I felt a powerful unease – a sense that the world suddenly seemed more vulnerable. Especially in the age of Trump, Herb’s honesty, integrity, humility, and effectiveness served as an essential counterweight to frustration and despair.

To those who knew his love (like Annie, his children, grandchildren, and great granddaughter, and his dog Sparky), it was total and unconditional. He brought this boundless caring to mentorship and to friendship. His humor could light up a room. His generosity of spirit is matched by too few leaders in academia. It was my privilege to be counted among his friends. He was one of a kind, and I will miss him.
 

Dr. Meyer is former chair of psychiatry at the University of Connecticut, New Haven. He also served as principal investigator of the Alcohol Research Center and executive dean at UConn. In addition, Dr. Meyer is former vice president of health affairs at George Washington University in Washington, former CEO of Best Practice Project Management (a consulting company), and former professor of psychiatry at Pennsylvania State University, Hershey.

AUSTIN, TEX. – The question of where and how to house transgender inmates is a challenging one that involves a range of factors and considerations, according to Ariana Nesbit, MD, a psychiatrist at San Diego Central Jail in California.

RapidEye/iStock/Getty Images Plus

The transgender community makes up about 0.1%-0.5% of the U.S. population, but 19%-65% of transgender individuals have been* incarcerated, compared with just 3% of the cisgender U.S. population, she said at the annual meeting of the American Academy of Psychiatry and the Law. (“Cisgender” refers to individuals whose gender identity matches the sex assigned to them at birth.)

The high incarceration rate likely results from the difficult lives these individuals have led: “Pervasive stigma begins early in life,” Dr. Nesbit said.

More than a third (36%) of transgender individuals report having to leave school because of harassment related to their gender identity, and more 90% report experiencing discrimination at work. About one in seven transgender people are unemployed, and 19-30% have histories of homelessness.*

Their social marginalization leads many to seek illegal means of securing income and housing: Prostitution is one of the two most common offenses that land transgender people in prison. The other is substance use.

“There is a high comorbidity of mental illness and substance use in this population, which confounds the issue because these are also risk factors for incarceration,” Dr. Nesbit explained, though noting that being transgender itself is not a mental illness.

Once incarcerated, transgender people are at much higher risk for victimization because of the hierarchical, hypermasculine culture of the correctional environment, Dr. Nesbit said.

“Inmates rank-order one another based on how masculine they seem, and hypermasculinity is associated with sexual or physical aggression or bias toward women, and transgender people in these facilities are often classified as ‘queens,’ ” Dr. Nesbit said. They experience verbal harassment, beatings, and rape, and they might seek protection from other inmates to survive, she said.

“On the one hand, this may decrease their overall risk of violence,” Dr. Nesbit said. “On the other hand, to maintain this partnership, the transgender inmate is usually forced into subservience to this other partner and that often includes things such as performing sexual favors.”

Correctional staff also can contribute to victimization, by doing mandatory strip searches that humiliate them or placing them in administrative segregation, or ad seg, for protection, which then worsens their mental health, Dr. Nesbit said. Ad seg, also known as “the hole,” is solitary confinement in a tiny cell with little furniture and no windows.

Research also has shown far greater victimization among transgender inmates than the cisgender incarcerated population. A 2007 study involving one-on-one interviews with 322 cisgender and 39 transgender inmates showed that 59% of the transgender inmates had experienced sexual abuse, compared with 4.4% of the cisgender ones.

• The person’s name, because it might pose to safety and security of facility.
• Charges against the inmate.
• The inmate’s personal characteristics.
• Risk to the inmate or other inmates at the facility.
• Hormone status.
• Recommendations by the inmate’s medical doctor.
• The inmate’s preference.
• Any concerns about staff threats to the inmate’s safety.

But it’s unlikely that the United States will see similar policies become widespread under the current administration: The Trump administration made changes in 2018 that mandate officials to “use biological sex as the initial determination” for housing placement decisions and allow consideration of gender identity only in “rare cases,” Dr. Nesbit said.

Despite protests from the National Center for Transgender Equality, which said the change directly defies PREA requirements, Bureau of Prisons spokesperson Nancy Ayers reportedly said that “the manual now addresses and articulates the balance of safety needs of transgender inmates as well as other inmates, including those with histories of trauma, privacy concerns, etc., on a case-by-case basis.” That leaves where to house transgender inmates as an open questions still. No data exist regarding the safest arrangements, and housing based only on genitalia is problematic, Dr. Nesbit said. Placement based on gender identity only is problematic also, since it’s not always the inmate’s preference and violence concerns remain, both for transgender males in male facilities and for transgender females in female facilities.

Though some advocate for placement in separate facilities entirely, which San Francisco does, this is a resource-intensive solution that “may limit access to educational, medical, rehabilitative, and vocational services,” Dr. Nesbit said.

“One-size-fit-all policies that rigidly assign housing do not work,” Dr. Nesbit said, yet no empirical studies exist on individualized approaches. Meanwhile, the best recommendations are to train correctional staff to improve their knowledge about transgender inmates, implement correctional intervention programs that address hypermasculinity, and recognize that transgender incarceration rates and inmate victimization are part of a larger problem of social marginalization, she said.

*Correction, 11/1/2018: An earlier version of this story misstated the timing of transgender individuals' incarceration and homelessness.

AUSTIN, TEX. – The question of where and how to house transgender inmates is a challenging one that involves a range of factors and considerations, according to Ariana Nesbit, MD, a psychiatrist at San Diego Central Jail in California.

RapidEye/iStock/Getty Images Plus

The transgender community makes up about 0.1%-0.5% of the U.S. population, but 19%-65% of transgender individuals have been* incarcerated, compared with just 3% of the cisgender U.S. population, she said at the annual meeting of the American Academy of Psychiatry and the Law. (“Cisgender” refers to individuals whose gender identity matches the sex assigned to them at birth.)

The high incarceration rate likely results from the difficult lives these individuals have led: “Pervasive stigma begins early in life,” Dr. Nesbit said.

More than a third (36%) of transgender individuals report having to leave school because of harassment related to their gender identity, and more 90% report experiencing discrimination at work. About one in seven transgender people are unemployed, and 19-30% have histories of homelessness.*

Their social marginalization leads many to seek illegal means of securing income and housing: Prostitution is one of the two most common offenses that land transgender people in prison. The other is substance use.

“There is a high comorbidity of mental illness and substance use in this population, which confounds the issue because these are also risk factors for incarceration,” Dr. Nesbit explained, though noting that being transgender itself is not a mental illness.

Once incarcerated, transgender people are at much higher risk for victimization because of the hierarchical, hypermasculine culture of the correctional environment, Dr. Nesbit said.

“Inmates rank-order one another based on how masculine they seem, and hypermasculinity is associated with sexual or physical aggression or bias toward women, and transgender people in these facilities are often classified as ‘queens,’ ” Dr. Nesbit said. They experience verbal harassment, beatings, and rape, and they might seek protection from other inmates to survive, she said.

“On the one hand, this may decrease their overall risk of violence,” Dr. Nesbit said. “On the other hand, to maintain this partnership, the transgender inmate is usually forced into subservience to this other partner and that often includes things such as performing sexual favors.”

Correctional staff also can contribute to victimization, by doing mandatory strip searches that humiliate them or placing them in administrative segregation, or ad seg, for protection, which then worsens their mental health, Dr. Nesbit said. Ad seg, also known as “the hole,” is solitary confinement in a tiny cell with little furniture and no windows.

Research also has shown far greater victimization among transgender inmates than the cisgender incarcerated population. A 2007 study involving one-on-one interviews with 322 cisgender and 39 transgender inmates showed that 59% of the transgender inmates had experienced sexual abuse, compared with 4.4% of the cisgender ones.

• The person’s name, because it might pose to safety and security of facility.
• Charges against the inmate.
• The inmate’s personal characteristics.
• Risk to the inmate or other inmates at the facility.
• Hormone status.
• Recommendations by the inmate’s medical doctor.
• The inmate’s preference.
• Any concerns about staff threats to the inmate’s safety.

But it’s unlikely that the United States will see similar policies become widespread under the current administration: The Trump administration made changes in 2018 that mandate officials to “use biological sex as the initial determination” for housing placement decisions and allow consideration of gender identity only in “rare cases,” Dr. Nesbit said.

Despite protests from the National Center for Transgender Equality, which said the change directly defies PREA requirements, Bureau of Prisons spokesperson Nancy Ayers reportedly said that “the manual now addresses and articulates the balance of safety needs of transgender inmates as well as other inmates, including those with histories of trauma, privacy concerns, etc., on a case-by-case basis.” That leaves where to house transgender inmates as an open questions still. No data exist regarding the safest arrangements, and housing based only on genitalia is problematic, Dr. Nesbit said. Placement based on gender identity only is problematic also, since it’s not always the inmate’s preference and violence concerns remain, both for transgender males in male facilities and for transgender females in female facilities.

Though some advocate for placement in separate facilities entirely, which San Francisco does, this is a resource-intensive solution that “may limit access to educational, medical, rehabilitative, and vocational services,” Dr. Nesbit said.

“One-size-fit-all policies that rigidly assign housing do not work,” Dr. Nesbit said, yet no empirical studies exist on individualized approaches. Meanwhile, the best recommendations are to train correctional staff to improve their knowledge about transgender inmates, implement correctional intervention programs that address hypermasculinity, and recognize that transgender incarceration rates and inmate victimization are part of a larger problem of social marginalization, she said.

*Correction, 11/1/2018: An earlier version of this story misstated the timing of transgender individuals' incarceration and homelessness.

AUSTIN, TEX. – The question of where and how to house transgender inmates is a challenging one that involves a range of factors and considerations, according to Ariana Nesbit, MD, a psychiatrist at San Diego Central Jail in California.

RapidEye/iStock/Getty Images Plus

The transgender community makes up about 0.1%-0.5% of the U.S. population, but 19%-65% of transgender individuals have been* incarcerated, compared with just 3% of the cisgender U.S. population, she said at the annual meeting of the American Academy of Psychiatry and the Law. (“Cisgender” refers to individuals whose gender identity matches the sex assigned to them at birth.)

The high incarceration rate likely results from the difficult lives these individuals have led: “Pervasive stigma begins early in life,” Dr. Nesbit said.

