MDedge Dermatology

Patients who take methotrexate for a variety of immune-mediated inflammatory diseases and pause taking the drug following receipt of a COVID-19 vaccine dose did not have a higher risk of disease flare and had higher antireceptor binding domain (anti-RBD) antibody titers and increased immunogenicity when compared with continuing the drug, three recent studies suggest.

In one study, British researchers examined the effects of a 2-week break in methotrexate therapy on anti-RBD titers following receipt of a third COVID-19 vaccine dose. In their paper published in The Lancet: Respiratory Medicine, they reported results from a randomized, open-label, superiority trial that suggested pausing the drug improved immunogenicity, compared with no break.

In two trials presented at the European Alliance of Associations for Rheumatology (EULAR) 2022 Congress, a team from India set out to determine whether holding methotrexate after receiving both doses of a COVID-19 vaccine, or holding it only after the second dose, was safe and effective. They found that pausing methotrexate only following the second dose contributed to a lower flare risk, and that patients had higher anti-RBD titers when holding methotrexate for 2 weeks following each dose.
 

Pausing methotrexate after booster

The 2-week methotrexate break and booster vaccine dose data in the Vaccine Response On Off Methotrexate (VROOM) trial showed that after a month, the geometric mean antispike 1 (S1)-RBD antibody titer was 10,798 U/mL (95% confidence interval [CI], 8,970-12,997) in the group that continued methotrexate and 22,750 U/mL (95% CI, 19,314-26,796) in the group that suspended methotrexate; the geometric mean ratio was 2.19 (P < .0001; mixed-effects model), reported Abhishek Abhishek, MD, PhD, professor of rheumatology at the University of Nottingham in Nottingham, England, and colleagues.

Prior research showed that stopping methotrexate therapy for 2 weeks following the seasonal influenza vaccine contributed to better vaccine immunity among patients with rheumatoid arthritis, but there was no impact of stopping the drug for up to 4 weeks before vaccination on vaccine-related immunity, the researchers noted.

It is crucial in maximizing long-lasting vaccine protection in people who are possibly susceptible through immune suppression at this point in the COVID-19 vaccination regimen, the study team noted.

“Evidence from this study will be useful for policymakers, national immunization advisory committees, and specialist societies formulating recommendations on the use of methotrexate around the time of COVID-19 vaccination. This evidence will help patients and clinicians make informed choices about the risks and benefits of interrupting methotrexate treatment around the time of COVID-19 vaccination, with implications for the potential to extend such approaches to other therapeutics,” they wrote.

In American College of Rheumatology (ACR) guidance for COVID-19 vaccination, the organization advised against using standard synthetic disease-modifying antirheumatic medicines such as methotrexate “for 1-2 weeks (as disease activity allows) after each COVID-19 vaccine dose,” given the at-risk population and public health concerns, Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine and associate physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, and Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School, noted in an accompanying editorial in The Lancet: Respiratory Medicine.

However, when the ACR developed this statement, there was only one trial involving patients with rheumatoid arthritis who paused methotrexate following seasonal influenza vaccination, the editorialists said.

Expert commentary

This current study is consistent with other studies over the last several months showing that methotrexate harms both humoral and cell-mediated COVID-19 responses, noted Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study. “And so now the new wave of studies are like this one, where they are holding methotrexate experimentally and seeing if it makes a difference,” he said.

“The one shortcoming of this study – and so far, the studies to date – is that no one has looked at whether the experimental hold has resulted in a change in T-cell responses, which ... we are [now] recognizing [the importance of] more and more in long-term protection, particularly in severe disease. Theoretically, holding [methotrexate] might help enhance T-cell responses, but that hasn’t been shown experimentally.”

Dr. Winthrop pointed out that one might get the same benefit from holding methotrexate for 1 week instead of 2 and that there likely is a reduced risk of flare-up from underlying autoimmune disease.

It is still not certain that this benefit extends to other vaccines, Dr. Winthrop noted. “It is probably true for most vaccines that if you hold methotrexate for 1 or 2 weeks, you might see some short-term benefit in responsiveness, but you don’t know that there is any clinical meaningfulness of this. That’s going to take other long-term studies. You don’t know how long this benefit lasts.”
 

Pausing methotrexate during initial COVID vaccine doses

Patients with either rheumatoid arthritis or psoriatic arthritis had higher anti-RBD antibody titers when methotrexate was stopped after both doses of the AstraZeneca vaccine, or simply after the second dose, than when methotrexate was continued, according to results from two single-center, randomized controlled trials called MIVAC I and II, Anu Sreekanth, MD, of Sree Sudheendra Medical Mission in Kochi, Kerala, India, and colleagues reported at EULAR 2022.

Results from MIVAC I indicated that there was a higher flare rate when methotrexate was stopped after both vaccine doses, but there was no difference in flare rate in MIVAC II when methotrexate was stopped only after the second dose as opposed to stopping it after both doses.

In the MIVAC I trial, 158 unvaccinated patients were randomized 1:1 to a cohort in which methotrexate was held for 2 weeks after both doses and a cohort in which methotrexate was continued despite the vaccine. In MIVAC II, 157 patients continued methotrexate while receiving the first vaccine dose. These patients were subsequently randomized either to continue or to stop methotrexate for 2 weeks following the second dose.

The findings from MIVAC I demonstrated the flare rate was lower in the methotrexate-continue group than in the methotrexate-pause group (8% vs. 25%; P = .005) and that the median anti-RBD titer was significantly higher for the methotrexate-pause group than the methotrexate-continue group (2,484 vs. 1,147; P = .001).

The results from MIVAC II trial indicated that there was no difference in flare rates between the two study groups (7.9% vs. 11.8%; P = .15). Yet, the median anti-RBD titer was significantly higher in the methotrexate-pause cohort than in the methotrexate-continue cohort (2,553 vs. 990; P = .001).

The report suggests there is a flare risk when methotrexate is stopped, Dr. Sreekanth noted. “It appears more logical to hold only after the second dose, as comparable anti-RBD titers are generated” with either approach, Dr. Sreekanth said.

Expert commentary: MIVAC I and II

Inés Colmegna, MD, associate professor at McGill University in Montreal, noted that it was intriguing that the risk of flares in MIVAC II is half of that reported after each of the doses of MIVAC I. “It is also worth emphasizing that despite the reported frequency of flares, the actual disease activity [as measured by the Disease Activity Score in 28 joints] in patients who did or did not withhold methotrexate was similar.

“MIVAC I and II have practical implications as they help to adequately inform patients about the risk and benefit trade of withholding methotrexate post–COVID-19 vaccination,” Dr. Colmegna told this news organization.

“Additional information would help to [further] interpret the findings of these studies, including whether any of the participants were taking any other DMARDs; data on the severity of the flares and functional impact; analysis of factors that predict the risk of flares, such as higher doses of methotrexate; [and change in] disease activity scores pre- and postvaccination,” Dr. Colmegna concluded.

Dr. Abhishek disclosed relationships with Springer, UpTodate, Oxford, Immunotec, AstraZeneca, Inflazome, NGM Biopharmaceuticals, Menarini Pharmaceuticals, and Cadila Pharmaceuticals. Dr. Abhishek is cochair of the ACR/EULAR CPPD Classification Criteria Working Group and the OMERACT CPPD Working Group. Dr. Sparks disclosed relationships with Gilead, Boehringer Ingelheim, Amgen, Bristol-Myers Squibb, and AbbVie, unrelated to this study. Dr. Tedeschi disclosed relationships with ModernaTx and NGM Biopharmaceuticals. Dr. Winthrop disclosed a research grant and serving as a scientific consultant for Pfizer. Dr. Sreekanth  and Dr. Colmegna have disclosed no relevant financial relationships.

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

Patients who take methotrexate for a variety of immune-mediated inflammatory diseases and pause taking the drug following receipt of a COVID-19 vaccine dose did not have a higher risk of disease flare and had higher antireceptor binding domain (anti-RBD) antibody titers and increased immunogenicity when compared with continuing the drug, three recent studies suggest.

In one study, British researchers examined the effects of a 2-week break in methotrexate therapy on anti-RBD titers following receipt of a third COVID-19 vaccine dose. In their paper published in The Lancet: Respiratory Medicine, they reported results from a randomized, open-label, superiority trial that suggested pausing the drug improved immunogenicity, compared with no break.

In two trials presented at the European Alliance of Associations for Rheumatology (EULAR) 2022 Congress, a team from India set out to determine whether holding methotrexate after receiving both doses of a COVID-19 vaccine, or holding it only after the second dose, was safe and effective. They found that pausing methotrexate only following the second dose contributed to a lower flare risk, and that patients had higher anti-RBD titers when holding methotrexate for 2 weeks following each dose.
 

Pausing methotrexate after booster

The 2-week methotrexate break and booster vaccine dose data in the Vaccine Response On Off Methotrexate (VROOM) trial showed that after a month, the geometric mean antispike 1 (S1)-RBD antibody titer was 10,798 U/mL (95% confidence interval [CI], 8,970-12,997) in the group that continued methotrexate and 22,750 U/mL (95% CI, 19,314-26,796) in the group that suspended methotrexate; the geometric mean ratio was 2.19 (P < .0001; mixed-effects model), reported Abhishek Abhishek, MD, PhD, professor of rheumatology at the University of Nottingham in Nottingham, England, and colleagues.

Prior research showed that stopping methotrexate therapy for 2 weeks following the seasonal influenza vaccine contributed to better vaccine immunity among patients with rheumatoid arthritis, but there was no impact of stopping the drug for up to 4 weeks before vaccination on vaccine-related immunity, the researchers noted.

It is crucial in maximizing long-lasting vaccine protection in people who are possibly susceptible through immune suppression at this point in the COVID-19 vaccination regimen, the study team noted.

“Evidence from this study will be useful for policymakers, national immunization advisory committees, and specialist societies formulating recommendations on the use of methotrexate around the time of COVID-19 vaccination. This evidence will help patients and clinicians make informed choices about the risks and benefits of interrupting methotrexate treatment around the time of COVID-19 vaccination, with implications for the potential to extend such approaches to other therapeutics,” they wrote.

In American College of Rheumatology (ACR) guidance for COVID-19 vaccination, the organization advised against using standard synthetic disease-modifying antirheumatic medicines such as methotrexate “for 1-2 weeks (as disease activity allows) after each COVID-19 vaccine dose,” given the at-risk population and public health concerns, Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine and associate physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, and Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School, noted in an accompanying editorial in The Lancet: Respiratory Medicine.

However, when the ACR developed this statement, there was only one trial involving patients with rheumatoid arthritis who paused methotrexate following seasonal influenza vaccination, the editorialists said.

Expert commentary

This current study is consistent with other studies over the last several months showing that methotrexate harms both humoral and cell-mediated COVID-19 responses, noted Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study. “And so now the new wave of studies are like this one, where they are holding methotrexate experimentally and seeing if it makes a difference,” he said.

“The one shortcoming of this study – and so far, the studies to date – is that no one has looked at whether the experimental hold has resulted in a change in T-cell responses, which ... we are [now] recognizing [the importance of] more and more in long-term protection, particularly in severe disease. Theoretically, holding [methotrexate] might help enhance T-cell responses, but that hasn’t been shown experimentally.”

Dr. Winthrop pointed out that one might get the same benefit from holding methotrexate for 1 week instead of 2 and that there likely is a reduced risk of flare-up from underlying autoimmune disease.

It is still not certain that this benefit extends to other vaccines, Dr. Winthrop noted. “It is probably true for most vaccines that if you hold methotrexate for 1 or 2 weeks, you might see some short-term benefit in responsiveness, but you don’t know that there is any clinical meaningfulness of this. That’s going to take other long-term studies. You don’t know how long this benefit lasts.”
 

Pausing methotrexate during initial COVID vaccine doses

Patients with either rheumatoid arthritis or psoriatic arthritis had higher anti-RBD antibody titers when methotrexate was stopped after both doses of the AstraZeneca vaccine, or simply after the second dose, than when methotrexate was continued, according to results from two single-center, randomized controlled trials called MIVAC I and II, Anu Sreekanth, MD, of Sree Sudheendra Medical Mission in Kochi, Kerala, India, and colleagues reported at EULAR 2022.

Results from MIVAC I indicated that there was a higher flare rate when methotrexate was stopped after both vaccine doses, but there was no difference in flare rate in MIVAC II when methotrexate was stopped only after the second dose as opposed to stopping it after both doses.

In the MIVAC I trial, 158 unvaccinated patients were randomized 1:1 to a cohort in which methotrexate was held for 2 weeks after both doses and a cohort in which methotrexate was continued despite the vaccine. In MIVAC II, 157 patients continued methotrexate while receiving the first vaccine dose. These patients were subsequently randomized either to continue or to stop methotrexate for 2 weeks following the second dose.

The findings from MIVAC I demonstrated the flare rate was lower in the methotrexate-continue group than in the methotrexate-pause group (8% vs. 25%; P = .005) and that the median anti-RBD titer was significantly higher for the methotrexate-pause group than the methotrexate-continue group (2,484 vs. 1,147; P = .001).

The results from MIVAC II trial indicated that there was no difference in flare rates between the two study groups (7.9% vs. 11.8%; P = .15). Yet, the median anti-RBD titer was significantly higher in the methotrexate-pause cohort than in the methotrexate-continue cohort (2,553 vs. 990; P = .001).

The report suggests there is a flare risk when methotrexate is stopped, Dr. Sreekanth noted. “It appears more logical to hold only after the second dose, as comparable anti-RBD titers are generated” with either approach, Dr. Sreekanth said.