More than a third (36%) of transgender individuals report having to leave school because of harassment related to their gender identity, and more 90% report experiencing discrimination at work. About one in seven transgender people are unemployed, and 19-30% have histories of homelessness.*

Their social marginalization leads many to seek illegal means of securing income and housing: Prostitution is one of the two most common offenses that land transgender people in prison. The other is substance use.

“There is a high comorbidity of mental illness and substance use in this population, which confounds the issue because these are also risk factors for incarceration,” Dr. Nesbit explained, though noting that being transgender itself is not a mental illness.

Once incarcerated, transgender people are at much higher risk for victimization because of the hierarchical, hypermasculine culture of the correctional environment, Dr. Nesbit said.

“Inmates rank-order one another based on how masculine they seem, and hypermasculinity is associated with sexual or physical aggression or bias toward women, and transgender people in these facilities are often classified as ‘queens,’ ” Dr. Nesbit said. They experience verbal harassment, beatings, and rape, and they might seek protection from other inmates to survive, she said.

“On the one hand, this may decrease their overall risk of violence,” Dr. Nesbit said. “On the other hand, to maintain this partnership, the transgender inmate is usually forced into subservience to this other partner and that often includes things such as performing sexual favors.”

Correctional staff also can contribute to victimization, by doing mandatory strip searches that humiliate them or placing them in administrative segregation, or ad seg, for protection, which then worsens their mental health, Dr. Nesbit said. Ad seg, also known as “the hole,” is solitary confinement in a tiny cell with little furniture and no windows.

Research also has shown far greater victimization among transgender inmates than the cisgender incarcerated population. A 2007 study involving one-on-one interviews with 322 cisgender and 39 transgender inmates showed that 59% of the transgender inmates had experienced sexual abuse, compared with 4.4% of the cisgender ones.

• The person’s name, because it might pose to safety and security of facility.
• Charges against the inmate.
• The inmate’s personal characteristics.
• Risk to the inmate or other inmates at the facility.
• Hormone status.
• Recommendations by the inmate’s medical doctor.
• The inmate’s preference.
• Any concerns about staff threats to the inmate’s safety.

But it’s unlikely that the United States will see similar policies become widespread under the current administration: The Trump administration made changes in 2018 that mandate officials to “use biological sex as the initial determination” for housing placement decisions and allow consideration of gender identity only in “rare cases,” Dr. Nesbit said.

Despite protests from the National Center for Transgender Equality, which said the change directly defies PREA requirements, Bureau of Prisons spokesperson Nancy Ayers reportedly said that “the manual now addresses and articulates the balance of safety needs of transgender inmates as well as other inmates, including those with histories of trauma, privacy concerns, etc., on a case-by-case basis.” That leaves where to house transgender inmates as an open questions still. No data exist regarding the safest arrangements, and housing based only on genitalia is problematic, Dr. Nesbit said. Placement based on gender identity only is problematic also, since it’s not always the inmate’s preference and violence concerns remain, both for transgender males in male facilities and for transgender females in female facilities.

Though some advocate for placement in separate facilities entirely, which San Francisco does, this is a resource-intensive solution that “may limit access to educational, medical, rehabilitative, and vocational services,” Dr. Nesbit said.

“One-size-fit-all policies that rigidly assign housing do not work,” Dr. Nesbit said, yet no empirical studies exist on individualized approaches. Meanwhile, the best recommendations are to train correctional staff to improve their knowledge about transgender inmates, implement correctional intervention programs that address hypermasculinity, and recognize that transgender incarceration rates and inmate victimization are part of a larger problem of social marginalization, she said.

*Correction, 11/1/2018: An earlier version of this story misstated the timing of transgender individuals' incarceration and homelessness.

The psychosocial impact of psoriasis is a critical component of disease burden. Psoriatic patients have high rates of depression and anxiety, problems at work, and difficulties with interpersonal relationships and intimacy.¹ A National Psoriasis Foundation (NPF) survey from 2003 to 2011 reported that psoriasis affects overall emotional well-being in 88% of patients and enjoyment of life in 82% of patients.²

The reasons for psychosocial burden stem from public misconceptions and disease stigma. A survey of 1005 individuals (age range, 16–64 years) about their perceptions of psoriasis revealed that 16.5% believed that psoriasis is contagious and 6.8% believed that psoriasis is related to personal hygiene.³ Fifty percent practiced discriminatory behavior toward psoriatic patients, including reluctance to shake hands (28.8%) and engage in sexual relations/intercourse (44.1%). Sixty-five percent of psoriatic patients felt their appearance is unsightly, and 73% felt self-conscious about having psoriasis.²

The psychosocial burden exists despite medical treatment of the disease. In a cross-sectional study of 1184 psoriatic patients, 70.2% had impaired quality of life (QOL) as measured by the dermatology life quality index (DLQI), even after receiving a 4-week treatment for psoriasis.⁴ Medical treatment of psoriasis is not enough; providers need to assess overall QOL and provide treatment and resources for these patients in addition to symptomatic management.

There have been many studies on the psychosocial burden of psoriasis, but few have focused on a dermatology resident’s role in addressing this issue. This article will review psychosocial domains—psychiatric comorbidities and social functioning including occupational functioning, interpersonal relationships, and sexual functioning— and discuss a dermatology resident’s role in assessing and addressing each of these areas.

Methods

A PubMed search of articles indexed for MEDLINE was conducted using the following terms: psoriasis, depression, anxiety, work productivity, sexual functioning, and interpersonal relationships. Selected articles covered prevalence, assessment, and management of each psychosocial domain.

Results

Psychiatric Comorbidities

Prevalence
A high prevalence of psychiatric comorbidities exists in psoriatic patients. In a study of 469,097 patients with psoriasis, depression was the third most prevalent comorbidity (17.91%), following hyperlipidemia (45.64%) and hypertension (42.19%).⁵ In a 10-year longitudinal, population-based, prospective cohort study, antidepressant prescriptions were twice as frequent in psoriatic patients (17.8%) compared to control (7.9%)(P<.001).⁶ In a meta-analysis of 98 studies investigating psoriatic patients and psychiatric comorbidities, patients with psoriasis were 1.5 times more likely to experience depression (odds ratio [OR]: 1.57; 95% CI, 1.40-1.76) and use antidepressants (OR: 4.24; 95% CI, 1.53-11.76) compared to control.⁷ Patients with psoriasis were more likely to attempt suicide (OR: 1.32; 95% CI, 1.14-1.54) and complete suicide (OR: 1.20; 95% CI, 1.04-1.39) compared to people without psoriasis.⁸ A 1-year cross-sectional study of 90 psoriatic patients reported 78.7% were diagnosed with depression and 76.7% were diagnosed with anxiety. Seventy-two percent reported both anxiety and depression, correlating with worse QOL (χ²=26.7; P<.05).⁹

Assessment
Psychiatric comorbidities are assessed using clinical judgment and formal screening questionnaires in research studies. Signs of depression in patients with psoriasis can manifest as poor treatment adherence and recurrent flares of psoriasis.^10,11 Psoriatic patients with psychiatric comorbidities were less likely to be adherent to treatment (risk ratio: 0.35; P<.003).¹⁰ The patient health questionnaire (PHQ) 9 and generalized anxiety disorder scale (GAD) 7 are validated and reliable questionnaires. The first 2 questions in PHQ-9 and GAD-7 screen for depression and anxiety, respectively.^12-14 These 2-question screens are practical in a fast-paced dermatology outpatient setting. Systematic questionnaires specifically targeting mood disorders may be more beneficial than the widely used DLQI, which may not adequately capture mood disorders. Over the course of 10 months, 607 patients with psoriasis were asked to fill out the PHQ-9, GAD-7, and DLQI. Thirty-eight percent of patients with major depressive disorder had a DLQI score lower than 10, while 46% of patients with generalized anxiety disorder had a DLQI score lower than 10.¹⁵ Other questionnaires, including the hospital anxiety and depression scale and Beck depression inventory, are valid instruments with high sensitivity but are commonly used for research purposes and may not be clinically feasible.¹⁶

Management
Dermatologists should refer patients with depression and/or anxiety to psychiatry. Interventions include pharmacologic and nonpharmacologic management. First-line therapy for depression and anxiety is a combination of selective serotonin reuptake inhibitors and cognitive behavioral therapy.¹⁷ In addition, providers can direct patients to online resources such as the NPF website, where patients with psoriasis can access information about the signs and symptoms of mood disorders and contact the patient navigation center for further help.¹⁸

Social Functioning

Occupational Prevalence
The NPF found that 92% of patients with psoriasis or psoriatic arthritis (PsA) surveyed between 2003 and 2011 cited their psoriasis as reason for unemployment.² In a survey of 43 patients asked about social and occupational functioning using the social and occupational assessment scale, 62.5% of psoriatic patients reported distress at work and 51.1% reported decreased efficiency at work.¹⁹ A national online survey that was conducted in France and issued to patients with and without psoriasis assessed overall QOL and work productivity using the work productivity and activity impairment questionnaire for psoriasis (WPAI-PSO). Of 714 patients with psoriasis and PsA, the latter had a 57.6% decrease in work productivity over 7 days compared to 27.9% in controls (P<.05).²⁰ Occupational impairment leads to lost wages and hinders advancement, further exacerbating the psychosocial burden of psoriasis.²¹

Occupational Assessment
Formal assessment of occupational function can be done with the WPAI-PSO, a 6-question valid instrument.²² Providers may look for risk factors associated with greater loss in work productivity to help identify and offer support for patients. Patients with increased severity of itching, pain, and scaling experienced a greater decrease in work productivity.^21,23 Patients with PsA warrant early detection and treatment because they experience greater physical restraints that can interfere with work activities. Of the 459 psoriatic patients without a prior diagnosis of PsA who filled out the PsA screening and evaluation questionnaire, 144 (31.4%) received a score of 44 or higher and were referred to rheumatology for further evaluation with the classification criteria for PsA. Nine percent of patients failed to be screened and remained undiagnosed with PsA.²⁴ In a study using the health assessment questionnaire to assess 400 patients with PsA, those with worse physical function due to joint pain and stiffness were less likely to remain employed (OR: 0.56; P=.02).²⁵