Expert commentary: MIVAC I and II

Inés Colmegna, MD, associate professor at McGill University in Montreal, noted that it was intriguing that the risk of flares in MIVAC II is half of that reported after each of the doses of MIVAC I. “It is also worth emphasizing that despite the reported frequency of flares, the actual disease activity [as measured by the Disease Activity Score in 28 joints] in patients who did or did not withhold methotrexate was similar.

“MIVAC I and II have practical implications as they help to adequately inform patients about the risk and benefit trade of withholding methotrexate post–COVID-19 vaccination,” Dr. Colmegna told this news organization.

“Additional information would help to [further] interpret the findings of these studies, including whether any of the participants were taking any other DMARDs; data on the severity of the flares and functional impact; analysis of factors that predict the risk of flares, such as higher doses of methotrexate; [and change in] disease activity scores pre- and postvaccination,” Dr. Colmegna concluded.

Dr. Abhishek disclosed relationships with Springer, UpTodate, Oxford, Immunotec, AstraZeneca, Inflazome, NGM Biopharmaceuticals, Menarini Pharmaceuticals, and Cadila Pharmaceuticals. Dr. Abhishek is cochair of the ACR/EULAR CPPD Classification Criteria Working Group and the OMERACT CPPD Working Group. Dr. Sparks disclosed relationships with Gilead, Boehringer Ingelheim, Amgen, Bristol-Myers Squibb, and AbbVie, unrelated to this study. Dr. Tedeschi disclosed relationships with ModernaTx and NGM Biopharmaceuticals. Dr. Winthrop disclosed a research grant and serving as a scientific consultant for Pfizer. Dr. Sreekanth  and Dr. Colmegna have disclosed no relevant financial relationships.

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

Patients who take methotrexate for a variety of immune-mediated inflammatory diseases and pause taking the drug following receipt of a COVID-19 vaccine dose did not have a higher risk of disease flare and had higher antireceptor binding domain (anti-RBD) antibody titers and increased immunogenicity when compared with continuing the drug, three recent studies suggest.

In one study, British researchers examined the effects of a 2-week break in methotrexate therapy on anti-RBD titers following receipt of a third COVID-19 vaccine dose. In their paper published in The Lancet: Respiratory Medicine, they reported results from a randomized, open-label, superiority trial that suggested pausing the drug improved immunogenicity, compared with no break.

In two trials presented at the European Alliance of Associations for Rheumatology (EULAR) 2022 Congress, a team from India set out to determine whether holding methotrexate after receiving both doses of a COVID-19 vaccine, or holding it only after the second dose, was safe and effective. They found that pausing methotrexate only following the second dose contributed to a lower flare risk, and that patients had higher anti-RBD titers when holding methotrexate for 2 weeks following each dose.
 

Pausing methotrexate after booster

The 2-week methotrexate break and booster vaccine dose data in the Vaccine Response On Off Methotrexate (VROOM) trial showed that after a month, the geometric mean antispike 1 (S1)-RBD antibody titer was 10,798 U/mL (95% confidence interval [CI], 8,970-12,997) in the group that continued methotrexate and 22,750 U/mL (95% CI, 19,314-26,796) in the group that suspended methotrexate; the geometric mean ratio was 2.19 (P < .0001; mixed-effects model), reported Abhishek Abhishek, MD, PhD, professor of rheumatology at the University of Nottingham in Nottingham, England, and colleagues.

Prior research showed that stopping methotrexate therapy for 2 weeks following the seasonal influenza vaccine contributed to better vaccine immunity among patients with rheumatoid arthritis, but there was no impact of stopping the drug for up to 4 weeks before vaccination on vaccine-related immunity, the researchers noted.

It is crucial in maximizing long-lasting vaccine protection in people who are possibly susceptible through immune suppression at this point in the COVID-19 vaccination regimen, the study team noted.

“Evidence from this study will be useful for policymakers, national immunization advisory committees, and specialist societies formulating recommendations on the use of methotrexate around the time of COVID-19 vaccination. This evidence will help patients and clinicians make informed choices about the risks and benefits of interrupting methotrexate treatment around the time of COVID-19 vaccination, with implications for the potential to extend such approaches to other therapeutics,” they wrote.

In American College of Rheumatology (ACR) guidance for COVID-19 vaccination, the organization advised against using standard synthetic disease-modifying antirheumatic medicines such as methotrexate “for 1-2 weeks (as disease activity allows) after each COVID-19 vaccine dose,” given the at-risk population and public health concerns, Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine and associate physician at Brigham and Women’s Hospital and Harvard Medical School, Boston, and Sara K. Tedeschi, MD, MPH, assistant professor of medicine at Harvard Medical School, noted in an accompanying editorial in The Lancet: Respiratory Medicine.

However, when the ACR developed this statement, there was only one trial involving patients with rheumatoid arthritis who paused methotrexate following seasonal influenza vaccination, the editorialists said.

Expert commentary

This current study is consistent with other studies over the last several months showing that methotrexate harms both humoral and cell-mediated COVID-19 responses, noted Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study. “And so now the new wave of studies are like this one, where they are holding methotrexate experimentally and seeing if it makes a difference,” he said.

“The one shortcoming of this study – and so far, the studies to date – is that no one has looked at whether the experimental hold has resulted in a change in T-cell responses, which ... we are [now] recognizing [the importance of] more and more in long-term protection, particularly in severe disease. Theoretically, holding [methotrexate] might help enhance T-cell responses, but that hasn’t been shown experimentally.”

Dr. Winthrop pointed out that one might get the same benefit from holding methotrexate for 1 week instead of 2 and that there likely is a reduced risk of flare-up from underlying autoimmune disease.

It is still not certain that this benefit extends to other vaccines, Dr. Winthrop noted. “It is probably true for most vaccines that if you hold methotrexate for 1 or 2 weeks, you might see some short-term benefit in responsiveness, but you don’t know that there is any clinical meaningfulness of this. That’s going to take other long-term studies. You don’t know how long this benefit lasts.”
 

Pausing methotrexate during initial COVID vaccine doses

Patients with either rheumatoid arthritis or psoriatic arthritis had higher anti-RBD antibody titers when methotrexate was stopped after both doses of the AstraZeneca vaccine, or simply after the second dose, than when methotrexate was continued, according to results from two single-center, randomized controlled trials called MIVAC I and II, Anu Sreekanth, MD, of Sree Sudheendra Medical Mission in Kochi, Kerala, India, and colleagues reported at EULAR 2022.

Results from MIVAC I indicated that there was a higher flare rate when methotrexate was stopped after both vaccine doses, but there was no difference in flare rate in MIVAC II when methotrexate was stopped only after the second dose as opposed to stopping it after both doses.

In the MIVAC I trial, 158 unvaccinated patients were randomized 1:1 to a cohort in which methotrexate was held for 2 weeks after both doses and a cohort in which methotrexate was continued despite the vaccine. In MIVAC II, 157 patients continued methotrexate while receiving the first vaccine dose. These patients were subsequently randomized either to continue or to stop methotrexate for 2 weeks following the second dose.

The findings from MIVAC I demonstrated the flare rate was lower in the methotrexate-continue group than in the methotrexate-pause group (8% vs. 25%; P = .005) and that the median anti-RBD titer was significantly higher for the methotrexate-pause group than the methotrexate-continue group (2,484 vs. 1,147; P = .001).

The results from MIVAC II trial indicated that there was no difference in flare rates between the two study groups (7.9% vs. 11.8%; P = .15). Yet, the median anti-RBD titer was significantly higher in the methotrexate-pause cohort than in the methotrexate-continue cohort (2,553 vs. 990; P = .001).

The report suggests there is a flare risk when methotrexate is stopped, Dr. Sreekanth noted. “It appears more logical to hold only after the second dose, as comparable anti-RBD titers are generated” with either approach, Dr. Sreekanth said.

Expert commentary: MIVAC I and II

Inés Colmegna, MD, associate professor at McGill University in Montreal, noted that it was intriguing that the risk of flares in MIVAC II is half of that reported after each of the doses of MIVAC I. “It is also worth emphasizing that despite the reported frequency of flares, the actual disease activity [as measured by the Disease Activity Score in 28 joints] in patients who did or did not withhold methotrexate was similar.

“MIVAC I and II have practical implications as they help to adequately inform patients about the risk and benefit trade of withholding methotrexate post–COVID-19 vaccination,” Dr. Colmegna told this news organization.

“Additional information would help to [further] interpret the findings of these studies, including whether any of the participants were taking any other DMARDs; data on the severity of the flares and functional impact; analysis of factors that predict the risk of flares, such as higher doses of methotrexate; [and change in] disease activity scores pre- and postvaccination,” Dr. Colmegna concluded.

Dr. Abhishek disclosed relationships with Springer, UpTodate, Oxford, Immunotec, AstraZeneca, Inflazome, NGM Biopharmaceuticals, Menarini Pharmaceuticals, and Cadila Pharmaceuticals. Dr. Abhishek is cochair of the ACR/EULAR CPPD Classification Criteria Working Group and the OMERACT CPPD Working Group. Dr. Sparks disclosed relationships with Gilead, Boehringer Ingelheim, Amgen, Bristol-Myers Squibb, and AbbVie, unrelated to this study. Dr. Tedeschi disclosed relationships with ModernaTx and NGM Biopharmaceuticals. Dr. Winthrop disclosed a research grant and serving as a scientific consultant for Pfizer. Dr. Sreekanth  and Dr. Colmegna have disclosed no relevant financial relationships.

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

INDIANAPOLIS – In the opinion of Elena Pope, MD, MSc, it’s time to think of morphea in children as a systemic, chronic condition with associated extracutaneous manifestations and the potential for relapse.

“There is no correlation between the extent and activity of skin lesions and the presence, severity, and activity of extracutaneous manifestations,” Dr. Pope, professor of pediatrics at the University of Toronto and division head of pediatric dermatology at the Hospital for Sick Children in Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “Treatment needs to be tailored to the extent of cutaneous manifestations, and I think we need to be aware of and address the impact on patients’ quality of life,” she added. There is also a need for more research “on targeted and better-tolerated therapies to put a stop to the progression of disease.”

Congenital morphea is a form of localized scleroderma that presents at birth but can be confused with port wine stain. Results from a multicenter retrospective review of 25 cases conducted by Dr. Pope and colleagues found that the median age at diagnosis was 2.9 years and 76% had linear-type lesions. In addition, 48% had extracutaneous involvement (all of these patients had linear morphea), most commonly of the central nervous system.

“It’s important to realize these lesions may become active over time,” Dr. Pope said. “In my experience, there are two different courses. Either you have innocuous lesions when the patients are born and they may become active around 3-4 years of age, or you have early intrauterine involvement, with lesions inactive at birth but with potential for significant damage in utero.”

She cautioned against treating a suspected port wine stain lesion with laser until congenital morphea is ruled out. “I’m aware of at least one lawsuit of a child where someone used a laser in a child who had progression with significant sclerosis,” she said. “The parents assumed it was the use of the laser that led to the progression, not the actual disease.”

Extracutaneous manifestations are common in morphea patients. A multicenter study of 750 patients with juvenile scleroderma found that 22% had extracutaneous manifestations. Almost half of patients (47%) had arthritis, but 17% had neurologic findings such as seizures and headaches, 9% had vascular manifestations, and 8% had uveitis. Subsequent studies found that neurological disease affects between 11% and 19% of cases, especially in those involving the head and neck.

“There is a wide range of manifestations from headache and neuropsychiatric changes to brain atrophy, seizures, and CNS cavernoma,” Dr. Pope said. “There also can be orthodental involvement such as malocclusion. It’s important to do a brain MRI, eye exam for uveitis, and don’t forget the orthodental assessment.”

She recalled a 10-year-old boy who presented to the Hospital for Sick Children with tissue loss on the forehead and eyebrow and eyelashes. He had no other congenital morphea symptoms and the MRI was normal, but the eye exam revealed uveitis. “It’s important to remember that uveitis is asymptomatic, so unless you look for it, you’re not going to find it,” she said.

According to unpublished data in 42 congenital morphea patients with lesions limited to the head and neck, who underwent MRI imaging at the Hospital for Sick Children, 57% had CNS changes that were ipsilateral in 68% of cases. “White matter changes were the most common, and to our surprise, there were patients who had progressive CNS disease, including CNS vasculitis, new lesions, and enhancement of prior stable lesions,” Dr. Pope said.

She recalled the case of an 8-year-old boy who presented to the hospital with intractable seizures. Upon completion of the MRI, one of the radiologists noted that the imaging showed subtle thinning of the forehead, and he was referred to Dr. Pope and colleagues for assessment. In the span of 4 years, despite aggressive treatment, the boy’s CNS disease progressed. “There was more enhancement, more tissue loss, his seizures are very hard to control, and he has many neurodevelopmental changes,” she recalled. “What I learned from this case is that skin activity does not correlate with imaging. Don’t assume that just because the skin is burnt out that the CNS will be the same. Also, the extent of skin disease does not predict involvement or progression of the CNS.”

Linear lesions on the lower extremities are a harbinger of orthopedic complications, which can occur in about half of patients. Joint contractures in this subset of patients are seen in about 81% of cases, while other sequelae can include arthritis, limb atrophy, leg-leg discrepancy, and angular deformity. “About 14% of patients require intervention,” Dr. Pope said. “In terms of working those patients up, you need to do an MRI and assess the extent of muscle and fascial involvement. Early physiotherapy and an orthopedic evaluation are also recommended.”

As for possible markers of morphea, antinuclear antibody is positive in 22%-68% of cases and correlates with disease severity, extracutaneous manifestations, and disease flare-up. Antihistone antibodies (AHA) are positive in about 47% of cases, “and that tends to correlate with the extent of skin and muscle involvement,” Dr. Pope said. “Anti–double-stranded DNA correlates with extent of disease, but the only known biomarker to date that correlates with disease activity is CXCL9/10. This has been documented in the skin as well as in the blood. So, this marker may help us determine if the patient needs to be treated or not.”