Occupational Management
Identifying and coordinating symptoms of PsA between dermatology and rheumatology is beneficial for patients who experience debilitating symptoms. There are a variety of treatments available for PsA. According to the European League Against Rheumatism 2015 guidelines developed from expert opinion and systematic reviews for PsA management, there are 4 phases of treatment, with reassessment every 3 to 6 months for effectiveness of therapy.^26,27 Phase I involves initiating nonsteroidal anti-inflammatory drugs with or without glucocorticoid injections. Phase II involves synthetic disease-modifying drugs, including methotrexate, leflunomide, sulfasalazine, or cyclosporine. Phase III involves adding a second synthetic disease-modifying drug or starting a biologic, such as an anti–tumor necrosis factor, IL-12/IL-23, or IL-17 inhibitor. Phase IV involves switching to a different drug in either aforementioned class.^26,27 Treatment with biologics improves work productivity as assessed by WPAI-PSO for psoriasis and PsA.^28-30 Encouraging patients to speak up in the workplace and request small accommodations such as timely breaks or ergonomic chairs can help patients feel more comfortable and supported in the work environment.¹⁸ Patients who felt supported at work were more likely to remain employed.²⁵

Interpersonal Relationships Prevalence
Misinformation about psoriasis, fear of rejection, and feelings of isolation may contribute to interpersonal conflict. Patients have feelings of shame and self-consciousness that hinder them from engaging in social activities and seeking out relationships.³¹ Twenty-nine percent of patients feel that psoriasis has interfered with establishing relationships because of negative self-esteem associated with the disease,³² and 26.3% have experienced people avoiding physical contact.³³ Family and spouses of patients with psoriasis may be secondarily affected due to economic and emotional distress. Ninety-eight percent of family members of psoriatic patients experienced emotional distress and 54% experienced the burden of care.³⁴ In a survey of 63 relatives and partners of patients with psoriasis, 57% experienced psychological distress, including anxiety and worry over a psoriatic patient’s future.³⁵

Interpersonal Relationships Assessment
Current available tools, including the DLQI and short form health survey, measure overall QOL, including social functioning, but may not be practical in a clinic setting. Although no quick-screening test to assess for this domain exists, providers are encouraged to ask patients about disease impact on interpersonal relationships. The family DLQI questionnaire, adapted from the DLQI, may help physicians and social workers evaluate the burden on a patient’s family members.³⁴

Interpersonal Relationships Management
It may be difficult for providers to address problems with interpersonal relationships without accessible tools. Patients may not be accompanied by family or friends during appointments, and it is difficult to screen for these issues during visits. Providers may offer resources such as the NPF website, which provides information about support groups. It also provides tips on dating and connecting to others in the community who share similar experiences.¹⁸ Encouraging patients to seek family or couples therapy also may be beneficial. Increased social support can lead to better QOL and fewer depressive symptoms.³⁶

Sexual Functioning Prevalence
Psoriasis affects both physical and psychological components of sexual function. Among 3485 patients with skin conditions who were surveyed about sexual function, 34% of psoriatic patients reported that psoriasis interfered with sexual functioning at least to a certain degree.³⁷ Sexual impairment was strongly associated with depression, anxiety, and suicidal ideation; 24% of depressed patients and 20% of anxious patients experienced sexual problems a lot or very much, based on the DLQI.³⁷ Depending on the questionnaire used, the prevalence of sexual dysfunction due to psoriasis ranged from 35.5% to 71.3%.³⁸ In an observational cohort study of 158 participants (n=79 psoriasis patients and n=79 controls), 34.2% of patients with psoriasis experienced erectile dysfunction compared to 17.7% of controls.³⁹ Forty-two percent of psoriatic patients with genital involvement reported dyspareunia, 32% reported worsening of genital psoriasis after intercourse, and 43% reported decreased frequency of intercourse.⁴⁰

Sexual Functioning Assessment
The Skindex-29, DLQI, and psoriasis disability index are available QOL tools that include one question evaluating difficulties with sexual function. The Massachusetts General Hospital sexual functioning questionnaire is a 5-item validated tool that specifically assesses sexual dysfunction.⁴¹ Distribution of lesions can help identify patients who are more likely to experience sexual dysfunction. In 160 patients who completed the questionnaire and self-reported psoriasis area and severity index, lesions on the abdomen, genitals, lumbar region, and buttocks were associated with worse sexual functioning (OR: 7.9; 95% CI, 2.3-33.4; P<.05).⁴² Dermatologists could assess for sexual problems using either formal questionnaires or direct conversations during the routine psoriasis visit, as patients may be suffering in silence due to this sensitive topic.

Sexual Functioning Management
Better disease control leads to improved sexual function, as patients experience fewer feelings of shame, anxiety, and depression, as well as improvement of physical symptoms that can interfere with sexual functioning.^38,43,44 Reducing friction, warmth, and moisture, as well as avoiding tight clothing, can help those with genital psoriasis. Patients are advised to reapply topical medications after sexual intercourse. Patients also can apply makeup to disguise psoriasis and help reduce feelings of self-consciousness that can impede sexual intimacy.¹⁸

Comment

The psychosocial burden of psoriasis penetrates many facets of patient lives. Psoriasis can invoke feelings of shame and embarrassment that are worsened by the public’s misconceptions about psoriasis, resulting in serious mental health issues that can cause even greater disability. Depression and anxiety are prevalent in patients with psoriasis. The characteristic symptoms of pain and pruritus along with psychiatric comorbidities can have an underestimated impact on daily activities, including employment, interpersonal relationships, and sexual function. Such dysfunctions have serious implications toward wages, professional advancement, social support, and overall QOL.

Dermatology providers play an important role in screening for these problems through validated questionnaires and identifying risks. Simple screening questions such as the PHQ-9 can be beneficial and feasible during dermatology visits. Screening for PsA can help patients avoid problems at work. Sexual dysfunction is a sensitive topic; however, providers can use a 1-question screen from valid questionnaires and inquire about the location of lesions as opportunities to address this issue.

Interventions lead to better disease control, which concurrently improves overall QOL. These interventions depend on both patient adherence and a physician’s commitment to finding an optimal treatment regimen for each individual. Medical management; coordinating care; developing treatment plans with psychiatry, rheumatology, and primary care providers; and psychological counseling and services may be necessary and beneficial (Table). Offering accessible resources such as the NPF website helps patients access information outside the clinic when it is not feasible to address all these concerns in a single visit. Psoriasis requires more than just medical management; it requires dermatology providers to use a multidisciplinary approach to address the psychosocial aspects of the disease.

Conclusion

The psychosocial burden of psoriasis is immense. Stigma, public misconception, mental health concerns, and occupational and interpersonal difficulty are the basis of disease burden. Providers play a vital role in assessing the effect psoriasis has on different areas of patients’ lives and providing appropriate interventions and resources to reduce disease burden.

The psychosocial impact of psoriasis is a critical component of disease burden. Psoriatic patients have high rates of depression and anxiety, problems at work, and difficulties with interpersonal relationships and intimacy.¹ A National Psoriasis Foundation (NPF) survey from 2003 to 2011 reported that psoriasis affects overall emotional well-being in 88% of patients and enjoyment of life in 82% of patients.²

The reasons for psychosocial burden stem from public misconceptions and disease stigma. A survey of 1005 individuals (age range, 16–64 years) about their perceptions of psoriasis revealed that 16.5% believed that psoriasis is contagious and 6.8% believed that psoriasis is related to personal hygiene.³ Fifty percent practiced discriminatory behavior toward psoriatic patients, including reluctance to shake hands (28.8%) and engage in sexual relations/intercourse (44.1%). Sixty-five percent of psoriatic patients felt their appearance is unsightly, and 73% felt self-conscious about having psoriasis.²

The psychosocial burden exists despite medical treatment of the disease. In a cross-sectional study of 1184 psoriatic patients, 70.2% had impaired quality of life (QOL) as measured by the dermatology life quality index (DLQI), even after receiving a 4-week treatment for psoriasis.⁴ Medical treatment of psoriasis is not enough; providers need to assess overall QOL and provide treatment and resources for these patients in addition to symptomatic management.

There have been many studies on the psychosocial burden of psoriasis, but few have focused on a dermatology resident’s role in addressing this issue. This article will review psychosocial domains—psychiatric comorbidities and social functioning including occupational functioning, interpersonal relationships, and sexual functioning— and discuss a dermatology resident’s role in assessing and addressing each of these areas.

Methods

A PubMed search of articles indexed for MEDLINE was conducted using the following terms: psoriasis, depression, anxiety, work productivity, sexual functioning, and interpersonal relationships. Selected articles covered prevalence, assessment, and management of each psychosocial domain.

Results

Psychiatric Comorbidities

Prevalence
A high prevalence of psychiatric comorbidities exists in psoriatic patients. In a study of 469,097 patients with psoriasis, depression was the third most prevalent comorbidity (17.91%), following hyperlipidemia (45.64%) and hypertension (42.19%).⁵ In a 10-year longitudinal, population-based, prospective cohort study, antidepressant prescriptions were twice as frequent in psoriatic patients (17.8%) compared to control (7.9%)(P<.001).⁶ In a meta-analysis of 98 studies investigating psoriatic patients and psychiatric comorbidities, patients with psoriasis were 1.5 times more likely to experience depression (odds ratio [OR]: 1.57; 95% CI, 1.40-1.76) and use antidepressants (OR: 4.24; 95% CI, 1.53-11.76) compared to control.⁷ Patients with psoriasis were more likely to attempt suicide (OR: 1.32; 95% CI, 1.14-1.54) and complete suicide (OR: 1.20; 95% CI, 1.04-1.39) compared to people without psoriasis.⁸ A 1-year cross-sectional study of 90 psoriatic patients reported 78.7% were diagnosed with depression and 76.7% were diagnosed with anxiety. Seventy-two percent reported both anxiety and depression, correlating with worse QOL (χ²=26.7; P<.05).⁹

Assessment
Psychiatric comorbidities are assessed using clinical judgment and formal screening questionnaires in research studies. Signs of depression in patients with psoriasis can manifest as poor treatment adherence and recurrent flares of psoriasis.^10,11 Psoriatic patients with psychiatric comorbidities were less likely to be adherent to treatment (risk ratio: 0.35; P<.003).¹⁰ The patient health questionnaire (PHQ) 9 and generalized anxiety disorder scale (GAD) 7 are validated and reliable questionnaires. The first 2 questions in PHQ-9 and GAD-7 screen for depression and anxiety, respectively.^12-14 These 2-question screens are practical in a fast-paced dermatology outpatient setting. Systematic questionnaires specifically targeting mood disorders may be more beneficial than the widely used DLQI, which may not adequately capture mood disorders. Over the course of 10 months, 607 patients with psoriasis were asked to fill out the PHQ-9, GAD-7, and DLQI. Thirty-eight percent of patients with major depressive disorder had a DLQI score lower than 10, while 46% of patients with generalized anxiety disorder had a DLQI score lower than 10.¹⁵ Other questionnaires, including the hospital anxiety and depression scale and Beck depression inventory, are valid instruments with high sensitivity but are commonly used for research purposes and may not be clinically feasible.¹⁶

Management
Dermatologists should refer patients with depression and/or anxiety to psychiatry. Interventions include pharmacologic and nonpharmacologic management. First-line therapy for depression and anxiety is a combination of selective serotonin reuptake inhibitors and cognitive behavioral therapy.¹⁷ In addition, providers can direct patients to online resources such as the NPF website, where patients with psoriasis can access information about the signs and symptoms of mood disorders and contact the patient navigation center for further help.¹⁸

Social Functioning

Occupational Prevalence
The NPF found that 92% of patients with psoriasis or psoriatic arthritis (PsA) surveyed between 2003 and 2011 cited their psoriasis as reason for unemployment.² In a survey of 43 patients asked about social and occupational functioning using the social and occupational assessment scale, 62.5% of psoriatic patients reported distress at work and 51.1% reported decreased efficiency at work.¹⁹ A national online survey that was conducted in France and issued to patients with and without psoriasis assessed overall QOL and work productivity using the work productivity and activity impairment questionnaire for psoriasis (WPAI-PSO). Of 714 patients with psoriasis and PsA, the latter had a 57.6% decrease in work productivity over 7 days compared to 27.9% in controls (P<.05).²⁰ Occupational impairment leads to lost wages and hinders advancement, further exacerbating the psychosocial burden of psoriasis.²¹

Occupational Assessment
Formal assessment of occupational function can be done with the WPAI-PSO, a 6-question valid instrument.²² Providers may look for risk factors associated with greater loss in work productivity to help identify and offer support for patients. Patients with increased severity of itching, pain, and scaling experienced a greater decrease in work productivity.^21,23 Patients with PsA warrant early detection and treatment because they experience greater physical restraints that can interfere with work activities. Of the 459 psoriatic patients without a prior diagnosis of PsA who filled out the PsA screening and evaluation questionnaire, 144 (31.4%) received a score of 44 or higher and were referred to rheumatology for further evaluation with the classification criteria for PsA. Nine percent of patients failed to be screened and remained undiagnosed with PsA.²⁴ In a study using the health assessment questionnaire to assess 400 patients with PsA, those with worse physical function due to joint pain and stiffness were less likely to remain employed (OR: 0.56; P=.02).²⁵

Occupational Management
Identifying and coordinating symptoms of PsA between dermatology and rheumatology is beneficial for patients who experience debilitating symptoms. There are a variety of treatments available for PsA. According to the European League Against Rheumatism 2015 guidelines developed from expert opinion and systematic reviews for PsA management, there are 4 phases of treatment, with reassessment every 3 to 6 months for effectiveness of therapy.^26,27 Phase I involves initiating nonsteroidal anti-inflammatory drugs with or without glucocorticoid injections. Phase II involves synthetic disease-modifying drugs, including methotrexate, leflunomide, sulfasalazine, or cyclosporine. Phase III involves adding a second synthetic disease-modifying drug or starting a biologic, such as an anti–tumor necrosis factor, IL-12/IL-23, or IL-17 inhibitor. Phase IV involves switching to a different drug in either aforementioned class.^26,27 Treatment with biologics improves work productivity as assessed by WPAI-PSO for psoriasis and PsA.^28-30 Encouraging patients to speak up in the workplace and request small accommodations such as timely breaks or ergonomic chairs can help patients feel more comfortable and supported in the work environment.¹⁸ Patients who felt supported at work were more likely to remain employed.²⁵

Interpersonal Relationships Prevalence
Misinformation about psoriasis, fear of rejection, and feelings of isolation may contribute to interpersonal conflict. Patients have feelings of shame and self-consciousness that hinder them from engaging in social activities and seeking out relationships.³¹ Twenty-nine percent of patients feel that psoriasis has interfered with establishing relationships because of negative self-esteem associated with the disease,³² and 26.3% have experienced people avoiding physical contact.³³ Family and spouses of patients with psoriasis may be secondarily affected due to economic and emotional distress. Ninety-eight percent of family members of psoriatic patients experienced emotional distress and 54% experienced the burden of care.³⁴ In a survey of 63 relatives and partners of patients with psoriasis, 57% experienced psychological distress, including anxiety and worry over a psoriatic patient’s future.³⁵

Interpersonal Relationships Assessment
Current available tools, including the DLQI and short form health survey, measure overall QOL, including social functioning, but may not be practical in a clinic setting. Although no quick-screening test to assess for this domain exists, providers are encouraged to ask patients about disease impact on interpersonal relationships. The family DLQI questionnaire, adapted from the DLQI, may help physicians and social workers evaluate the burden on a patient’s family members.³⁴

Interpersonal Relationships Management
It may be difficult for providers to address problems with interpersonal relationships without accessible tools. Patients may not be accompanied by family or friends during appointments, and it is difficult to screen for these issues during visits. Providers may offer resources such as the NPF website, which provides information about support groups. It also provides tips on dating and connecting to others in the community who share similar experiences.¹⁸ Encouraging patients to seek family or couples therapy also may be beneficial. Increased social support can lead to better QOL and fewer depressive symptoms.³⁶

Sexual Functioning Prevalence
Psoriasis affects both physical and psychological components of sexual function. Among 3485 patients with skin conditions who were surveyed about sexual function, 34% of psoriatic patients reported that psoriasis interfered with sexual functioning at least to a certain degree.³⁷ Sexual impairment was strongly associated with depression, anxiety, and suicidal ideation; 24% of depressed patients and 20% of anxious patients experienced sexual problems a lot or very much, based on the DLQI.³⁷ Depending on the questionnaire used, the prevalence of sexual dysfunction due to psoriasis ranged from 35.5% to 71.3%.³⁸ In an observational cohort study of 158 participants (n=79 psoriasis patients and n=79 controls), 34.2% of patients with psoriasis experienced erectile dysfunction compared to 17.7% of controls.³⁹ Forty-two percent of psoriatic patients with genital involvement reported dyspareunia, 32% reported worsening of genital psoriasis after intercourse, and 43% reported decreased frequency of intercourse.⁴⁰

Sexual Functioning Assessment
The Skindex-29, DLQI, and psoriasis disability index are available QOL tools that include one question evaluating difficulties with sexual function. The Massachusetts General Hospital sexual functioning questionnaire is a 5-item validated tool that specifically assesses sexual dysfunction.⁴¹ Distribution of lesions can help identify patients who are more likely to experience sexual dysfunction. In 160 patients who completed the questionnaire and self-reported psoriasis area and severity index, lesions on the abdomen, genitals, lumbar region, and buttocks were associated with worse sexual functioning (OR: 7.9; 95% CI, 2.3-33.4; P<.05).⁴² Dermatologists could assess for sexual problems using either formal questionnaires or direct conversations during the routine psoriasis visit, as patients may be suffering in silence due to this sensitive topic.

Sexual Functioning Management
Better disease control leads to improved sexual function, as patients experience fewer feelings of shame, anxiety, and depression, as well as improvement of physical symptoms that can interfere with sexual functioning.^38,43,44 Reducing friction, warmth, and moisture, as well as avoiding tight clothing, can help those with genital psoriasis. Patients are advised to reapply topical medications after sexual intercourse. Patients also can apply makeup to disguise psoriasis and help reduce feelings of self-consciousness that can impede sexual intimacy.¹⁸

Comment

The psychosocial burden of psoriasis penetrates many facets of patient lives. Psoriasis can invoke feelings of shame and embarrassment that are worsened by the public’s misconceptions about psoriasis, resulting in serious mental health issues that can cause even greater disability. Depression and anxiety are prevalent in patients with psoriasis. The characteristic symptoms of pain and pruritus along with psychiatric comorbidities can have an underestimated impact on daily activities, including employment, interpersonal relationships, and sexual function. Such dysfunctions have serious implications toward wages, professional advancement, social support, and overall QOL.

Dermatology providers play an important role in screening for these problems through validated questionnaires and identifying risks. Simple screening questions such as the PHQ-9 can be beneficial and feasible during dermatology visits. Screening for PsA can help patients avoid problems at work. Sexual dysfunction is a sensitive topic; however, providers can use a 1-question screen from valid questionnaires and inquire about the location of lesions as opportunities to address this issue.

Interventions lead to better disease control, which concurrently improves overall QOL. These interventions depend on both patient adherence and a physician’s commitment to finding an optimal treatment regimen for each individual. Medical management; coordinating care; developing treatment plans with psychiatry, rheumatology, and primary care providers; and psychological counseling and services may be necessary and beneficial (Table). Offering accessible resources such as the NPF website helps patients access information outside the clinic when it is not feasible to address all these concerns in a single visit. Psoriasis requires more than just medical management; it requires dermatology providers to use a multidisciplinary approach to address the psychosocial aspects of the disease.

Conclusion

The psychosocial burden of psoriasis is immense. Stigma, public misconception, mental health concerns, and occupational and interpersonal difficulty are the basis of disease burden. Providers play a vital role in assessing the effect psoriasis has on different areas of patients’ lives and providing appropriate interventions and resources to reduce disease burden.

The psychosocial impact of psoriasis is a critical component of disease burden. Psoriatic patients have high rates of depression and anxiety, problems at work, and difficulties with interpersonal relationships and intimacy.¹ A National Psoriasis Foundation (NPF) survey from 2003 to 2011 reported that psoriasis affects overall emotional well-being in 88% of patients and enjoyment of life in 82% of patients.²

The reasons for psychosocial burden stem from public misconceptions and disease stigma. A survey of 1005 individuals (age range, 16–64 years) about their perceptions of psoriasis revealed that 16.5% believed that psoriasis is contagious and 6.8% believed that psoriasis is related to personal hygiene.³ Fifty percent practiced discriminatory behavior toward psoriatic patients, including reluctance to shake hands (28.8%) and engage in sexual relations/intercourse (44.1%). Sixty-five percent of psoriatic patients felt their appearance is unsightly, and 73% felt self-conscious about having psoriasis.²

The psychosocial burden exists despite medical treatment of the disease. In a cross-sectional study of 1184 psoriatic patients, 70.2% had impaired quality of life (QOL) as measured by the dermatology life quality index (DLQI), even after receiving a 4-week treatment for psoriasis.⁴ Medical treatment of psoriasis is not enough; providers need to assess overall QOL and provide treatment and resources for these patients in addition to symptomatic management.