Treatments

For treatment of active localized disease, topical medications are helpful in some cases. Options include topical steroids, calcipotriol with or without betamethasone, imiquimod, and tacrolimus. “In my experience the combination of calcipotriol with betamethasone is best,” she said. “It really shuts down the activity fairly soon, and you can scale down to calcipotriol alone. I don’t find imiquimod very helpful for active lesions, although it has a role for inactive lesions.”

For patients with linear or generalized/mixed disease, “the combination of methotrexate and corticosteroids or methotrexate alone is probably the way to go,” Dr. Pope said. “The addition of steroids really depends on where the lesion is and how worried you are about other problems.”

According to the best available literature, 88% of patients should respond to treatment with methotrexate (MTX) and/or steroids within 3-6 months, and 74% within 3 months. “If they don’t, you have to wonder if the patient’s taking the medication, or you need to think about other alternative treatments,” she said. “Complete remission is possible in most of the patients, and the longer you treat the more you will see that. On average, most of us treat patients for about 3 years, but there are treatment failures as well. This can occur in up to 16% of patients.”

As for second-line treatment agents for congenital morphea, clinicians often turn to mycophenolate mofetil (MMF). Results from a retrospective longitudinal study of juvenile localized scleroderma patients found that after a mean of 9 years 91% of patients on MMF and 100% of patients on MTX had inactive disease. “There were no differences in relapse rates, although MMF seems to have a more sustained long-term effect and overall is better tolerated,” said Dr. Pope, who was not involved with the study. “However, it’s more immunosuppressive than MTX, which is important, especially in the era of COVID-19. You also need to think about the potential for more hematological suppression with MMF use.” If standard therapy fails, there is anecdotal data supporting the use of abatacept (which suppresses the T-cell activity in affected patients), tofacitinib (which inhibits transforming growth factor–beta), or dupilumab (which inhibits interleukin-4).

Dr. Pope emphasized the effect congenital morphea has on quality of life. Remarks from patients with facial morphea and their parents who participated in a focus group on the topic organized by the Hospital for Sick Children included, “You just want to stay inside because you are afraid of what people will say,” “They laugh at her. They make fun of her, and it’s terrible,” and “MTX makes me feel weird. I would throw up, feel dizzy.”

“You have to take that into consideration, because we cannot make the treatment worse than the disease,” Dr. Pope said. “There are many domains where patients could be affected, including skin symptoms, physical functioning, body image and social support, side effects of medication, and presence of extracutaneous manifestations. Predictors of poor quality of life include female sex and involvement of hands and feet.”

Dr. Pope disclosed that she has received grants/research support from AbbVie, Centocor, and Amgen. She has also received consulting fees from AbbVie, Sanofi, Novartis, Boehringer-Ingelheim, Phoenix, Amryt Pharma, and Timber Pharmaceuticals.

INDIANAPOLIS – In the opinion of Elena Pope, MD, MSc, it’s time to think of morphea in children as a systemic, chronic condition with associated extracutaneous manifestations and the potential for relapse.

“There is no correlation between the extent and activity of skin lesions and the presence, severity, and activity of extracutaneous manifestations,” Dr. Pope, professor of pediatrics at the University of Toronto and division head of pediatric dermatology at the Hospital for Sick Children in Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “Treatment needs to be tailored to the extent of cutaneous manifestations, and I think we need to be aware of and address the impact on patients’ quality of life,” she added. There is also a need for more research “on targeted and better-tolerated therapies to put a stop to the progression of disease.”

Congenital morphea is a form of localized scleroderma that presents at birth but can be confused with port wine stain. Results from a multicenter retrospective review of 25 cases conducted by Dr. Pope and colleagues found that the median age at diagnosis was 2.9 years and 76% had linear-type lesions. In addition, 48% had extracutaneous involvement (all of these patients had linear morphea), most commonly of the central nervous system.

“It’s important to realize these lesions may become active over time,” Dr. Pope said. “In my experience, there are two different courses. Either you have innocuous lesions when the patients are born and they may become active around 3-4 years of age, or you have early intrauterine involvement, with lesions inactive at birth but with potential for significant damage in utero.”

She cautioned against treating a suspected port wine stain lesion with laser until congenital morphea is ruled out. “I’m aware of at least one lawsuit of a child where someone used a laser in a child who had progression with significant sclerosis,” she said. “The parents assumed it was the use of the laser that led to the progression, not the actual disease.”

Extracutaneous manifestations are common in morphea patients. A multicenter study of 750 patients with juvenile scleroderma found that 22% had extracutaneous manifestations. Almost half of patients (47%) had arthritis, but 17% had neurologic findings such as seizures and headaches, 9% had vascular manifestations, and 8% had uveitis. Subsequent studies found that neurological disease affects between 11% and 19% of cases, especially in those involving the head and neck.

“There is a wide range of manifestations from headache and neuropsychiatric changes to brain atrophy, seizures, and CNS cavernoma,” Dr. Pope said. “There also can be orthodental involvement such as malocclusion. It’s important to do a brain MRI, eye exam for uveitis, and don’t forget the orthodental assessment.”

She recalled a 10-year-old boy who presented to the Hospital for Sick Children with tissue loss on the forehead and eyebrow and eyelashes. He had no other congenital morphea symptoms and the MRI was normal, but the eye exam revealed uveitis. “It’s important to remember that uveitis is asymptomatic, so unless you look for it, you’re not going to find it,” she said.

According to unpublished data in 42 congenital morphea patients with lesions limited to the head and neck, who underwent MRI imaging at the Hospital for Sick Children, 57% had CNS changes that were ipsilateral in 68% of cases. “White matter changes were the most common, and to our surprise, there were patients who had progressive CNS disease, including CNS vasculitis, new lesions, and enhancement of prior stable lesions,” Dr. Pope said.

She recalled the case of an 8-year-old boy who presented to the hospital with intractable seizures. Upon completion of the MRI, one of the radiologists noted that the imaging showed subtle thinning of the forehead, and he was referred to Dr. Pope and colleagues for assessment. In the span of 4 years, despite aggressive treatment, the boy’s CNS disease progressed. “There was more enhancement, more tissue loss, his seizures are very hard to control, and he has many neurodevelopmental changes,” she recalled. “What I learned from this case is that skin activity does not correlate with imaging. Don’t assume that just because the skin is burnt out that the CNS will be the same. Also, the extent of skin disease does not predict involvement or progression of the CNS.”

Linear lesions on the lower extremities are a harbinger of orthopedic complications, which can occur in about half of patients. Joint contractures in this subset of patients are seen in about 81% of cases, while other sequelae can include arthritis, limb atrophy, leg-leg discrepancy, and angular deformity. “About 14% of patients require intervention,” Dr. Pope said. “In terms of working those patients up, you need to do an MRI and assess the extent of muscle and fascial involvement. Early physiotherapy and an orthopedic evaluation are also recommended.”

As for possible markers of morphea, antinuclear antibody is positive in 22%-68% of cases and correlates with disease severity, extracutaneous manifestations, and disease flare-up. Antihistone antibodies (AHA) are positive in about 47% of cases, “and that tends to correlate with the extent of skin and muscle involvement,” Dr. Pope said. “Anti–double-stranded DNA correlates with extent of disease, but the only known biomarker to date that correlates with disease activity is CXCL9/10. This has been documented in the skin as well as in the blood. So, this marker may help us determine if the patient needs to be treated or not.”



Treatments

For treatment of active localized disease, topical medications are helpful in some cases. Options include topical steroids, calcipotriol with or without betamethasone, imiquimod, and tacrolimus. “In my experience the combination of calcipotriol with betamethasone is best,” she said. “It really shuts down the activity fairly soon, and you can scale down to calcipotriol alone. I don’t find imiquimod very helpful for active lesions, although it has a role for inactive lesions.”

For patients with linear or generalized/mixed disease, “the combination of methotrexate and corticosteroids or methotrexate alone is probably the way to go,” Dr. Pope said. “The addition of steroids really depends on where the lesion is and how worried you are about other problems.”

According to the best available literature, 88% of patients should respond to treatment with methotrexate (MTX) and/or steroids within 3-6 months, and 74% within 3 months. “If they don’t, you have to wonder if the patient’s taking the medication, or you need to think about other alternative treatments,” she said. “Complete remission is possible in most of the patients, and the longer you treat the more you will see that. On average, most of us treat patients for about 3 years, but there are treatment failures as well. This can occur in up to 16% of patients.”

As for second-line treatment agents for congenital morphea, clinicians often turn to mycophenolate mofetil (MMF). Results from a retrospective longitudinal study of juvenile localized scleroderma patients found that after a mean of 9 years 91% of patients on MMF and 100% of patients on MTX had inactive disease. “There were no differences in relapse rates, although MMF seems to have a more sustained long-term effect and overall is better tolerated,” said Dr. Pope, who was not involved with the study. “However, it’s more immunosuppressive than MTX, which is important, especially in the era of COVID-19. You also need to think about the potential for more hematological suppression with MMF use.” If standard therapy fails, there is anecdotal data supporting the use of abatacept (which suppresses the T-cell activity in affected patients), tofacitinib (which inhibits transforming growth factor–beta), or dupilumab (which inhibits interleukin-4).

Dr. Pope emphasized the effect congenital morphea has on quality of life. Remarks from patients with facial morphea and their parents who participated in a focus group on the topic organized by the Hospital for Sick Children included, “You just want to stay inside because you are afraid of what people will say,” “They laugh at her. They make fun of her, and it’s terrible,” and “MTX makes me feel weird. I would throw up, feel dizzy.”

“You have to take that into consideration, because we cannot make the treatment worse than the disease,” Dr. Pope said. “There are many domains where patients could be affected, including skin symptoms, physical functioning, body image and social support, side effects of medication, and presence of extracutaneous manifestations. Predictors of poor quality of life include female sex and involvement of hands and feet.”

Dr. Pope disclosed that she has received grants/research support from AbbVie, Centocor, and Amgen. She has also received consulting fees from AbbVie, Sanofi, Novartis, Boehringer-Ingelheim, Phoenix, Amryt Pharma, and Timber Pharmaceuticals.

INDIANAPOLIS – In the opinion of Elena Pope, MD, MSc, it’s time to think of morphea in children as a systemic, chronic condition with associated extracutaneous manifestations and the potential for relapse.

“There is no correlation between the extent and activity of skin lesions and the presence, severity, and activity of extracutaneous manifestations,” Dr. Pope, professor of pediatrics at the University of Toronto and division head of pediatric dermatology at the Hospital for Sick Children in Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “Treatment needs to be tailored to the extent of cutaneous manifestations, and I think we need to be aware of and address the impact on patients’ quality of life,” she added. There is also a need for more research “on targeted and better-tolerated therapies to put a stop to the progression of disease.”

Congenital morphea is a form of localized scleroderma that presents at birth but can be confused with port wine stain. Results from a multicenter retrospective review of 25 cases conducted by Dr. Pope and colleagues found that the median age at diagnosis was 2.9 years and 76% had linear-type lesions. In addition, 48% had extracutaneous involvement (all of these patients had linear morphea), most commonly of the central nervous system.

“It’s important to realize these lesions may become active over time,” Dr. Pope said. “In my experience, there are two different courses. Either you have innocuous lesions when the patients are born and they may become active around 3-4 years of age, or you have early intrauterine involvement, with lesions inactive at birth but with potential for significant damage in utero.”

She cautioned against treating a suspected port wine stain lesion with laser until congenital morphea is ruled out. “I’m aware of at least one lawsuit of a child where someone used a laser in a child who had progression with significant sclerosis,” she said. “The parents assumed it was the use of the laser that led to the progression, not the actual disease.”

Extracutaneous manifestations are common in morphea patients. A multicenter study of 750 patients with juvenile scleroderma found that 22% had extracutaneous manifestations. Almost half of patients (47%) had arthritis, but 17% had neurologic findings such as seizures and headaches, 9% had vascular manifestations, and 8% had uveitis. Subsequent studies found that neurological disease affects between 11% and 19% of cases, especially in those involving the head and neck.

“There is a wide range of manifestations from headache and neuropsychiatric changes to brain atrophy, seizures, and CNS cavernoma,” Dr. Pope said. “There also can be orthodental involvement such as malocclusion. It’s important to do a brain MRI, eye exam for uveitis, and don’t forget the orthodental assessment.”

She recalled a 10-year-old boy who presented to the Hospital for Sick Children with tissue loss on the forehead and eyebrow and eyelashes. He had no other congenital morphea symptoms and the MRI was normal, but the eye exam revealed uveitis. “It’s important to remember that uveitis is asymptomatic, so unless you look for it, you’re not going to find it,” she said.

According to unpublished data in 42 congenital morphea patients with lesions limited to the head and neck, who underwent MRI imaging at the Hospital for Sick Children, 57% had CNS changes that were ipsilateral in 68% of cases. “White matter changes were the most common, and to our surprise, there were patients who had progressive CNS disease, including CNS vasculitis, new lesions, and enhancement of prior stable lesions,” Dr. Pope said.

She recalled the case of an 8-year-old boy who presented to the hospital with intractable seizures. Upon completion of the MRI, one of the radiologists noted that the imaging showed subtle thinning of the forehead, and he was referred to Dr. Pope and colleagues for assessment. In the span of 4 years, despite aggressive treatment, the boy’s CNS disease progressed. “There was more enhancement, more tissue loss, his seizures are very hard to control, and he has many neurodevelopmental changes,” she recalled. “What I learned from this case is that skin activity does not correlate with imaging. Don’t assume that just because the skin is burnt out that the CNS will be the same. Also, the extent of skin disease does not predict involvement or progression of the CNS.”