There have been many studies on the psychosocial burden of psoriasis, but few have focused on a dermatology resident’s role in addressing this issue. This article will review psychosocial domains—psychiatric comorbidities and social functioning including occupational functioning, interpersonal relationships, and sexual functioning— and discuss a dermatology resident’s role in assessing and addressing each of these areas.

Methods

A PubMed search of articles indexed for MEDLINE was conducted using the following terms: psoriasis, depression, anxiety, work productivity, sexual functioning, and interpersonal relationships. Selected articles covered prevalence, assessment, and management of each psychosocial domain.

Results

Psychiatric Comorbidities

Prevalence
A high prevalence of psychiatric comorbidities exists in psoriatic patients. In a study of 469,097 patients with psoriasis, depression was the third most prevalent comorbidity (17.91%), following hyperlipidemia (45.64%) and hypertension (42.19%).⁵ In a 10-year longitudinal, population-based, prospective cohort study, antidepressant prescriptions were twice as frequent in psoriatic patients (17.8%) compared to control (7.9%)(P<.001).⁶ In a meta-analysis of 98 studies investigating psoriatic patients and psychiatric comorbidities, patients with psoriasis were 1.5 times more likely to experience depression (odds ratio [OR]: 1.57; 95% CI, 1.40-1.76) and use antidepressants (OR: 4.24; 95% CI, 1.53-11.76) compared to control.⁷ Patients with psoriasis were more likely to attempt suicide (OR: 1.32; 95% CI, 1.14-1.54) and complete suicide (OR: 1.20; 95% CI, 1.04-1.39) compared to people without psoriasis.⁸ A 1-year cross-sectional study of 90 psoriatic patients reported 78.7% were diagnosed with depression and 76.7% were diagnosed with anxiety. Seventy-two percent reported both anxiety and depression, correlating with worse QOL (χ²=26.7; P<.05).⁹

Assessment
Psychiatric comorbidities are assessed using clinical judgment and formal screening questionnaires in research studies. Signs of depression in patients with psoriasis can manifest as poor treatment adherence and recurrent flares of psoriasis.^10,11 Psoriatic patients with psychiatric comorbidities were less likely to be adherent to treatment (risk ratio: 0.35; P<.003).¹⁰ The patient health questionnaire (PHQ) 9 and generalized anxiety disorder scale (GAD) 7 are validated and reliable questionnaires. The first 2 questions in PHQ-9 and GAD-7 screen for depression and anxiety, respectively.^12-14 These 2-question screens are practical in a fast-paced dermatology outpatient setting. Systematic questionnaires specifically targeting mood disorders may be more beneficial than the widely used DLQI, which may not adequately capture mood disorders. Over the course of 10 months, 607 patients with psoriasis were asked to fill out the PHQ-9, GAD-7, and DLQI. Thirty-eight percent of patients with major depressive disorder had a DLQI score lower than 10, while 46% of patients with generalized anxiety disorder had a DLQI score lower than 10.¹⁵ Other questionnaires, including the hospital anxiety and depression scale and Beck depression inventory, are valid instruments with high sensitivity but are commonly used for research purposes and may not be clinically feasible.¹⁶

Management
Dermatologists should refer patients with depression and/or anxiety to psychiatry. Interventions include pharmacologic and nonpharmacologic management. First-line therapy for depression and anxiety is a combination of selective serotonin reuptake inhibitors and cognitive behavioral therapy.¹⁷ In addition, providers can direct patients to online resources such as the NPF website, where patients with psoriasis can access information about the signs and symptoms of mood disorders and contact the patient navigation center for further help.¹⁸

Social Functioning

Occupational Prevalence
The NPF found that 92% of patients with psoriasis or psoriatic arthritis (PsA) surveyed between 2003 and 2011 cited their psoriasis as reason for unemployment.² In a survey of 43 patients asked about social and occupational functioning using the social and occupational assessment scale, 62.5% of psoriatic patients reported distress at work and 51.1% reported decreased efficiency at work.¹⁹ A national online survey that was conducted in France and issued to patients with and without psoriasis assessed overall QOL and work productivity using the work productivity and activity impairment questionnaire for psoriasis (WPAI-PSO). Of 714 patients with psoriasis and PsA, the latter had a 57.6% decrease in work productivity over 7 days compared to 27.9% in controls (P<.05).²⁰ Occupational impairment leads to lost wages and hinders advancement, further exacerbating the psychosocial burden of psoriasis.²¹

Occupational Assessment
Formal assessment of occupational function can be done with the WPAI-PSO, a 6-question valid instrument.²² Providers may look for risk factors associated with greater loss in work productivity to help identify and offer support for patients. Patients with increased severity of itching, pain, and scaling experienced a greater decrease in work productivity.^21,23 Patients with PsA warrant early detection and treatment because they experience greater physical restraints that can interfere with work activities. Of the 459 psoriatic patients without a prior diagnosis of PsA who filled out the PsA screening and evaluation questionnaire, 144 (31.4%) received a score of 44 or higher and were referred to rheumatology for further evaluation with the classification criteria for PsA. Nine percent of patients failed to be screened and remained undiagnosed with PsA.²⁴ In a study using the health assessment questionnaire to assess 400 patients with PsA, those with worse physical function due to joint pain and stiffness were less likely to remain employed (OR: 0.56; P=.02).²⁵

Occupational Management
Identifying and coordinating symptoms of PsA between dermatology and rheumatology is beneficial for patients who experience debilitating symptoms. There are a variety of treatments available for PsA. According to the European League Against Rheumatism 2015 guidelines developed from expert opinion and systematic reviews for PsA management, there are 4 phases of treatment, with reassessment every 3 to 6 months for effectiveness of therapy.^26,27 Phase I involves initiating nonsteroidal anti-inflammatory drugs with or without glucocorticoid injections. Phase II involves synthetic disease-modifying drugs, including methotrexate, leflunomide, sulfasalazine, or cyclosporine. Phase III involves adding a second synthetic disease-modifying drug or starting a biologic, such as an anti–tumor necrosis factor, IL-12/IL-23, or IL-17 inhibitor. Phase IV involves switching to a different drug in either aforementioned class.^26,27 Treatment with biologics improves work productivity as assessed by WPAI-PSO for psoriasis and PsA.^28-30 Encouraging patients to speak up in the workplace and request small accommodations such as timely breaks or ergonomic chairs can help patients feel more comfortable and supported in the work environment.¹⁸ Patients who felt supported at work were more likely to remain employed.²⁵

Interpersonal Relationships Prevalence
Misinformation about psoriasis, fear of rejection, and feelings of isolation may contribute to interpersonal conflict. Patients have feelings of shame and self-consciousness that hinder them from engaging in social activities and seeking out relationships.³¹ Twenty-nine percent of patients feel that psoriasis has interfered with establishing relationships because of negative self-esteem associated with the disease,³² and 26.3% have experienced people avoiding physical contact.³³ Family and spouses of patients with psoriasis may be secondarily affected due to economic and emotional distress. Ninety-eight percent of family members of psoriatic patients experienced emotional distress and 54% experienced the burden of care.³⁴ In a survey of 63 relatives and partners of patients with psoriasis, 57% experienced psychological distress, including anxiety and worry over a psoriatic patient’s future.³⁵

Interpersonal Relationships Assessment
Current available tools, including the DLQI and short form health survey, measure overall QOL, including social functioning, but may not be practical in a clinic setting. Although no quick-screening test to assess for this domain exists, providers are encouraged to ask patients about disease impact on interpersonal relationships. The family DLQI questionnaire, adapted from the DLQI, may help physicians and social workers evaluate the burden on a patient’s family members.³⁴

Interpersonal Relationships Management
It may be difficult for providers to address problems with interpersonal relationships without accessible tools. Patients may not be accompanied by family or friends during appointments, and it is difficult to screen for these issues during visits. Providers may offer resources such as the NPF website, which provides information about support groups. It also provides tips on dating and connecting to others in the community who share similar experiences.¹⁸ Encouraging patients to seek family or couples therapy also may be beneficial. Increased social support can lead to better QOL and fewer depressive symptoms.³⁶

Sexual Functioning Prevalence
Psoriasis affects both physical and psychological components of sexual function. Among 3485 patients with skin conditions who were surveyed about sexual function, 34% of psoriatic patients reported that psoriasis interfered with sexual functioning at least to a certain degree.³⁷ Sexual impairment was strongly associated with depression, anxiety, and suicidal ideation; 24% of depressed patients and 20% of anxious patients experienced sexual problems a lot or very much, based on the DLQI.³⁷ Depending on the questionnaire used, the prevalence of sexual dysfunction due to psoriasis ranged from 35.5% to 71.3%.³⁸ In an observational cohort study of 158 participants (n=79 psoriasis patients and n=79 controls), 34.2% of patients with psoriasis experienced erectile dysfunction compared to 17.7% of controls.³⁹ Forty-two percent of psoriatic patients with genital involvement reported dyspareunia, 32% reported worsening of genital psoriasis after intercourse, and 43% reported decreased frequency of intercourse.⁴⁰

Sexual Functioning Assessment
The Skindex-29, DLQI, and psoriasis disability index are available QOL tools that include one question evaluating difficulties with sexual function. The Massachusetts General Hospital sexual functioning questionnaire is a 5-item validated tool that specifically assesses sexual dysfunction.⁴¹ Distribution of lesions can help identify patients who are more likely to experience sexual dysfunction. In 160 patients who completed the questionnaire and self-reported psoriasis area and severity index, lesions on the abdomen, genitals, lumbar region, and buttocks were associated with worse sexual functioning (OR: 7.9; 95% CI, 2.3-33.4; P<.05).⁴² Dermatologists could assess for sexual problems using either formal questionnaires or direct conversations during the routine psoriasis visit, as patients may be suffering in silence due to this sensitive topic.

Sexual Functioning Management
Better disease control leads to improved sexual function, as patients experience fewer feelings of shame, anxiety, and depression, as well as improvement of physical symptoms that can interfere with sexual functioning.^38,43,44 Reducing friction, warmth, and moisture, as well as avoiding tight clothing, can help those with genital psoriasis. Patients are advised to reapply topical medications after sexual intercourse. Patients also can apply makeup to disguise psoriasis and help reduce feelings of self-consciousness that can impede sexual intimacy.¹⁸

Comment

The psychosocial burden of psoriasis penetrates many facets of patient lives. Psoriasis can invoke feelings of shame and embarrassment that are worsened by the public’s misconceptions about psoriasis, resulting in serious mental health issues that can cause even greater disability. Depression and anxiety are prevalent in patients with psoriasis. The characteristic symptoms of pain and pruritus along with psychiatric comorbidities can have an underestimated impact on daily activities, including employment, interpersonal relationships, and sexual function. Such dysfunctions have serious implications toward wages, professional advancement, social support, and overall QOL.

Dermatology providers play an important role in screening for these problems through validated questionnaires and identifying risks. Simple screening questions such as the PHQ-9 can be beneficial and feasible during dermatology visits. Screening for PsA can help patients avoid problems at work. Sexual dysfunction is a sensitive topic; however, providers can use a 1-question screen from valid questionnaires and inquire about the location of lesions as opportunities to address this issue.

Interventions lead to better disease control, which concurrently improves overall QOL. These interventions depend on both patient adherence and a physician’s commitment to finding an optimal treatment regimen for each individual. Medical management; coordinating care; developing treatment plans with psychiatry, rheumatology, and primary care providers; and psychological counseling and services may be necessary and beneficial (Table). Offering accessible resources such as the NPF website helps patients access information outside the clinic when it is not feasible to address all these concerns in a single visit. Psoriasis requires more than just medical management; it requires dermatology providers to use a multidisciplinary approach to address the psychosocial aspects of the disease.

Conclusion

The psychosocial burden of psoriasis is immense. Stigma, public misconception, mental health concerns, and occupational and interpersonal difficulty are the basis of disease burden. Providers play a vital role in assessing the effect psoriasis has on different areas of patients’ lives and providing appropriate interventions and resources to reduce disease burden.

Psoriasis is a chronic autoimmune skin disease affecting approximately 6.7 million adults in the United States.¹ Although its pathogenesis is not yet clear, risk factors and triggers provide insight into potential pathways by which psoriasis can occur. There is notable overlap between risk factors and triggers of psoriasis; perceived risk factors might, in fact, be triggers causing manifestation of disease in predisposed persons. In this review, we summarize the key factors contributing to onset and exacerbation of psoriasis. When learning to manage this chronic disease, it also may be helpful to educate patients about how these elements may affect the course of psoriasis.

Genetics

The pathogenesis of psoriasis has a strong genetic component, with approximately 70% and 20% concordance rates in monozygotic and dizygotic twins, respectively.² Moreover, studies have shown a positive family history in approximately 35% of patients.^3,4 Family-based studies have found a 50% risk of developing psoriasis in patients with 2 affected parents.⁵ However, the genetics of psoriasis are complex and are attributed to many different genes. Thus far, genes involving antigen presentation, T-cell receptor development and polarization, and the nuclear factor κβ (NF-κβ) pathway have been identified.⁶

HLA-Cw6
The most well-studied gene implicated in psoriasis is HLA-Cw6, which encodes a major histocompatibility complex class I allele supporting psoriasis as a T cell–mediated reaction to an autoantigen.⁶ Two potential antigens for HLA-Cw6 recently have been identified: LL-37, a cathelicidin-related antimicrobial peptide, and the A disintegrin and metalloproteinase with thrombospondin motifs-like protein 5 (ADAMTSL5), found on melanocytes and keratinocytes.⁷ The percentage of psoriasis patients with HLA-Cw6 ranges from 10.5% to 77.2%, with higher frequency in white individuals than in Asians.⁷

HLA-Cw6 manifests as specific features in psoriasis, including onset of disease before 21 years of age.⁸ It also is more strongly associated with guttate-type psoriasis, greater body surface area involvement, and higher incidence of Köbner phenomenon. Patients with positive HLA-Cw6 also reported worsening of psoriasis during and after throat infection.⁹

Caspase Recruitment Domain Family Member 14
Another gene mutation implicated in psoriasis pathogenesis is caspase recruitment domain family member 14, CARD14 (formerly PSORS2), a gene encoding a scaffolding protein important in the activation of NF-κβ.^10,11 Missense CARD14 mutations cause upregulation of NF-κβ through formation of a complex with adapter protein B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1),¹² which, in turn, causes increased transcription of cytokines IL-8, C-C motif chemokine ligand 20 (CCL-20), and IL-36 gamma in the keratinocyte.¹³ Mutations in CARD14 alone lead to psoriasiform skin in mice through amplified activation of the IL-23/IL-17 axis.^14,15 Patients with a mutation in a CARD14 variant (p.Arg820Trp) have demonstrated better response to tumor necrosis factor (TNF) inhibitors.¹⁶

Further characterization of the genetic pathogenesis of psoriasis might lead to better targeted therapies, including the possibility of MALT1 inhibitors as a treatment option.¹²

Infection

Streptococcus
The association between streptococcal infection and psoriasis was first documented more than 100 years ago, specifically the onset of acute guttate psoriasis.^17,18 Although classically described following throat infection, psoriasis also occurs following streptococcal vulvovaginitis and perianal streptococcal infection.^19,20

This type of psoriasis is typically self-limited but can recur with subsequent streptococcal infections or initiate a more chronic plaque psoriasis. Patients have a 1 in 3 risk of developing chronic psoriasis within 10 years of a single episode of acute guttate psoriasis.²¹ Moreover, in many patients with existing plaque psoriasis, throat infection exacerbates psoriatic symptoms.²² The mechanism of exacerbation is likely due to cross-reactivity between streptococcal M surface antigen and human keratinocytes and might also be influenced by inherited abnormalities in immune response.^23-26 Therefore, tonsillectomy has been studied as a possible treatment of psoriasis but is likely helpful only in patients with exacerbations of disease that are closely associated with recurrent tonsillitis.²⁷

Human Immunodeficiency Virus
The prevalence of psoriasis in human immunodeficiency virus (HIV) patients is similar to or greater than the general population.²⁸ Human immunodeficiency virus infection causes new onset of psoriasis and exacerbation of existing psoriasis; severity often is correlated with worsening immune function.^28,29

The clinical subtypes of psoriasis that occur most frequently with HIV include guttate, inverse, and erythrodermic, though patients may present with any subtype.²⁸ The mechanism is puzzling because HIV is primarily mediated by helper T cell 2 (T_H2) cytokines, whereas psoriasis is mainly driven by helper T cell 1 (T_H1) cytokines.³⁰ Furthermore, despite increased severity with lower CD4⁺ counts, treatments further lowering T-cell counts paradoxically improve symptoms.³¹ Current literature suggests that expansion of CD8⁺ memory T cells might be the primary mechanism in the exacerbation of psoriasis in HIV-mediated immunosuppression.³⁰

Treatment of HIV-associated psoriasis presents challenges because many therapeutics cause further immunosuppression. The National Psoriasis Foundation recommends topical preparations as first-line agents for mild to moderate psoriasis.³² For moderate to severe psoriasis, retroviral agents may be effective as first-line monotherapy or when supplemented by phototherapy with UVB or psoralen plus UVA. Retinoids can be used as second-line agents.³² For cases of severe refractory psoriasis, cyclosporine, methotrexate, TNF inhibitors, or hydroxyurea can be considered. There also is evidence that apremilast is effective without risk for worsening immune function.³³

Other Infections
Other bacteria associated with triggering or exacerbating psoriasis include Staphylococcus aureus and Helicobacter pylori.^34,35 Fungi, such as species of the genera Malassezia and Candida, and other viruses, including papillomaviruses and retroviruses, also have been implicated.³⁴

Medications

Numerous medications can trigger psoriasis, including lithium, nonsteroidal anti-inflammatory drugs, antimalarials, beta-blockers, and angiotensin-converting enzyme inhibitors.³⁴ More recent literature suggests that TNF inhibitors also can paradoxically induce psoriasis in rare cases.³⁵

Lithium
Psoriasis is the most common cutaneous adverse effect of lithium.³⁴ It is more likely to exacerbate existing disease but also can induce onset of psoriasis; it also can cause disease that is more refractory to treatment.^34,36 Current literature hypothesizes that lithium triggers psoriasis by interference of intracellular calcium channels through reduction of inositol, thereby affecting keratinocyte proliferation and differentiation.³⁴ Lithium also inhibits glycogen synthase kinase-3 (GSK-3), a serine threonine kinase, which, in turn, induces human keratinocyte proliferation.³⁷ However, it is unlikely lithium alone can induce psoriasis; genetic predisposition is necessary.

TNF Inhibitors
Tumor necrosis factor inhibitors such as adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab are used in various inflammatory diseases, including psoriasis. Interestingly, there have been more than 200 reported cases of suspected TNF inhibitor–induced or –exacerbated psoriasis.³⁸ This phenomenon appears to occur more frequently with infliximab and is most likely to occur in the first year of treatment of Crohn disease and rheumatoid arthritis.³⁸ Plaque psoriasis is the most common form, but 15% to 26% of cases presented with 2 or more morphologies.^38,39

Treatment options include discontinuing therapy, though many patients experience resolution while continuing treatment or switching to another TNF inhibitor.^38-40 Traditional topical therapies also have been used with success.⁴⁰ The pathogenesis of this phenomenon is still unclear but is thought to involve both the IL-23/helper T cell 17 (T_H17) axis and dysregulation of IFN-α in the setting of TNF suppression.³⁸

Lifestyle

Obesity is a chronic low-grade inflammatory state that can contribute to the onset of psoriasis or exacerbation of existing disease.^41,42 Smoking also is thought to increase the risk for psoriasis, perhaps by a similar mechanism. Lee et al⁴³ found a strong positive correlation between the amount or duration of smoking and the incidence of psoriasis.

The relationship between psoriasis and alcohol consumption is less clear than it is between psoriasis and obesity or smoking; greater consumption is found in psoriasis patients, but evidence is insufficient to deem alcohol a risk factor.⁴⁴

Conclusion

Various factors, including genetics, infection, pharmacotherapeutic, and lifestyle, can all contribute to the induction or exacerbation of psoriasis. These factors can provide clues to the pathogenesis of psoriasis as well as help clinicians better counsel patients about their disease.

Psoriasis is a chronic autoimmune skin disease affecting approximately 6.7 million adults in the United States.¹ Although its pathogenesis is not yet clear, risk factors and triggers provide insight into potential pathways by which psoriasis can occur. There is notable overlap between risk factors and triggers of psoriasis; perceived risk factors might, in fact, be triggers causing manifestation of disease in predisposed persons. In this review, we summarize the key factors contributing to onset and exacerbation of psoriasis. When learning to manage this chronic disease, it also may be helpful to educate patients about how these elements may affect the course of psoriasis.