Linear lesions on the lower extremities are a harbinger of orthopedic complications, which can occur in about half of patients. Joint contractures in this subset of patients are seen in about 81% of cases, while other sequelae can include arthritis, limb atrophy, leg-leg discrepancy, and angular deformity. “About 14% of patients require intervention,” Dr. Pope said. “In terms of working those patients up, you need to do an MRI and assess the extent of muscle and fascial involvement. Early physiotherapy and an orthopedic evaluation are also recommended.”

As for possible markers of morphea, antinuclear antibody is positive in 22%-68% of cases and correlates with disease severity, extracutaneous manifestations, and disease flare-up. Antihistone antibodies (AHA) are positive in about 47% of cases, “and that tends to correlate with the extent of skin and muscle involvement,” Dr. Pope said. “Anti–double-stranded DNA correlates with extent of disease, but the only known biomarker to date that correlates with disease activity is CXCL9/10. This has been documented in the skin as well as in the blood. So, this marker may help us determine if the patient needs to be treated or not.”



Treatments

For treatment of active localized disease, topical medications are helpful in some cases. Options include topical steroids, calcipotriol with or without betamethasone, imiquimod, and tacrolimus. “In my experience the combination of calcipotriol with betamethasone is best,” she said. “It really shuts down the activity fairly soon, and you can scale down to calcipotriol alone. I don’t find imiquimod very helpful for active lesions, although it has a role for inactive lesions.”

For patients with linear or generalized/mixed disease, “the combination of methotrexate and corticosteroids or methotrexate alone is probably the way to go,” Dr. Pope said. “The addition of steroids really depends on where the lesion is and how worried you are about other problems.”

According to the best available literature, 88% of patients should respond to treatment with methotrexate (MTX) and/or steroids within 3-6 months, and 74% within 3 months. “If they don’t, you have to wonder if the patient’s taking the medication, or you need to think about other alternative treatments,” she said. “Complete remission is possible in most of the patients, and the longer you treat the more you will see that. On average, most of us treat patients for about 3 years, but there are treatment failures as well. This can occur in up to 16% of patients.”

As for second-line treatment agents for congenital morphea, clinicians often turn to mycophenolate mofetil (MMF). Results from a retrospective longitudinal study of juvenile localized scleroderma patients found that after a mean of 9 years 91% of patients on MMF and 100% of patients on MTX had inactive disease. “There were no differences in relapse rates, although MMF seems to have a more sustained long-term effect and overall is better tolerated,” said Dr. Pope, who was not involved with the study. “However, it’s more immunosuppressive than MTX, which is important, especially in the era of COVID-19. You also need to think about the potential for more hematological suppression with MMF use.” If standard therapy fails, there is anecdotal data supporting the use of abatacept (which suppresses the T-cell activity in affected patients), tofacitinib (which inhibits transforming growth factor–beta), or dupilumab (which inhibits interleukin-4).

Dr. Pope emphasized the effect congenital morphea has on quality of life. Remarks from patients with facial morphea and their parents who participated in a focus group on the topic organized by the Hospital for Sick Children included, “You just want to stay inside because you are afraid of what people will say,” “They laugh at her. They make fun of her, and it’s terrible,” and “MTX makes me feel weird. I would throw up, feel dizzy.”

“You have to take that into consideration, because we cannot make the treatment worse than the disease,” Dr. Pope said. “There are many domains where patients could be affected, including skin symptoms, physical functioning, body image and social support, side effects of medication, and presence of extracutaneous manifestations. Predictors of poor quality of life include female sex and involvement of hands and feet.”

Dr. Pope disclosed that she has received grants/research support from AbbVie, Centocor, and Amgen. She has also received consulting fees from AbbVie, Sanofi, Novartis, Boehringer-Ingelheim, Phoenix, Amryt Pharma, and Timber Pharmaceuticals.

The Diagnosis: Cutaneous Blastomycosis

A skin biopsy and fungal cultures confirmed the diagnosis of cutaneous blastomycosis. Grocott- Gomori methenamine-silver staining highlighted fungal organisms with refractile walls and broad-based budding consistent with cutaneous blastomycosis (Figure 1). The histopathologic specimen also demonstrated marked pseudoepitheliomatous hyperplasia (Figure 2A) with neutrophilic microabscesses (Figure 2B). Acid-fast bacillus and Fite staining were negative for bacterial organisms. A fungal culture was positive for Blastomyces dermatitidis. Urine and serum blastomycosis antigen were positive. Although Histoplasma serum antigen also was positive, this likely was from cross-reactivity. Chest radiography was negative for lung involvement, and the patient displayed no neurologic symptoms. He was started on oral itraconazole therapy for the treatment of cutaneous blastomycosis.

Blastomyces dermatitidis, the causative organism of blastomycosis, is endemic to the Ohio and Mississippi River valleys, Great Lakes region, and southeastern United States. It is a thermally dimorphic fungus found in soils that grows as a mold at 25 °C and yeast at 37 °C. Primary infection of the lungs—blastomycosis pneumonia—often is the only clinical manifestation¹; however, subsequent hematogenous dissemination to extrapulmonary sites such as the skin, bones, and genitourinary system can occur. Cutaneous blastomycosis, the most common extrapulmonary manifestation, typically follows pulmonary infection. In rare cases, it can occur from direct inoculation.^2,3 Skin lesions can occur anywhere but frequently are found on exposed surfaces of the head, neck, and extremities. Lesions classically present as verrucous crusting plaques with draining microabscesses. Violaceous nodules, ulcers, and pustules also may occur.¹

Diagnosis involves obtaining a thorough history of possible environmental exposures such as the patient’s geographic area of residence, occupation, and outdoor activities involving soil or decaying wood. Because blastomycosis can remain latent, remote exposures are relevant. Definitive diagnosis of cutaneous blastomycosis involves skin biopsy of the lesion with fungal culture, but the yeast’s distinctive thick wall and broad-based budding seen with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining provides a rapid presumptive diagnosis.³ Pseudoepitheliomatous hyperplasia and microabscesses also are characteristic features.² Urine antigen testing for a component of the polysaccharide cell wall has a sensitivity of 93% but a lower specificity of 79% due to cross-reactivity with histoplasmosis.⁴ Treatment consists of itraconazole for mild to moderate blastomycosis or amphotericin B for those with severe disease or central nervous system involvement or those who are immunosuppressed.¹

The differential diagnosis for our patient’s lesion included infectious vs neoplastic etiologies. Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, also is endemic to the Ohio and Mississippi River valleys. It is found in soil and droppings of some bats and birds such as chickens and pigeons. Similar to blastomycosis, the primary infection site most commonly is the lungs. It subsequently may disseminate to the skin or less commonly via direct inoculation of injured skin. It can present as papules, plaques, ulcers, purpura, or abscesses. Unlike blastomycosis, tissue biopsy of a cutaneous lesion reveals granuloma formation and distinctive oval, narrow-based budding yeast.⁵ Atypical mycobacteria are another source of infection to consider. For example, cutaneous Mycobacterium kansasii may present as papules and pustules forming verrucous or granulomatous plaques and ulceration. Histopathologic findings distinguishing mycobacterial infection from blastomycosis include granulomas and acid-fast bacilli in histiocytes.⁶

Noninfectious etiologies in the differential may include cutaneous squamous cell carcinoma or pemphigus vegetans. Squamous cell carcinoma may present with a broad range of clinical features—papules, plaques, or nodules with smooth, scaly, verrucous, or ulcerative secondary features all are possible presentations.⁷ Fairskinned individuals, such as our patient, would be at a higher risk in sun-damaged skin. Histologically, cutaneous squamous cell carcinoma is defined as an invasion of the dermis by neoplastic squamous epithelial cells in the form of cords, sheets, individual cells, nodules, or cystic structures.⁷ Pemphigus vegetans is the rarest variant of a group of autoimmune vesiculobullous diseases known as pemphigus. It can be differentiated from the most common variant—pemphigus vulgaris—by the presence of vegetative plaques in intertriginous areas. However, these verrucous vegetations can be misleading and make clinical diagnosis difficult. Histopathologic findings of hyperkeratosis, pseudoepitheliomatous hyperplasia, papillomatosis, and acantholysis with a suprabasal cleft would confirm the diagnosis.⁸

In summary, cutaneous blastomycosis classically presents as verrucous crusting plaques, as seen in our patient. It is important to conduct a thorough history for environmental exposures, but definitive diagnosis of cutaneous blastomycosis involves skin biopsy with fungal culture. Treatment depends on the severity of disease and organ involvement. Itraconazole would be appropriate for mild to moderate blastomycosis.

The Diagnosis: Cutaneous Blastomycosis

A skin biopsy and fungal cultures confirmed the diagnosis of cutaneous blastomycosis. Grocott- Gomori methenamine-silver staining highlighted fungal organisms with refractile walls and broad-based budding consistent with cutaneous blastomycosis (Figure 1). The histopathologic specimen also demonstrated marked pseudoepitheliomatous hyperplasia (Figure 2A) with neutrophilic microabscesses (Figure 2B). Acid-fast bacillus and Fite staining were negative for bacterial organisms. A fungal culture was positive for Blastomyces dermatitidis. Urine and serum blastomycosis antigen were positive. Although Histoplasma serum antigen also was positive, this likely was from cross-reactivity. Chest radiography was negative for lung involvement, and the patient displayed no neurologic symptoms. He was started on oral itraconazole therapy for the treatment of cutaneous blastomycosis.

Blastomyces dermatitidis, the causative organism of blastomycosis, is endemic to the Ohio and Mississippi River valleys, Great Lakes region, and southeastern United States. It is a thermally dimorphic fungus found in soils that grows as a mold at 25 °C and yeast at 37 °C. Primary infection of the lungs—blastomycosis pneumonia—often is the only clinical manifestation¹; however, subsequent hematogenous dissemination to extrapulmonary sites such as the skin, bones, and genitourinary system can occur. Cutaneous blastomycosis, the most common extrapulmonary manifestation, typically follows pulmonary infection. In rare cases, it can occur from direct inoculation.^2,3 Skin lesions can occur anywhere but frequently are found on exposed surfaces of the head, neck, and extremities. Lesions classically present as verrucous crusting plaques with draining microabscesses. Violaceous nodules, ulcers, and pustules also may occur.¹

Diagnosis involves obtaining a thorough history of possible environmental exposures such as the patient’s geographic area of residence, occupation, and outdoor activities involving soil or decaying wood. Because blastomycosis can remain latent, remote exposures are relevant. Definitive diagnosis of cutaneous blastomycosis involves skin biopsy of the lesion with fungal culture, but the yeast’s distinctive thick wall and broad-based budding seen with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining provides a rapid presumptive diagnosis.³ Pseudoepitheliomatous hyperplasia and microabscesses also are characteristic features.² Urine antigen testing for a component of the polysaccharide cell wall has a sensitivity of 93% but a lower specificity of 79% due to cross-reactivity with histoplasmosis.⁴ Treatment consists of itraconazole for mild to moderate blastomycosis or amphotericin B for those with severe disease or central nervous system involvement or those who are immunosuppressed.¹

The differential diagnosis for our patient’s lesion included infectious vs neoplastic etiologies. Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, also is endemic to the Ohio and Mississippi River valleys. It is found in soil and droppings of some bats and birds such as chickens and pigeons. Similar to blastomycosis, the primary infection site most commonly is the lungs. It subsequently may disseminate to the skin or less commonly via direct inoculation of injured skin. It can present as papules, plaques, ulcers, purpura, or abscesses. Unlike blastomycosis, tissue biopsy of a cutaneous lesion reveals granuloma formation and distinctive oval, narrow-based budding yeast.⁵ Atypical mycobacteria are another source of infection to consider. For example, cutaneous Mycobacterium kansasii may present as papules and pustules forming verrucous or granulomatous plaques and ulceration. Histopathologic findings distinguishing mycobacterial infection from blastomycosis include granulomas and acid-fast bacilli in histiocytes.⁶

Noninfectious etiologies in the differential may include cutaneous squamous cell carcinoma or pemphigus vegetans. Squamous cell carcinoma may present with a broad range of clinical features—papules, plaques, or nodules with smooth, scaly, verrucous, or ulcerative secondary features all are possible presentations.⁷ Fairskinned individuals, such as our patient, would be at a higher risk in sun-damaged skin. Histologically, cutaneous squamous cell carcinoma is defined as an invasion of the dermis by neoplastic squamous epithelial cells in the form of cords, sheets, individual cells, nodules, or cystic structures.⁷ Pemphigus vegetans is the rarest variant of a group of autoimmune vesiculobullous diseases known as pemphigus. It can be differentiated from the most common variant—pemphigus vulgaris—by the presence of vegetative plaques in intertriginous areas. However, these verrucous vegetations can be misleading and make clinical diagnosis difficult. Histopathologic findings of hyperkeratosis, pseudoepitheliomatous hyperplasia, papillomatosis, and acantholysis with a suprabasal cleft would confirm the diagnosis.⁸

In summary, cutaneous blastomycosis classically presents as verrucous crusting plaques, as seen in our patient. It is important to conduct a thorough history for environmental exposures, but definitive diagnosis of cutaneous blastomycosis involves skin biopsy with fungal culture. Treatment depends on the severity of disease and organ involvement. Itraconazole would be appropriate for mild to moderate blastomycosis.

The Diagnosis: Cutaneous Blastomycosis

A skin biopsy and fungal cultures confirmed the diagnosis of cutaneous blastomycosis. Grocott- Gomori methenamine-silver staining highlighted fungal organisms with refractile walls and broad-based budding consistent with cutaneous blastomycosis (Figure 1). The histopathologic specimen also demonstrated marked pseudoepitheliomatous hyperplasia (Figure 2A) with neutrophilic microabscesses (Figure 2B). Acid-fast bacillus and Fite staining were negative for bacterial organisms. A fungal culture was positive for Blastomyces dermatitidis. Urine and serum blastomycosis antigen were positive. Although Histoplasma serum antigen also was positive, this likely was from cross-reactivity. Chest radiography was negative for lung involvement, and the patient displayed no neurologic symptoms. He was started on oral itraconazole therapy for the treatment of cutaneous blastomycosis.

Blastomyces dermatitidis, the causative organism of blastomycosis, is endemic to the Ohio and Mississippi River valleys, Great Lakes region, and southeastern United States. It is a thermally dimorphic fungus found in soils that grows as a mold at 25 °C and yeast at 37 °C. Primary infection of the lungs—blastomycosis pneumonia—often is the only clinical manifestation¹; however, subsequent hematogenous dissemination to extrapulmonary sites such as the skin, bones, and genitourinary system can occur. Cutaneous blastomycosis, the most common extrapulmonary manifestation, typically follows pulmonary infection. In rare cases, it can occur from direct inoculation.^2,3 Skin lesions can occur anywhere but frequently are found on exposed surfaces of the head, neck, and extremities. Lesions classically present as verrucous crusting plaques with draining microabscesses. Violaceous nodules, ulcers, and pustules also may occur.¹

Diagnosis involves obtaining a thorough history of possible environmental exposures such as the patient’s geographic area of residence, occupation, and outdoor activities involving soil or decaying wood. Because blastomycosis can remain latent, remote exposures are relevant. Definitive diagnosis of cutaneous blastomycosis involves skin biopsy of the lesion with fungal culture, but the yeast’s distinctive thick wall and broad-based budding seen with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining provides a rapid presumptive diagnosis.³ Pseudoepitheliomatous hyperplasia and microabscesses also are characteristic features.² Urine antigen testing for a component of the polysaccharide cell wall has a sensitivity of 93% but a lower specificity of 79% due to cross-reactivity with histoplasmosis.⁴ Treatment consists of itraconazole for mild to moderate blastomycosis or amphotericin B for those with severe disease or central nervous system involvement or those who are immunosuppressed.¹

The differential diagnosis for our patient’s lesion included infectious vs neoplastic etiologies. Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, also is endemic to the Ohio and Mississippi River valleys. It is found in soil and droppings of some bats and birds such as chickens and pigeons. Similar to blastomycosis, the primary infection site most commonly is the lungs. It subsequently may disseminate to the skin or less commonly via direct inoculation of injured skin. It can present as papules, plaques, ulcers, purpura, or abscesses. Unlike blastomycosis, tissue biopsy of a cutaneous lesion reveals granuloma formation and distinctive oval, narrow-based budding yeast.⁵ Atypical mycobacteria are another source of infection to consider. For example, cutaneous Mycobacterium kansasii may present as papules and pustules forming verrucous or granulomatous plaques and ulceration. Histopathologic findings distinguishing mycobacterial infection from blastomycosis include granulomas and acid-fast bacilli in histiocytes.⁶

Noninfectious etiologies in the differential may include cutaneous squamous cell carcinoma or pemphigus vegetans. Squamous cell carcinoma may present with a broad range of clinical features—papules, plaques, or nodules with smooth, scaly, verrucous, or ulcerative secondary features all are possible presentations.⁷ Fairskinned individuals, such as our patient, would be at a higher risk in sun-damaged skin. Histologically, cutaneous squamous cell carcinoma is defined as an invasion of the dermis by neoplastic squamous epithelial cells in the form of cords, sheets, individual cells, nodules, or cystic structures.⁷ Pemphigus vegetans is the rarest variant of a group of autoimmune vesiculobullous diseases known as pemphigus. It can be differentiated from the most common variant—pemphigus vulgaris—by the presence of vegetative plaques in intertriginous areas. However, these verrucous vegetations can be misleading and make clinical diagnosis difficult. Histopathologic findings of hyperkeratosis, pseudoepitheliomatous hyperplasia, papillomatosis, and acantholysis with a suprabasal cleft would confirm the diagnosis.⁸

In summary, cutaneous blastomycosis classically presents as verrucous crusting plaques, as seen in our patient. It is important to conduct a thorough history for environmental exposures, but definitive diagnosis of cutaneous blastomycosis involves skin biopsy with fungal culture. Treatment depends on the severity of disease and organ involvement. Itraconazole would be appropriate for mild to moderate blastomycosis.

When I began in private practice several eons ago, I employed only registered nurses (RNs) and licensed practical nurses (LPNs) in my office – as did, I think, most other physicians.

That is still the preferred way to go from an efficiency perspective, as well as the ability to delegate such tasks as blood collection and administering intramuscular injections. Unfortunately, the current state of medical practice – driven by payment reform, regulatory changes, technology costs, inflation, and other factors – has forced most independent practitioners to pivot from RNs and LPNs to medical assistants in a majority of situations.

Given this reality, it makes sense to understand how the use of medical assistants has changed private medical practice, and how the most effective MAs manage their roles and maximize their efficiency in the office.

A recent article by two physicians at the University of Michigan, Ann Arbor, is one of the few published papers to address this issue. It presents the results of a cross-sectional study examining the MA’s experience and key factors that enhance or reduce efficiencies.

The authors sent an email survey to 86 MAs working in six clinics within the department of family medicine at the University of Michigan Medical Center, and received responses from 75 of them, including 61 who completed the entire survey. They then singled out 18 individuals deemed “most efficient” by their peers and conducted face-to-face interviews with them.

The surveys and interviews looked at how MAs identified personal strategies for efficiency, dealt with barriers to implementing those strategies, and navigated interoffice relationships, as well as how all of this affected overall job satisfaction.

All 61 respondents who completed the full survey agreed that the MA role was “very important to keep the clinic functioning” and nearly all said that working in health care was “a calling” for them. About half agreed that their work was very stressful, and about the same percentage reported that there was inadequate MA staffing at their clinic. Others complained of limited pay and promotion opportunities.

The surveyed MAs described important work values that increased their efficiency. These included good communication, strong teamwork, and workload sharing, as well as individual strategies such as multitasking, limiting patient conversations, and completing tasks in a consistent way to improve accuracy.

Other strategies identified as contributing to an efficient operation included preclinic huddles, reviews of patient records before the patient’s arrival, and completing routine office duties before the start of office hours.

Respondents were then asked to identify barriers to clinic efficiency, and most of them involved physicians who barked orders at them, did not complete paperwork or sign orders in a timely manner, and agreed to see late-arriving patients. Some MAs suggested that physicians refrain from “talking down” to them, and teach rather than criticize. They also faulted decisions affecting patient flow made by other staffers without soliciting the MAs’ input.

Despite these barriers, the authors found that most of the surveyed MAs agreed that their work was valued by doctors. “Proper training of managers to provide ... support and ensure equitable workloads may be one strategy to ensure that staff members feel the workplace is fair and collegial,” they said.

“Many described the working relationships with physicians as critical to their satisfaction at work and indicated that strong partnerships motivated them to do their best to make the physician’s day easier,” they added.

At the same time, the authors noted that most survey subjects reported that their jobs were “stressful,” and believed that their stress went underrecognized by physicians. They argued that “it’s important for physicians to be cognizant of these patterns and clinic culture, as reducing a hierarchy-based environment will be appreciated by MAs.”

Since this study involved only MAs in a family practice setting, further studies will be needed to determine whether these results translate to specialty offices – and whether the unique issues inherent in various specialty environments elicit different efficiency contributors and barriers.

Overall, though, “staff job satisfaction is linked to improved quality of care, so treating staff well contributes to high-value care for patients,” the authors wrote. “Disseminating practices that staff members themselves have identified as effective, and being attentive to how staff members are treated, may increase individual efficiency while improving staff retention and satisfaction.”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

When I began in private practice several eons ago, I employed only registered nurses (RNs) and licensed practical nurses (LPNs) in my office – as did, I think, most other physicians.

That is still the preferred way to go from an efficiency perspective, as well as the ability to delegate such tasks as blood collection and administering intramuscular injections. Unfortunately, the current state of medical practice – driven by payment reform, regulatory changes, technology costs, inflation, and other factors – has forced most independent practitioners to pivot from RNs and LPNs to medical assistants in a majority of situations.

Given this reality, it makes sense to understand how the use of medical assistants has changed private medical practice, and how the most effective MAs manage their roles and maximize their efficiency in the office.

A recent article by two physicians at the University of Michigan, Ann Arbor, is one of the few published papers to address this issue. It presents the results of a cross-sectional study examining the MA’s experience and key factors that enhance or reduce efficiencies.

The authors sent an email survey to 86 MAs working in six clinics within the department of family medicine at the University of Michigan Medical Center, and received responses from 75 of them, including 61 who completed the entire survey. They then singled out 18 individuals deemed “most efficient” by their peers and conducted face-to-face interviews with them.

The surveys and interviews looked at how MAs identified personal strategies for efficiency, dealt with barriers to implementing those strategies, and navigated interoffice relationships, as well as how all of this affected overall job satisfaction.

All 61 respondents who completed the full survey agreed that the MA role was “very important to keep the clinic functioning” and nearly all said that working in health care was “a calling” for them. About half agreed that their work was very stressful, and about the same percentage reported that there was inadequate MA staffing at their clinic. Others complained of limited pay and promotion opportunities.

The surveyed MAs described important work values that increased their efficiency. These included good communication, strong teamwork, and workload sharing, as well as individual strategies such as multitasking, limiting patient conversations, and completing tasks in a consistent way to improve accuracy.

Other strategies identified as contributing to an efficient operation included preclinic huddles, reviews of patient records before the patient’s arrival, and completing routine office duties before the start of office hours.

Respondents were then asked to identify barriers to clinic efficiency, and most of them involved physicians who barked orders at them, did not complete paperwork or sign orders in a timely manner, and agreed to see late-arriving patients. Some MAs suggested that physicians refrain from “talking down” to them, and teach rather than criticize. They also faulted decisions affecting patient flow made by other staffers without soliciting the MAs’ input.

Despite these barriers, the authors found that most of the surveyed MAs agreed that their work was valued by doctors. “Proper training of managers to provide ... support and ensure equitable workloads may be one strategy to ensure that staff members feel the workplace is fair and collegial,” they said.

“Many described the working relationships with physicians as critical to their satisfaction at work and indicated that strong partnerships motivated them to do their best to make the physician’s day easier,” they added.

At the same time, the authors noted that most survey subjects reported that their jobs were “stressful,” and believed that their stress went underrecognized by physicians. They argued that “it’s important for physicians to be cognizant of these patterns and clinic culture, as reducing a hierarchy-based environment will be appreciated by MAs.”

Since this study involved only MAs in a family practice setting, further studies will be needed to determine whether these results translate to specialty offices – and whether the unique issues inherent in various specialty environments elicit different efficiency contributors and barriers.

Overall, though, “staff job satisfaction is linked to improved quality of care, so treating staff well contributes to high-value care for patients,” the authors wrote. “Disseminating practices that staff members themselves have identified as effective, and being attentive to how staff members are treated, may increase individual efficiency while improving staff retention and satisfaction.”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

When I began in private practice several eons ago, I employed only registered nurses (RNs) and licensed practical nurses (LPNs) in my office – as did, I think, most other physicians.

That is still the preferred way to go from an efficiency perspective, as well as the ability to delegate such tasks as blood collection and administering intramuscular injections. Unfortunately, the current state of medical practice – driven by payment reform, regulatory changes, technology costs, inflation, and other factors – has forced most independent practitioners to pivot from RNs and LPNs to medical assistants in a majority of situations.

Given this reality, it makes sense to understand how the use of medical assistants has changed private medical practice, and how the most effective MAs manage their roles and maximize their efficiency in the office.

A recent article by two physicians at the University of Michigan, Ann Arbor, is one of the few published papers to address this issue. It presents the results of a cross-sectional study examining the MA’s experience and key factors that enhance or reduce efficiencies.

The authors sent an email survey to 86 MAs working in six clinics within the department of family medicine at the University of Michigan Medical Center, and received responses from 75 of them, including 61 who completed the entire survey. They then singled out 18 individuals deemed “most efficient” by their peers and conducted face-to-face interviews with them.

The surveys and interviews looked at how MAs identified personal strategies for efficiency, dealt with barriers to implementing those strategies, and navigated interoffice relationships, as well as how all of this affected overall job satisfaction.

All 61 respondents who completed the full survey agreed that the MA role was “very important to keep the clinic functioning” and nearly all said that working in health care was “a calling” for them. About half agreed that their work was very stressful, and about the same percentage reported that there was inadequate MA staffing at their clinic. Others complained of limited pay and promotion opportunities.

The surveyed MAs described important work values that increased their efficiency. These included good communication, strong teamwork, and workload sharing, as well as individual strategies such as multitasking, limiting patient conversations, and completing tasks in a consistent way to improve accuracy.

Other strategies identified as contributing to an efficient operation included preclinic huddles, reviews of patient records before the patient’s arrival, and completing routine office duties before the start of office hours.

Respondents were then asked to identify barriers to clinic efficiency, and most of them involved physicians who barked orders at them, did not complete paperwork or sign orders in a timely manner, and agreed to see late-arriving patients. Some MAs suggested that physicians refrain from “talking down” to them, and teach rather than criticize. They also faulted decisions affecting patient flow made by other staffers without soliciting the MAs’ input.

Despite these barriers, the authors found that most of the surveyed MAs agreed that their work was valued by doctors. “Proper training of managers to provide ... support and ensure equitable workloads may be one strategy to ensure that staff members feel the workplace is fair and collegial,” they said.

“Many described the working relationships with physicians as critical to their satisfaction at work and indicated that strong partnerships motivated them to do their best to make the physician’s day easier,” they added.