Genetics

The pathogenesis of psoriasis has a strong genetic component, with approximately 70% and 20% concordance rates in monozygotic and dizygotic twins, respectively.² Moreover, studies have shown a positive family history in approximately 35% of patients.^3,4 Family-based studies have found a 50% risk of developing psoriasis in patients with 2 affected parents.⁵ However, the genetics of psoriasis are complex and are attributed to many different genes. Thus far, genes involving antigen presentation, T-cell receptor development and polarization, and the nuclear factor κβ (NF-κβ) pathway have been identified.⁶

HLA-Cw6
The most well-studied gene implicated in psoriasis is HLA-Cw6, which encodes a major histocompatibility complex class I allele supporting psoriasis as a T cell–mediated reaction to an autoantigen.⁶ Two potential antigens for HLA-Cw6 recently have been identified: LL-37, a cathelicidin-related antimicrobial peptide, and the A disintegrin and metalloproteinase with thrombospondin motifs-like protein 5 (ADAMTSL5), found on melanocytes and keratinocytes.⁷ The percentage of psoriasis patients with HLA-Cw6 ranges from 10.5% to 77.2%, with higher frequency in white individuals than in Asians.⁷

HLA-Cw6 manifests as specific features in psoriasis, including onset of disease before 21 years of age.⁸ It also is more strongly associated with guttate-type psoriasis, greater body surface area involvement, and higher incidence of Köbner phenomenon. Patients with positive HLA-Cw6 also reported worsening of psoriasis during and after throat infection.⁹

Caspase Recruitment Domain Family Member 14
Another gene mutation implicated in psoriasis pathogenesis is caspase recruitment domain family member 14, CARD14 (formerly PSORS2), a gene encoding a scaffolding protein important in the activation of NF-κβ.^10,11 Missense CARD14 mutations cause upregulation of NF-κβ through formation of a complex with adapter protein B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1),¹² which, in turn, causes increased transcription of cytokines IL-8, C-C motif chemokine ligand 20 (CCL-20), and IL-36 gamma in the keratinocyte.¹³ Mutations in CARD14 alone lead to psoriasiform skin in mice through amplified activation of the IL-23/IL-17 axis.^14,15 Patients with a mutation in a CARD14 variant (p.Arg820Trp) have demonstrated better response to tumor necrosis factor (TNF) inhibitors.¹⁶

Further characterization of the genetic pathogenesis of psoriasis might lead to better targeted therapies, including the possibility of MALT1 inhibitors as a treatment option.¹²

Infection

Streptococcus
The association between streptococcal infection and psoriasis was first documented more than 100 years ago, specifically the onset of acute guttate psoriasis.^17,18 Although classically described following throat infection, psoriasis also occurs following streptococcal vulvovaginitis and perianal streptococcal infection.^19,20

This type of psoriasis is typically self-limited but can recur with subsequent streptococcal infections or initiate a more chronic plaque psoriasis. Patients have a 1 in 3 risk of developing chronic psoriasis within 10 years of a single episode of acute guttate psoriasis.²¹ Moreover, in many patients with existing plaque psoriasis, throat infection exacerbates psoriatic symptoms.²² The mechanism of exacerbation is likely due to cross-reactivity between streptococcal M surface antigen and human keratinocytes and might also be influenced by inherited abnormalities in immune response.^23-26 Therefore, tonsillectomy has been studied as a possible treatment of psoriasis but is likely helpful only in patients with exacerbations of disease that are closely associated with recurrent tonsillitis.²⁷

Human Immunodeficiency Virus
The prevalence of psoriasis in human immunodeficiency virus (HIV) patients is similar to or greater than the general population.²⁸ Human immunodeficiency virus infection causes new onset of psoriasis and exacerbation of existing psoriasis; severity often is correlated with worsening immune function.^28,29

The clinical subtypes of psoriasis that occur most frequently with HIV include guttate, inverse, and erythrodermic, though patients may present with any subtype.²⁸ The mechanism is puzzling because HIV is primarily mediated by helper T cell 2 (T_H2) cytokines, whereas psoriasis is mainly driven by helper T cell 1 (T_H1) cytokines.³⁰ Furthermore, despite increased severity with lower CD4⁺ counts, treatments further lowering T-cell counts paradoxically improve symptoms.³¹ Current literature suggests that expansion of CD8⁺ memory T cells might be the primary mechanism in the exacerbation of psoriasis in HIV-mediated immunosuppression.³⁰

Treatment of HIV-associated psoriasis presents challenges because many therapeutics cause further immunosuppression. The National Psoriasis Foundation recommends topical preparations as first-line agents for mild to moderate psoriasis.³² For moderate to severe psoriasis, retroviral agents may be effective as first-line monotherapy or when supplemented by phototherapy with UVB or psoralen plus UVA. Retinoids can be used as second-line agents.³² For cases of severe refractory psoriasis, cyclosporine, methotrexate, TNF inhibitors, or hydroxyurea can be considered. There also is evidence that apremilast is effective without risk for worsening immune function.³³

Other Infections
Other bacteria associated with triggering or exacerbating psoriasis include Staphylococcus aureus and Helicobacter pylori.^34,35 Fungi, such as species of the genera Malassezia and Candida, and other viruses, including papillomaviruses and retroviruses, also have been implicated.³⁴

Medications

Numerous medications can trigger psoriasis, including lithium, nonsteroidal anti-inflammatory drugs, antimalarials, beta-blockers, and angiotensin-converting enzyme inhibitors.³⁴ More recent literature suggests that TNF inhibitors also can paradoxically induce psoriasis in rare cases.³⁵

Lithium
Psoriasis is the most common cutaneous adverse effect of lithium.³⁴ It is more likely to exacerbate existing disease but also can induce onset of psoriasis; it also can cause disease that is more refractory to treatment.^34,36 Current literature hypothesizes that lithium triggers psoriasis by interference of intracellular calcium channels through reduction of inositol, thereby affecting keratinocyte proliferation and differentiation.³⁴ Lithium also inhibits glycogen synthase kinase-3 (GSK-3), a serine threonine kinase, which, in turn, induces human keratinocyte proliferation.³⁷ However, it is unlikely lithium alone can induce psoriasis; genetic predisposition is necessary.

TNF Inhibitors
Tumor necrosis factor inhibitors such as adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab are used in various inflammatory diseases, including psoriasis. Interestingly, there have been more than 200 reported cases of suspected TNF inhibitor–induced or –exacerbated psoriasis.³⁸ This phenomenon appears to occur more frequently with infliximab and is most likely to occur in the first year of treatment of Crohn disease and rheumatoid arthritis.³⁸ Plaque psoriasis is the most common form, but 15% to 26% of cases presented with 2 or more morphologies.^38,39

Treatment options include discontinuing therapy, though many patients experience resolution while continuing treatment or switching to another TNF inhibitor.^38-40 Traditional topical therapies also have been used with success.⁴⁰ The pathogenesis of this phenomenon is still unclear but is thought to involve both the IL-23/helper T cell 17 (T_H17) axis and dysregulation of IFN-α in the setting of TNF suppression.³⁸

Lifestyle

Obesity is a chronic low-grade inflammatory state that can contribute to the onset of psoriasis or exacerbation of existing disease.^41,42 Smoking also is thought to increase the risk for psoriasis, perhaps by a similar mechanism. Lee et al⁴³ found a strong positive correlation between the amount or duration of smoking and the incidence of psoriasis.

The relationship between psoriasis and alcohol consumption is less clear than it is between psoriasis and obesity or smoking; greater consumption is found in psoriasis patients, but evidence is insufficient to deem alcohol a risk factor.⁴⁴

Conclusion

Various factors, including genetics, infection, pharmacotherapeutic, and lifestyle, can all contribute to the induction or exacerbation of psoriasis. These factors can provide clues to the pathogenesis of psoriasis as well as help clinicians better counsel patients about their disease.

Psoriasis is a chronic autoimmune skin disease affecting approximately 6.7 million adults in the United States.¹ Although its pathogenesis is not yet clear, risk factors and triggers provide insight into potential pathways by which psoriasis can occur. There is notable overlap between risk factors and triggers of psoriasis; perceived risk factors might, in fact, be triggers causing manifestation of disease in predisposed persons. In this review, we summarize the key factors contributing to onset and exacerbation of psoriasis. When learning to manage this chronic disease, it also may be helpful to educate patients about how these elements may affect the course of psoriasis.

Genetics

The pathogenesis of psoriasis has a strong genetic component, with approximately 70% and 20% concordance rates in monozygotic and dizygotic twins, respectively.² Moreover, studies have shown a positive family history in approximately 35% of patients.^3,4 Family-based studies have found a 50% risk of developing psoriasis in patients with 2 affected parents.⁵ However, the genetics of psoriasis are complex and are attributed to many different genes. Thus far, genes involving antigen presentation, T-cell receptor development and polarization, and the nuclear factor κβ (NF-κβ) pathway have been identified.⁶

HLA-Cw6
The most well-studied gene implicated in psoriasis is HLA-Cw6, which encodes a major histocompatibility complex class I allele supporting psoriasis as a T cell–mediated reaction to an autoantigen.⁶ Two potential antigens for HLA-Cw6 recently have been identified: LL-37, a cathelicidin-related antimicrobial peptide, and the A disintegrin and metalloproteinase with thrombospondin motifs-like protein 5 (ADAMTSL5), found on melanocytes and keratinocytes.⁷ The percentage of psoriasis patients with HLA-Cw6 ranges from 10.5% to 77.2%, with higher frequency in white individuals than in Asians.⁷

HLA-Cw6 manifests as specific features in psoriasis, including onset of disease before 21 years of age.⁸ It also is more strongly associated with guttate-type psoriasis, greater body surface area involvement, and higher incidence of Köbner phenomenon. Patients with positive HLA-Cw6 also reported worsening of psoriasis during and after throat infection.⁹