At the same time, the authors noted that most survey subjects reported that their jobs were “stressful,” and believed that their stress went underrecognized by physicians. They argued that “it’s important for physicians to be cognizant of these patterns and clinic culture, as reducing a hierarchy-based environment will be appreciated by MAs.”

Since this study involved only MAs in a family practice setting, further studies will be needed to determine whether these results translate to specialty offices – and whether the unique issues inherent in various specialty environments elicit different efficiency contributors and barriers.

Overall, though, “staff job satisfaction is linked to improved quality of care, so treating staff well contributes to high-value care for patients,” the authors wrote. “Disseminating practices that staff members themselves have identified as effective, and being attentive to how staff members are treated, may increase individual efficiency while improving staff retention and satisfaction.”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Two drugs have emerged as the optimal medications for treating insomnia based on the “best-available evidence,” but there are caveats.

In a comprehensive comparative-effectiveness analysis, lemborexant and eszopiclone showed the best efficacy, acceptability, and tolerability for acute and long-term insomnia treatment.

However, eszopiclone may cause substantial side effects – and safety data on lemborexant were inconclusive, the researchers note.

Not surprisingly, short-acting, intermediate-acting, and long-acting benzodiazepines were effective in the acute treatment of insomnia, but they have unfavorable tolerability and safety profiles, and there are no long-term data on these issues.

For many insomnia medications, there is a “striking” and “appalling” lack of long-term data, study investigator Andrea Cipriani, MD, PhD, professor of psychiatry, University of Oxford, United Kingdom, noted during a press briefing.

“This is a call for regulators to raise the bar and ask for long-term data when companies submit an application for licensing insomnia drugs,” Dr. Cipriani said.

The findings were published online  in The Lancet.
 

Prevalent, debilitating

Insomnia is highly prevalent, affecting up to 1 in 5 adults, and can have a profound impact on health, well-being, and productivity.

Sleep hygiene and cognitive-behavioral therapy for insomnia (CBT-I) are recommended first-line treatments, but they are often unavailable, which often leads patients and clinicians to turn to medications.

However, “insomnia drugs are not all created equal. Even within the same drug class there are differences,” Dr. Cipriani said.

In a large-scale systematic review and network meta-analysis, the researchers analyzed data from 154 double-blind, randomized controlled trials of medications (licensed or not) used for acute and long-term treatment of insomnia in 44,089 adults (mean age, 51.7 years; 63% women).

Results showed, for the acute treatment of insomnia, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more effective than placebo (standardized mean difference range, 0.36-0.83; high-to-moderate certainty of evidence).

In addition, benzodiazepines, eszopiclone, zolpidem, and zopiclone were more effective than melatonin, ramelteon, and zaleplon (SMD, 0.27-0.71; moderate-to-very low certainty of evidence).

“Our results show that the melatonergic drugs melatonin and ramelteon are not really effective. The data do not support the regular use of these drugs,” co-investigator Phil Cowen, PhD, professor of psychopharmacology, University of Oxford, said at the briefing.
 

Best available evidence

What little long-term data is available suggest eszopiclone and lemborexant are more effective than placebo. Plus, eszopiclone is more effective than ramelteon and zolpidem but with “very low” certainty of evidence, the researchers report.

“There was insufficient evidence to support the prescription of benzodiazepines and zolpidem in long-term treatment,” they write.

Another problem was lack of data on other important outcomes, they add.  

“We wanted to look at hangover effects, daytime sleepiness, [and] rebound effect, but often there was no data reported in trials. We need to collect data about these outcomes because they matter to clinicians and patients,” Dr. Cipriani said.

Summing up, the researchers note the current findings represent the “best available evidence base to guide the choice about pharmacological treatment for insomnia disorder in adults and will assist in shared decisionmaking between patients, carers, and their clinicians, as well as policy makers.”

They caution, however, that all statements comparing the merits of one drug with another “should be tempered by the potential limitations of the current analysis, the quality of the available evidence, the characteristics of the patient populations, and the uncertainties that might result from choice of dose or treatment setting.”

In addition, it is important to also consider nonpharmacologic treatments for insomnia disorder, as they are supported by “high-quality evidence and recommended as first-line treatment by guidelines,” the investigator write.
 

Shared decisionmaking

In an accompanying editorial, Myrto Samara, MD, University of Thessaly, Larissa, Greece, agrees with the researchers that discussion with patients is key.  

“For insomnia treatment, patient-physician shared decisionmaking is crucial to decide when a pharmacological intervention is deemed necessary and which drug [is] to be given by considering the trade-offs for efficacy and side effects,” Dr. Samara writes.  

The study was funded by the UK National Institute for Health Research (NIHR) Oxford Health Biomedical Research Center. Dr. Cipriani has received research and consultancy fees from the Italian Network for Pediatric Trials, CARIPLO Foundation, and Angelini Pharma, and is the chief and principal investigator of two trials of seltorexant in depression that are sponsored by Janssen. Dr. Samara has reported no relevant financial relationships.

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

Two drugs have emerged as the optimal medications for treating insomnia based on the “best-available evidence,” but there are caveats.

In a comprehensive comparative-effectiveness analysis, lemborexant and eszopiclone showed the best efficacy, acceptability, and tolerability for acute and long-term insomnia treatment.

However, eszopiclone may cause substantial side effects – and safety data on lemborexant were inconclusive, the researchers note.

Not surprisingly, short-acting, intermediate-acting, and long-acting benzodiazepines were effective in the acute treatment of insomnia, but they have unfavorable tolerability and safety profiles, and there are no long-term data on these issues.

For many insomnia medications, there is a “striking” and “appalling” lack of long-term data, study investigator Andrea Cipriani, MD, PhD, professor of psychiatry, University of Oxford, United Kingdom, noted during a press briefing.

“This is a call for regulators to raise the bar and ask for long-term data when companies submit an application for licensing insomnia drugs,” Dr. Cipriani said.

The findings were published online  in The Lancet.
 

Prevalent, debilitating

Insomnia is highly prevalent, affecting up to 1 in 5 adults, and can have a profound impact on health, well-being, and productivity.

Sleep hygiene and cognitive-behavioral therapy for insomnia (CBT-I) are recommended first-line treatments, but they are often unavailable, which often leads patients and clinicians to turn to medications.

However, “insomnia drugs are not all created equal. Even within the same drug class there are differences,” Dr. Cipriani said.

In a large-scale systematic review and network meta-analysis, the researchers analyzed data from 154 double-blind, randomized controlled trials of medications (licensed or not) used for acute and long-term treatment of insomnia in 44,089 adults (mean age, 51.7 years; 63% women).

Results showed, for the acute treatment of insomnia, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more effective than placebo (standardized mean difference range, 0.36-0.83; high-to-moderate certainty of evidence).

In addition, benzodiazepines, eszopiclone, zolpidem, and zopiclone were more effective than melatonin, ramelteon, and zaleplon (SMD, 0.27-0.71; moderate-to-very low certainty of evidence).

“Our results show that the melatonergic drugs melatonin and ramelteon are not really effective. The data do not support the regular use of these drugs,” co-investigator Phil Cowen, PhD, professor of psychopharmacology, University of Oxford, said at the briefing.
 

Best available evidence

What little long-term data is available suggest eszopiclone and lemborexant are more effective than placebo. Plus, eszopiclone is more effective than ramelteon and zolpidem but with “very low” certainty of evidence, the researchers report.

“There was insufficient evidence to support the prescription of benzodiazepines and zolpidem in long-term treatment,” they write.

Another problem was lack of data on other important outcomes, they add.  

“We wanted to look at hangover effects, daytime sleepiness, [and] rebound effect, but often there was no data reported in trials. We need to collect data about these outcomes because they matter to clinicians and patients,” Dr. Cipriani said.

Summing up, the researchers note the current findings represent the “best available evidence base to guide the choice about pharmacological treatment for insomnia disorder in adults and will assist in shared decisionmaking between patients, carers, and their clinicians, as well as policy makers.”

They caution, however, that all statements comparing the merits of one drug with another “should be tempered by the potential limitations of the current analysis, the quality of the available evidence, the characteristics of the patient populations, and the uncertainties that might result from choice of dose or treatment setting.”

In addition, it is important to also consider nonpharmacologic treatments for insomnia disorder, as they are supported by “high-quality evidence and recommended as first-line treatment by guidelines,” the investigator write.
 

Shared decisionmaking

In an accompanying editorial, Myrto Samara, MD, University of Thessaly, Larissa, Greece, agrees with the researchers that discussion with patients is key.  

“For insomnia treatment, patient-physician shared decisionmaking is crucial to decide when a pharmacological intervention is deemed necessary and which drug [is] to be given by considering the trade-offs for efficacy and side effects,” Dr. Samara writes.  

The study was funded by the UK National Institute for Health Research (NIHR) Oxford Health Biomedical Research Center. Dr. Cipriani has received research and consultancy fees from the Italian Network for Pediatric Trials, CARIPLO Foundation, and Angelini Pharma, and is the chief and principal investigator of two trials of seltorexant in depression that are sponsored by Janssen. Dr. Samara has reported no relevant financial relationships.

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

Two drugs have emerged as the optimal medications for treating insomnia based on the “best-available evidence,” but there are caveats.

In a comprehensive comparative-effectiveness analysis, lemborexant and eszopiclone showed the best efficacy, acceptability, and tolerability for acute and long-term insomnia treatment.

However, eszopiclone may cause substantial side effects – and safety data on lemborexant were inconclusive, the researchers note.

Not surprisingly, short-acting, intermediate-acting, and long-acting benzodiazepines were effective in the acute treatment of insomnia, but they have unfavorable tolerability and safety profiles, and there are no long-term data on these issues.

For many insomnia medications, there is a “striking” and “appalling” lack of long-term data, study investigator Andrea Cipriani, MD, PhD, professor of psychiatry, University of Oxford, United Kingdom, noted during a press briefing.

“This is a call for regulators to raise the bar and ask for long-term data when companies submit an application for licensing insomnia drugs,” Dr. Cipriani said.

The findings were published online  in The Lancet.
 

Prevalent, debilitating

Insomnia is highly prevalent, affecting up to 1 in 5 adults, and can have a profound impact on health, well-being, and productivity.

Sleep hygiene and cognitive-behavioral therapy for insomnia (CBT-I) are recommended first-line treatments, but they are often unavailable, which often leads patients and clinicians to turn to medications.

However, “insomnia drugs are not all created equal. Even within the same drug class there are differences,” Dr. Cipriani said.

In a large-scale systematic review and network meta-analysis, the researchers analyzed data from 154 double-blind, randomized controlled trials of medications (licensed or not) used for acute and long-term treatment of insomnia in 44,089 adults (mean age, 51.7 years; 63% women).

Results showed, for the acute treatment of insomnia, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more effective than placebo (standardized mean difference range, 0.36-0.83; high-to-moderate certainty of evidence).

In addition, benzodiazepines, eszopiclone, zolpidem, and zopiclone were more effective than melatonin, ramelteon, and zaleplon (SMD, 0.27-0.71; moderate-to-very low certainty of evidence).

“Our results show that the melatonergic drugs melatonin and ramelteon are not really effective. The data do not support the regular use of these drugs,” co-investigator Phil Cowen, PhD, professor of psychopharmacology, University of Oxford, said at the briefing.
 

Best available evidence

What little long-term data is available suggest eszopiclone and lemborexant are more effective than placebo. Plus, eszopiclone is more effective than ramelteon and zolpidem but with “very low” certainty of evidence, the researchers report.

“There was insufficient evidence to support the prescription of benzodiazepines and zolpidem in long-term treatment,” they write.

Another problem was lack of data on other important outcomes, they add.  

“We wanted to look at hangover effects, daytime sleepiness, [and] rebound effect, but often there was no data reported in trials. We need to collect data about these outcomes because they matter to clinicians and patients,” Dr. Cipriani said.

Summing up, the researchers note the current findings represent the “best available evidence base to guide the choice about pharmacological treatment for insomnia disorder in adults and will assist in shared decisionmaking between patients, carers, and their clinicians, as well as policy makers.”

They caution, however, that all statements comparing the merits of one drug with another “should be tempered by the potential limitations of the current analysis, the quality of the available evidence, the characteristics of the patient populations, and the uncertainties that might result from choice of dose or treatment setting.”

In addition, it is important to also consider nonpharmacologic treatments for insomnia disorder, as they are supported by “high-quality evidence and recommended as first-line treatment by guidelines,” the investigator write.
 

Shared decisionmaking

In an accompanying editorial, Myrto Samara, MD, University of Thessaly, Larissa, Greece, agrees with the researchers that discussion with patients is key.  

“For insomnia treatment, patient-physician shared decisionmaking is crucial to decide when a pharmacological intervention is deemed necessary and which drug [is] to be given by considering the trade-offs for efficacy and side effects,” Dr. Samara writes.  

The study was funded by the UK National Institute for Health Research (NIHR) Oxford Health Biomedical Research Center. Dr. Cipriani has received research and consultancy fees from the Italian Network for Pediatric Trials, CARIPLO Foundation, and Angelini Pharma, and is the chief and principal investigator of two trials of seltorexant in depression that are sponsored by Janssen. Dr. Samara has reported no relevant financial relationships.

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

NEW YORK – On the basis of MRI images of the hand, a neural network has been trained to distinguish seronegative and seropositive rheumatoid arthritis (RA) from psoriatic arthritis (PsA) as well as from each other, according to a study that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

In the work so far, the neural network was correct about 70% of the time in the absence of any further clinical analyses, according to David Simon, MD, a rheumatologist in the department of internal medicine at Friedrich-Alexander University, Erlangen, Germany.

Ted Bosworth/MDedge News

Previous to this work, “there has been no study that has exclusively used hand MRI data and deep learning without requiring further expert input for the classification of arthritides,” Dr. Simon said.

In fact, when demographic and clinical data were added, there was no improvement in the performance of patient classification relative to the deep learning classification alone, according to the data presented by Dr. Simon.

The images were evaluated with residual neural networks (ResNet), which represents a sophisticated form of deep learning to facilitate the flow of information across the network layers as they form to improve accuracy in their ability to distinguish one form of disease from the other. The training was performed on images from the T1 coronal, T2 corona1, T1 coronal fat suppressed with contrast, T1 axial fat suppressed with contrast, and T2 fat suppressed axial sequences.

The study included hand MRI scans from 135 patients with seronegative RA, 190 with seropositive RA, 177 with PsA, and 147 with psoriasis. The performance was judged on the basis of area under the receiver operating characteristics curve (AUROC) with and without input of clinical characteristics. Patients who had psoriasis without clinical arthritis were included as a control population.

The AUROC for accuracy was 75% for seropositive RA relative to PsA, 74% for seronegative RA relative to PsA, and 67% for seropositive relative to seronegative RA. Of the patients who had psoriasis without arthritis, 98% were classified as PsA and 2% as RA.

Subsequent to the classification of the patients with psoriasis, 14 of the 147 (9.5%) have developed PsA so far over a relatively short follow-up. All of these were among those identified as PsA by neural network evaluation of the hand MRIs.

This suggests that “a PsA-like pattern may be present early in the course of psoriatic disease,” Dr. Simon said.

In the groups with joint disease, who had mean ages ranging from 56 to 65, the mean disease durations were 2.6 years for those with seropositive RA, 1.3 years for those with seronegative RA, and 0.8 years for those with PsA. The patients with psoriasis were younger (mean age, 40.5 years) but had a longer disease duration (mean 4.2 years).

All of the MRI sequences were relevant for classification, but contrast did not appear to help with accuracy.

“If the images with contrast enhancement were deleted, the loss of performance was only marginal,” Dr. Simon reported.

The accuracy of neural networks increases with data, making it likely that further refinements in methodology will lead to a greater degree of accuracy, according to Dr. Simon. While the methodology is not yet ready for routine use in the clinic, the study demonstrates that neural network analysis of hand MRI to distinguish forms of arthritis “is possible.” Further studies are planned toward the goal of creating a viable clinical tool.

“Of course, if we could create an accurate tool with ultrasound, this would be even more practical,” said Dr. Simon, recognizing the value of an office tool, but he cautioned that this would be far more challenging.

“The precision of MRI is an important factor for effective neural network training,” he said.

Utility: ‘In challenging cases if the accuracy improves’?

A viable method for objectively and rapidly distinguishing inflammatory joint diseases, particularly in patients with an ambiguous clinical presentation, is an unmet need, according to Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center, Seattle.

Although the data presented are promising, Dr. Mease said in an interview that he believes there is a fair amount of work to be done before imaging analysis based on deep learning makes its way into routine clinical care. He is also hoping for methods to distinguish RA from PsA that are easier and less expensive, such as serum biomarkers. However, he agreed that a MRI-based tool could be useful when differentiating disease that is challenging.

“MRI is an expensive way for routine classification of disease, but this approach could be useful in challenging cases if the accuracy improves,” he said.

Meanwhile, other clinical researchers might want to test the principle. “You can try it,” said Dr. Simon, who reported that his team has made the methodology publicly available.

Dr. Simon reported no conflicts of interest. Dr. Mease reported financial relationships with more than 10 pharmaceutical companies, most of which make products used for the treatment of inflammatory joint diseases.

NEW YORK – On the basis of MRI images of the hand, a neural network has been trained to distinguish seronegative and seropositive rheumatoid arthritis (RA) from psoriatic arthritis (PsA) as well as from each other, according to a study that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

In the work so far, the neural network was correct about 70% of the time in the absence of any further clinical analyses, according to David Simon, MD, a rheumatologist in the department of internal medicine at Friedrich-Alexander University, Erlangen, Germany.

Ted Bosworth/MDedge News

Previous to this work, “there has been no study that has exclusively used hand MRI data and deep learning without requiring further expert input for the classification of arthritides,” Dr. Simon said.

In fact, when demographic and clinical data were added, there was no improvement in the performance of patient classification relative to the deep learning classification alone, according to the data presented by Dr. Simon.

The images were evaluated with residual neural networks (ResNet), which represents a sophisticated form of deep learning to facilitate the flow of information across the network layers as they form to improve accuracy in their ability to distinguish one form of disease from the other. The training was performed on images from the T1 coronal, T2 corona1, T1 coronal fat suppressed with contrast, T1 axial fat suppressed with contrast, and T2 fat suppressed axial sequences.

The study included hand MRI scans from 135 patients with seronegative RA, 190 with seropositive RA, 177 with PsA, and 147 with psoriasis. The performance was judged on the basis of area under the receiver operating characteristics curve (AUROC) with and without input of clinical characteristics. Patients who had psoriasis without clinical arthritis were included as a control population.

The AUROC for accuracy was 75% for seropositive RA relative to PsA, 74% for seronegative RA relative to PsA, and 67% for seropositive relative to seronegative RA. Of the patients who had psoriasis without arthritis, 98% were classified as PsA and 2% as RA.

Subsequent to the classification of the patients with psoriasis, 14 of the 147 (9.5%) have developed PsA so far over a relatively short follow-up. All of these were among those identified as PsA by neural network evaluation of the hand MRIs.

This suggests that “a PsA-like pattern may be present early in the course of psoriatic disease,” Dr. Simon said.

In the groups with joint disease, who had mean ages ranging from 56 to 65, the mean disease durations were 2.6 years for those with seropositive RA, 1.3 years for those with seronegative RA, and 0.8 years for those with PsA. The patients with psoriasis were younger (mean age, 40.5 years) but had a longer disease duration (mean 4.2 years).

All of the MRI sequences were relevant for classification, but contrast did not appear to help with accuracy.

“If the images with contrast enhancement were deleted, the loss of performance was only marginal,” Dr. Simon reported.

The accuracy of neural networks increases with data, making it likely that further refinements in methodology will lead to a greater degree of accuracy, according to Dr. Simon. While the methodology is not yet ready for routine use in the clinic, the study demonstrates that neural network analysis of hand MRI to distinguish forms of arthritis “is possible.” Further studies are planned toward the goal of creating a viable clinical tool.

“Of course, if we could create an accurate tool with ultrasound, this would be even more practical,” said Dr. Simon, recognizing the value of an office tool, but he cautioned that this would be far more challenging.

“The precision of MRI is an important factor for effective neural network training,” he said.

Utility: ‘In challenging cases if the accuracy improves’?

A viable method for objectively and rapidly distinguishing inflammatory joint diseases, particularly in patients with an ambiguous clinical presentation, is an unmet need, according to Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center, Seattle.

Although the data presented are promising, Dr. Mease said in an interview that he believes there is a fair amount of work to be done before imaging analysis based on deep learning makes its way into routine clinical care. He is also hoping for methods to distinguish RA from PsA that are easier and less expensive, such as serum biomarkers. However, he agreed that a MRI-based tool could be useful when differentiating disease that is challenging.

“MRI is an expensive way for routine classification of disease, but this approach could be useful in challenging cases if the accuracy improves,” he said.

Meanwhile, other clinical researchers might want to test the principle. “You can try it,” said Dr. Simon, who reported that his team has made the methodology publicly available.

Dr. Simon reported no conflicts of interest. Dr. Mease reported financial relationships with more than 10 pharmaceutical companies, most of which make products used for the treatment of inflammatory joint diseases.

NEW YORK – On the basis of MRI images of the hand, a neural network has been trained to distinguish seronegative and seropositive rheumatoid arthritis (RA) from psoriatic arthritis (PsA) as well as from each other, according to a study that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

In the work so far, the neural network was correct about 70% of the time in the absence of any further clinical analyses, according to David Simon, MD, a rheumatologist in the department of internal medicine at Friedrich-Alexander University, Erlangen, Germany.

Ted Bosworth/MDedge News

Previous to this work, “there has been no study that has exclusively used hand MRI data and deep learning without requiring further expert input for the classification of arthritides,” Dr. Simon said.

In fact, when demographic and clinical data were added, there was no improvement in the performance of patient classification relative to the deep learning classification alone, according to the data presented by Dr. Simon.

The images were evaluated with residual neural networks (ResNet), which represents a sophisticated form of deep learning to facilitate the flow of information across the network layers as they form to improve accuracy in their ability to distinguish one form of disease from the other. The training was performed on images from the T1 coronal, T2 corona1, T1 coronal fat suppressed with contrast, T1 axial fat suppressed with contrast, and T2 fat suppressed axial sequences.

The study included hand MRI scans from 135 patients with seronegative RA, 190 with seropositive RA, 177 with PsA, and 147 with psoriasis. The performance was judged on the basis of area under the receiver operating characteristics curve (AUROC) with and without input of clinical characteristics. Patients who had psoriasis without clinical arthritis were included as a control population.

The AUROC for accuracy was 75% for seropositive RA relative to PsA, 74% for seronegative RA relative to PsA, and 67% for seropositive relative to seronegative RA. Of the patients who had psoriasis without arthritis, 98% were classified as PsA and 2% as RA.

Subsequent to the classification of the patients with psoriasis, 14 of the 147 (9.5%) have developed PsA so far over a relatively short follow-up. All of these were among those identified as PsA by neural network evaluation of the hand MRIs.

This suggests that “a PsA-like pattern may be present early in the course of psoriatic disease,” Dr. Simon said.

In the groups with joint disease, who had mean ages ranging from 56 to 65, the mean disease durations were 2.6 years for those with seropositive RA, 1.3 years for those with seronegative RA, and 0.8 years for those with PsA. The patients with psoriasis were younger (mean age, 40.5 years) but had a longer disease duration (mean 4.2 years).

All of the MRI sequences were relevant for classification, but contrast did not appear to help with accuracy.

“If the images with contrast enhancement were deleted, the loss of performance was only marginal,” Dr. Simon reported.

The accuracy of neural networks increases with data, making it likely that further refinements in methodology will lead to a greater degree of accuracy, according to Dr. Simon. While the methodology is not yet ready for routine use in the clinic, the study demonstrates that neural network analysis of hand MRI to distinguish forms of arthritis “is possible.” Further studies are planned toward the goal of creating a viable clinical tool.

“Of course, if we could create an accurate tool with ultrasound, this would be even more practical,” said Dr. Simon, recognizing the value of an office tool, but he cautioned that this would be far more challenging.

“The precision of MRI is an important factor for effective neural network training,” he said.

Utility: ‘In challenging cases if the accuracy improves’?

A viable method for objectively and rapidly distinguishing inflammatory joint diseases, particularly in patients with an ambiguous clinical presentation, is an unmet need, according to Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center, Seattle.

Although the data presented are promising, Dr. Mease said in an interview that he believes there is a fair amount of work to be done before imaging analysis based on deep learning makes its way into routine clinical care. He is also hoping for methods to distinguish RA from PsA that are easier and less expensive, such as serum biomarkers. However, he agreed that a MRI-based tool could be useful when differentiating disease that is challenging.

“MRI is an expensive way for routine classification of disease, but this approach could be useful in challenging cases if the accuracy improves,” he said.

Meanwhile, other clinical researchers might want to test the principle. “You can try it,” said Dr. Simon, who reported that his team has made the methodology publicly available.

Dr. Simon reported no conflicts of interest. Dr. Mease reported financial relationships with more than 10 pharmaceutical companies, most of which make products used for the treatment of inflammatory joint diseases.

Vasculitis is a process in which blood vessels become inflamed and necrotic. Classic small vessel vasculitis reveals a leukocytoclastic vasculitis and most commonly presents as palpable purpura. Exercise-induced vasculitis (EIV) is a benign form of vasculitis involving the small vessels, brought on by exercise. It is also known as “golfer’s vasculitis.” A form of EIV has been described in the literature as “Disney dermatitis.” It is often seen in healthy adults after a long day of walking at the parks. Other forms of exercise, such as jogging, hiking, or swimming, may also cause the condition.

Clinically, EIV affects the lower legs and presents as purpuric macules. Edema may be present. Lesions may be asymptomatic or may present with pruritus or burning. Diagnosis is often made clinically. Skin biopsies for H&E and DIF (direct immunofluorescence) can help distinguish the type of vasculitis that is present. Laboratory tests may be needed to exclude other causes of vasculitis. Episodes may be recurrent.

Henoch-Schönlein purpura (HSP), also called anaphylactoid purpura, is a subtype of small-vessel vasculitis where IgA immunoglobulin is deposited in the vessel walls. It is the most common form of vasculitis is children (usually ages 4-8). In addition to skin, organs such as joints, kidneys, and intestines can be involved. Schamberg’s disease, or capillaritis, is also called pigmented purpura. In this benign condition, leakage from capillaries results in erythematous to brown patches on the lower extremities. A true vasculitis is not seen. The brown discoloration is due to hemosiderin deposition. Cryoglobulinemia is a rare condition in which abnormal immunoglobulin complexes deposit in tissues and vessels. Leukocytoclastic vasculitis is present in small vessels. Palpable purpura and livedo may be seen clinically, and systemic symptoms may be present.

Treatment of EIV is largely supportive as lesions will resolve on their own over 3-4 weeks. Postinflammatory hyperpigmentation may result. Temporary cessation of exercise and compression stockings can help speed up the resolution of lesions. Systemic medications used in the treatment of severe vasculitis, such as systemic steroids, dapsone, and colchicine, are not needed in EIV.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Vasculitis is a process in which blood vessels become inflamed and necrotic. Classic small vessel vasculitis reveals a leukocytoclastic vasculitis and most commonly presents as palpable purpura. Exercise-induced vasculitis (EIV) is a benign form of vasculitis involving the small vessels, brought on by exercise. It is also known as “golfer’s vasculitis.” A form of EIV has been described in the literature as “Disney dermatitis.” It is often seen in healthy adults after a long day of walking at the parks. Other forms of exercise, such as jogging, hiking, or swimming, may also cause the condition.