Caspase Recruitment Domain Family Member 14
Another gene mutation implicated in psoriasis pathogenesis is caspase recruitment domain family member 14, CARD14 (formerly PSORS2), a gene encoding a scaffolding protein important in the activation of NF-κβ.^10,11 Missense CARD14 mutations cause upregulation of NF-κβ through formation of a complex with adapter protein B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1),¹² which, in turn, causes increased transcription of cytokines IL-8, C-C motif chemokine ligand 20 (CCL-20), and IL-36 gamma in the keratinocyte.¹³ Mutations in CARD14 alone lead to psoriasiform skin in mice through amplified activation of the IL-23/IL-17 axis.^14,15 Patients with a mutation in a CARD14 variant (p.Arg820Trp) have demonstrated better response to tumor necrosis factor (TNF) inhibitors.¹⁶

Further characterization of the genetic pathogenesis of psoriasis might lead to better targeted therapies, including the possibility of MALT1 inhibitors as a treatment option.¹²

Infection

Streptococcus
The association between streptococcal infection and psoriasis was first documented more than 100 years ago, specifically the onset of acute guttate psoriasis.^17,18 Although classically described following throat infection, psoriasis also occurs following streptococcal vulvovaginitis and perianal streptococcal infection.^19,20

This type of psoriasis is typically self-limited but can recur with subsequent streptococcal infections or initiate a more chronic plaque psoriasis. Patients have a 1 in 3 risk of developing chronic psoriasis within 10 years of a single episode of acute guttate psoriasis.²¹ Moreover, in many patients with existing plaque psoriasis, throat infection exacerbates psoriatic symptoms.²² The mechanism of exacerbation is likely due to cross-reactivity between streptococcal M surface antigen and human keratinocytes and might also be influenced by inherited abnormalities in immune response.^23-26 Therefore, tonsillectomy has been studied as a possible treatment of psoriasis but is likely helpful only in patients with exacerbations of disease that are closely associated with recurrent tonsillitis.²⁷

Human Immunodeficiency Virus
The prevalence of psoriasis in human immunodeficiency virus (HIV) patients is similar to or greater than the general population.²⁸ Human immunodeficiency virus infection causes new onset of psoriasis and exacerbation of existing psoriasis; severity often is correlated with worsening immune function.^28,29

The clinical subtypes of psoriasis that occur most frequently with HIV include guttate, inverse, and erythrodermic, though patients may present with any subtype.²⁸ The mechanism is puzzling because HIV is primarily mediated by helper T cell 2 (T_H2) cytokines, whereas psoriasis is mainly driven by helper T cell 1 (T_H1) cytokines.³⁰ Furthermore, despite increased severity with lower CD4⁺ counts, treatments further lowering T-cell counts paradoxically improve symptoms.³¹ Current literature suggests that expansion of CD8⁺ memory T cells might be the primary mechanism in the exacerbation of psoriasis in HIV-mediated immunosuppression.³⁰

Treatment of HIV-associated psoriasis presents challenges because many therapeutics cause further immunosuppression. The National Psoriasis Foundation recommends topical preparations as first-line agents for mild to moderate psoriasis.³² For moderate to severe psoriasis, retroviral agents may be effective as first-line monotherapy or when supplemented by phototherapy with UVB or psoralen plus UVA. Retinoids can be used as second-line agents.³² For cases of severe refractory psoriasis, cyclosporine, methotrexate, TNF inhibitors, or hydroxyurea can be considered. There also is evidence that apremilast is effective without risk for worsening immune function.³³

Other Infections
Other bacteria associated with triggering or exacerbating psoriasis include Staphylococcus aureus and Helicobacter pylori.^34,35 Fungi, such as species of the genera Malassezia and Candida, and other viruses, including papillomaviruses and retroviruses, also have been implicated.³⁴

Medications

Numerous medications can trigger psoriasis, including lithium, nonsteroidal anti-inflammatory drugs, antimalarials, beta-blockers, and angiotensin-converting enzyme inhibitors.³⁴ More recent literature suggests that TNF inhibitors also can paradoxically induce psoriasis in rare cases.³⁵

Lithium
Psoriasis is the most common cutaneous adverse effect of lithium.³⁴ It is more likely to exacerbate existing disease but also can induce onset of psoriasis; it also can cause disease that is more refractory to treatment.^34,36 Current literature hypothesizes that lithium triggers psoriasis by interference of intracellular calcium channels through reduction of inositol, thereby affecting keratinocyte proliferation and differentiation.³⁴ Lithium also inhibits glycogen synthase kinase-3 (GSK-3), a serine threonine kinase, which, in turn, induces human keratinocyte proliferation.³⁷ However, it is unlikely lithium alone can induce psoriasis; genetic predisposition is necessary.

TNF Inhibitors
Tumor necrosis factor inhibitors such as adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab are used in various inflammatory diseases, including psoriasis. Interestingly, there have been more than 200 reported cases of suspected TNF inhibitor–induced or –exacerbated psoriasis.³⁸ This phenomenon appears to occur more frequently with infliximab and is most likely to occur in the first year of treatment of Crohn disease and rheumatoid arthritis.³⁸ Plaque psoriasis is the most common form, but 15% to 26% of cases presented with 2 or more morphologies.^38,39

Treatment options include discontinuing therapy, though many patients experience resolution while continuing treatment or switching to another TNF inhibitor.^38-40 Traditional topical therapies also have been used with success.⁴⁰ The pathogenesis of this phenomenon is still unclear but is thought to involve both the IL-23/helper T cell 17 (T_H17) axis and dysregulation of IFN-α in the setting of TNF suppression.³⁸

Lifestyle

Obesity is a chronic low-grade inflammatory state that can contribute to the onset of psoriasis or exacerbation of existing disease.^41,42 Smoking also is thought to increase the risk for psoriasis, perhaps by a similar mechanism. Lee et al⁴³ found a strong positive correlation between the amount or duration of smoking and the incidence of psoriasis.

The relationship between psoriasis and alcohol consumption is less clear than it is between psoriasis and obesity or smoking; greater consumption is found in psoriasis patients, but evidence is insufficient to deem alcohol a risk factor.⁴⁴

Conclusion

Various factors, including genetics, infection, pharmacotherapeutic, and lifestyle, can all contribute to the induction or exacerbation of psoriasis. These factors can provide clues to the pathogenesis of psoriasis as well as help clinicians better counsel patients about their disease.

CHICAGO – Encouraging patients with knee osteoarthritis to engage in brisk walking for at least 5 minutes per day pays big dividends in terms of reduced risk of total knee replacement, according to a new analysis of data from the National Institutes of Health-sponsored Osteoarthritis Initiative.
 

Vidyard Video

Whether walking increases or decreases the risk of structural deterioration and total knee replacement (TKR) in patients with knee osteoarthritis has been a controversial topic marked by conflicting data. That’s probably because prior studies haven’t taken into account walking intensity, Hiral Master said at the annual meeting of the American College of Rheumatology.

Ms. Master, a PhD candidate in physical therapy at the University of Delaware, Newark, presented a study of 1,854 patients with knee osteoarthritis who participated in the Osteoarthritis Initiative, all of whom had worn an accelerometer. This permitted calculation of time spent walking at various intensities. Subjects spent an average of 459 minutes per day not walking and 8 minutes walking at moderate to vigorous intensity, defined as a cadence of more than 100 steps per minute.


During 5 years of follow-up, the incidence of TKR was 6%. In this video interview, Ms. Master explains that patients who replaced 5 minutes of not walking with 5 minutes of brisk walking daily had an adjusted 14% reduction in the risk of TKR. A dose-response was evident, with more minutes of moderate to vigorous walking being associated with progressively larger reductions in the risk of this major surgery. Walking at a cadence of less than 100 steps per minute, regardless of duration, was nonprotective.

bjancin@mdedge.com

SOURCE: Master H et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 1166.

CHICAGO – Encouraging patients with knee osteoarthritis to engage in brisk walking for at least 5 minutes per day pays big dividends in terms of reduced risk of total knee replacement, according to a new analysis of data from the National Institutes of Health-sponsored Osteoarthritis Initiative.
 

Vidyard Video

Whether walking increases or decreases the risk of structural deterioration and total knee replacement (TKR) in patients with knee osteoarthritis has been a controversial topic marked by conflicting data. That’s probably because prior studies haven’t taken into account walking intensity, Hiral Master said at the annual meeting of the American College of Rheumatology.

Ms. Master, a PhD candidate in physical therapy at the University of Delaware, Newark, presented a study of 1,854 patients with knee osteoarthritis who participated in the Osteoarthritis Initiative, all of whom had worn an accelerometer. This permitted calculation of time spent walking at various intensities. Subjects spent an average of 459 minutes per day not walking and 8 minutes walking at moderate to vigorous intensity, defined as a cadence of more than 100 steps per minute.


During 5 years of follow-up, the incidence of TKR was 6%. In this video interview, Ms. Master explains that patients who replaced 5 minutes of not walking with 5 minutes of brisk walking daily had an adjusted 14% reduction in the risk of TKR. A dose-response was evident, with more minutes of moderate to vigorous walking being associated with progressively larger reductions in the risk of this major surgery. Walking at a cadence of less than 100 steps per minute, regardless of duration, was nonprotective.

bjancin@mdedge.com

SOURCE: Master H et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 1166.

CHICAGO – Encouraging patients with knee osteoarthritis to engage in brisk walking for at least 5 minutes per day pays big dividends in terms of reduced risk of total knee replacement, according to a new analysis of data from the National Institutes of Health-sponsored Osteoarthritis Initiative.
 

Vidyard Video

Whether walking increases or decreases the risk of structural deterioration and total knee replacement (TKR) in patients with knee osteoarthritis has been a controversial topic marked by conflicting data. That’s probably because prior studies haven’t taken into account walking intensity, Hiral Master said at the annual meeting of the American College of Rheumatology.

Ms. Master, a PhD candidate in physical therapy at the University of Delaware, Newark, presented a study of 1,854 patients with knee osteoarthritis who participated in the Osteoarthritis Initiative, all of whom had worn an accelerometer. This permitted calculation of time spent walking at various intensities. Subjects spent an average of 459 minutes per day not walking and 8 minutes walking at moderate to vigorous intensity, defined as a cadence of more than 100 steps per minute.


During 5 years of follow-up, the incidence of TKR was 6%. In this video interview, Ms. Master explains that patients who replaced 5 minutes of not walking with 5 minutes of brisk walking daily had an adjusted 14% reduction in the risk of TKR. A dose-response was evident, with more minutes of moderate to vigorous walking being associated with progressively larger reductions in the risk of this major surgery. Walking at a cadence of less than 100 steps per minute, regardless of duration, was nonprotective.

bjancin@mdedge.com

SOURCE: Master H et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 1166.