Clinically, EIV affects the lower legs and presents as purpuric macules. Edema may be present. Lesions may be asymptomatic or may present with pruritus or burning. Diagnosis is often made clinically. Skin biopsies for H&E and DIF (direct immunofluorescence) can help distinguish the type of vasculitis that is present. Laboratory tests may be needed to exclude other causes of vasculitis. Episodes may be recurrent.

Henoch-Schönlein purpura (HSP), also called anaphylactoid purpura, is a subtype of small-vessel vasculitis where IgA immunoglobulin is deposited in the vessel walls. It is the most common form of vasculitis is children (usually ages 4-8). In addition to skin, organs such as joints, kidneys, and intestines can be involved. Schamberg’s disease, or capillaritis, is also called pigmented purpura. In this benign condition, leakage from capillaries results in erythematous to brown patches on the lower extremities. A true vasculitis is not seen. The brown discoloration is due to hemosiderin deposition. Cryoglobulinemia is a rare condition in which abnormal immunoglobulin complexes deposit in tissues and vessels. Leukocytoclastic vasculitis is present in small vessels. Palpable purpura and livedo may be seen clinically, and systemic symptoms may be present.

Treatment of EIV is largely supportive as lesions will resolve on their own over 3-4 weeks. Postinflammatory hyperpigmentation may result. Temporary cessation of exercise and compression stockings can help speed up the resolution of lesions. Systemic medications used in the treatment of severe vasculitis, such as systemic steroids, dapsone, and colchicine, are not needed in EIV.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Vasculitis is a process in which blood vessels become inflamed and necrotic. Classic small vessel vasculitis reveals a leukocytoclastic vasculitis and most commonly presents as palpable purpura. Exercise-induced vasculitis (EIV) is a benign form of vasculitis involving the small vessels, brought on by exercise. It is also known as “golfer’s vasculitis.” A form of EIV has been described in the literature as “Disney dermatitis.” It is often seen in healthy adults after a long day of walking at the parks. Other forms of exercise, such as jogging, hiking, or swimming, may also cause the condition.

Clinically, EIV affects the lower legs and presents as purpuric macules. Edema may be present. Lesions may be asymptomatic or may present with pruritus or burning. Diagnosis is often made clinically. Skin biopsies for H&E and DIF (direct immunofluorescence) can help distinguish the type of vasculitis that is present. Laboratory tests may be needed to exclude other causes of vasculitis. Episodes may be recurrent.

Henoch-Schönlein purpura (HSP), also called anaphylactoid purpura, is a subtype of small-vessel vasculitis where IgA immunoglobulin is deposited in the vessel walls. It is the most common form of vasculitis is children (usually ages 4-8). In addition to skin, organs such as joints, kidneys, and intestines can be involved. Schamberg’s disease, or capillaritis, is also called pigmented purpura. In this benign condition, leakage from capillaries results in erythematous to brown patches on the lower extremities. A true vasculitis is not seen. The brown discoloration is due to hemosiderin deposition. Cryoglobulinemia is a rare condition in which abnormal immunoglobulin complexes deposit in tissues and vessels. Leukocytoclastic vasculitis is present in small vessels. Palpable purpura and livedo may be seen clinically, and systemic symptoms may be present.

Treatment of EIV is largely supportive as lesions will resolve on their own over 3-4 weeks. Postinflammatory hyperpigmentation may result. Temporary cessation of exercise and compression stockings can help speed up the resolution of lesions. Systemic medications used in the treatment of severe vasculitis, such as systemic steroids, dapsone, and colchicine, are not needed in EIV.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Ralph Newman, MD, got a taste of how dangerous medicine could be at age 10, when he witnessed a physician being shot by a patient.

“I was visiting a friend whose father was a psychiatrist,” Dr. Newman recalled. “We were playing in the living room when the doorbell rang. My friend went to the door and opened it. Then I heard a shot. I ran to the front hall and saw my friend’s father slumped at the bottom of the stairs. He had come down the stairs to see who was there. It was a patient armed with a shotgun.”

As a result of the shooting, a large portion of the psychiatrist’s intestines was removed. In spite of this traumatic incident, Dr. Newman went on to become a psychiatrist – who treated many violent prisoners. “I knew it was dangerous,” he said, “but I rationalized that I wouldn’t be attacked because I would be nicer.”

That attitude seemed to work until 2002, when a prisoner threw boiling oil on him. Dr. Newman was working at the Federal Medical Center Butner, a facility for prisoners in North Carolina. “A prisoner I had been treating was denied parole, based on my recommendation,” he said. “From then on, he was looking for a way to exact revenge.”

“One day I was sitting in the nursing station, typing up notes,” Dr. Newman said. “Two new nurses, who were also there, had forgotten to lock the door, and the prisoner noticed that. He heated up some baby oil in a microwave, which was available to prisoners at the time. Then he walked into the office, threw the oil on my back, and came at me with a sharp pencil.”

Dr. Newman said the nurses fled to an adjoining office, locked the door, and wouldn’t let him in. He went into another office and collapsed in exhaustion. He was saved by an inmate who came on the scene, fended off the attacker, and called for help.

“I was taken to the burn unit,” Dr. Newman recalled. “I had second- and third-degree burns on 9% of my body. It was extremely painful. It took me 45 days to recover enough to get back to work.” The two nurses were fired.
 

Doctors take threats by patients more seriously now

It is rare that patients murder their doctors, but when it happens, the news tears through the whole medical community. When orthopedic surgeon Preston Phillips, MD, was killed by a patient in Tulsa, Okla., on June 1, Jennifer M. Weiss, MD, recognized the potential danger to physicians.

“The news left me feeling very shaken,” said Dr. Weiss, a pediatric orthopedic surgeon at Southern California Permanente Medical Group, Los Angeles. “Every orthopedic surgeon I talked to about it felt shaken.”

Dr. Weiss said the impact of that event prompted her to take a patient’s abuse more seriously than she might have previously. “Before the killing, my colleagues and I might have swept the incident under the rug, but we reported it to the authorities,” she said.

“What happened was I told a parent of a school-aged child that the child wasn’t ready to go back to sports,” Dr. Weiss says. “This parent was incredibly triggered – screaming and making verbal threats. The parent was standing between me and the door, so I couldn’t get out.”

Coworkers down the hall heard the yelling and helped Dr. Weiss get out of the room. “The parent was escorted out of the building, and the incident was reported to our risk management team,” she said.
 

Shooters/killers vs. agitated patients

Patients who shoot to kill are very different from agitated patients seen by many doctors on a regular basis – particularly in emergency departments (EDs), psychiatric units, and pain clinics, said Scott Zeller, MD, a psychiatrist who is vice president of Acute Psychiatric Medicine at Vituity, a multistate physician partnership based in Emeryville, California.

“Agitated patients have trouble communicating their needs and can become physically and verbally aggressive,” Dr. Zeller said. He reports that there are 1.7 million such incidents a year in this country, but most of the incidents of verbal aggression can be kept from exploding into physical violence.

Shooters, however, are very hard to stop because they usually plan the action in advance, Dr. Zeller said. He recalled the 2017 murder of Todd Graham, MD, a friend from medical school. Dr. Graham, an orthopedic surgeon in South Bend, Ind., was gunned down by the husband of one of his patients after Dr. Graham declined to prescribe opioids for her.
 

Playing down the risk of violence

Doctors may play down the risk of violence, even after they have experienced it personally. “Patients can get angry and may make threatening comments,” Dr. Weiss said. “A lot of doctors just brush it off.”

Simple remarks can set off violence-prone patients, as happened to James P. Phillips, MD, director of disaster and operational medicine at George Washington University, Washington. He recalled asking a prisoner who was visiting his hospital to “lower the volume,” and the man exploded. “Even though he was handcuffed to the bed, he heaved an oxygen tank into a window,” Dr. Phillips said. “He said he would be coming back to kill me.”

Sometimes threats or other types of verbal abuse can be as destructive as physical violence. Diann Krywko, MD, an emergency physician at the Medical University of South Carolina (MUSC) Health, Charleston, has had some tough assignments. She worked in EDs in Detroit and Flint, Mich., for a decade before coming to MUSC, where she serves as director of wellness, health, and resilience. One of the incidents that has bothered her the most involved a threat.

It happened when Dr. Krywko denied a patient’s request for narcotics. “She was very angry and said she’d come to my home and cut my children’s heads off,” Dr. Krywko said. “To this day, what she said horrifies me. I still see her smile as she said that.”

Dr. Krywko considered filing for a restraining order against the patient but didn’t because the patient could have learned her address. Dr. Phillips said fear of retaliation is one reason many doctors don’t report threats from patients. “The patient you report knows where you work and may come there to take revenge,” he said. “Also, you may have to continue caring for the person who punched you.”

Online threats also may cause a great deal of angst. Dr. Phillips said he received many online threats when was a medical analyst for CNN in 2020. “Someone sent my address to his Twitter followers, and they shared it with others, so now the whole world knows where I live,” he said. “I had to upgrade security at my home.”
 

How to deal with volatile patients

Being nice may not always work, but in many cases, it can keep a volatile situation from exploding, according to Dr. Krywko.

“When patients begin to show signs of agitation or are already there, we always try to verbally deescalate the situation, which involves listening,” Dr. Krywko said. “They want someone to hear them out.”

Doctors speak to patients from a position of authority, but Dr. Krywko advises that they should not be too blunt. “Don’t tell patients they’re wrong,” she said. “Even if they may be incorrect, they feel their viewpoint is valid. Encourage a dialogue with words like, ‘Tell me more,’ ” Dr. Krywko said.
 

Defending yourself

Doctors may have little warning of an impending attack because a patient’s mood can change quickly. This happened several years ago to Jennifer Casaletto, MD, an emergency physician in Charlotte, N.C.

“A man was brought into my ED by ambulance,” she said. “He seemed very calm for a long while, but then he became completely unhinged. A male nurse placed himself between the patient and others and was attacked. He got hurt but was able to continue working.”

Dr. Zeller said health care teams sometimes overreact when patients lash out. “The old-fashioned way to deal with an agitated patient is to call in the cavalry – everyone does a group takedown,” he said. “The patient is put in restraints and heavily sedated. This is not good for anybody. Not only is it likely to injure and traumatize the patient, it can also injure the care team.”

Many hospital EDs have security guards. “I feel safer when a hospital has armed security guards, but they need to be well trained,” Dr. Casaletto said. “Many small hospitals and freestanding EDs do not have security officers at all, or the guards are undertrained or told not to touch anybody.”

In many electronic health record systems, doctors can flag violent patients so future caregivers can be forewarned. However, Dr. Zeller advises against writing about patients’ violence or rudeness in the medical record, because patients can have access to it and might take revenge.
 

Rising violence from patients

“It feels like it has become much more dangerous to work in the ED,” said Hasan Gokal, MD, an emergency physician working in EDs at the Texas Medical Center. “Just last week, a woman pulled out a gun and fired it in an ED near Houston.”

The statistics back up Dr. Gokal’s assessment. Injuries caused by violent attacks against medical professionals grew by 67% from 2011 to 2018, according to the U.S. Bureau of Labor Statistics. Those levels rose even more during the COVID-19 pandemic – the assault rate in hospitals rose 23% just in 2020.

Dr. Krywko said she had “a patient who said she wanted to hurt the next person who irritated her, and that happened to me. She jumped out of her bed swinging and punching, and I wasn’t ready for it. I yelled for help and the care team came.”

“The rise in violence has to do with a decline in respect for authority,” Dr. Phillips said. “Some people now believe doctors are lying to them about the need for COVID precautions because they are taking money from the vaccine companies. The pandemic has exacerbated violence in every way.”

Dr. Phillips said that a growing lack of resources had led to more anger among patients. “There are fewer nurses and reduced physician coverage,” he said. “That means longer wait times for patients, which increases patients’ frustrations.”

Dr. Weiss said patients have higher expectations. “In sports medicine, the expectations are incredible,” she said. “Parents want their kids to get back to playing as soon as possible.”

“Hospitals in particular are soft targets for violence,” Dr. Phillips said. “People know you can’t assault a flight attendant, because it’s a federal offense, but there is no such federal offense for violence against health care personnel.”

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

Ralph Newman, MD, got a taste of how dangerous medicine could be at age 10, when he witnessed a physician being shot by a patient.

“I was visiting a friend whose father was a psychiatrist,” Dr. Newman recalled. “We were playing in the living room when the doorbell rang. My friend went to the door and opened it. Then I heard a shot. I ran to the front hall and saw my friend’s father slumped at the bottom of the stairs. He had come down the stairs to see who was there. It was a patient armed with a shotgun.”

As a result of the shooting, a large portion of the psychiatrist’s intestines was removed. In spite of this traumatic incident, Dr. Newman went on to become a psychiatrist – who treated many violent prisoners. “I knew it was dangerous,” he said, “but I rationalized that I wouldn’t be attacked because I would be nicer.”

That attitude seemed to work until 2002, when a prisoner threw boiling oil on him. Dr. Newman was working at the Federal Medical Center Butner, a facility for prisoners in North Carolina. “A prisoner I had been treating was denied parole, based on my recommendation,” he said. “From then on, he was looking for a way to exact revenge.”

“One day I was sitting in the nursing station, typing up notes,” Dr. Newman said. “Two new nurses, who were also there, had forgotten to lock the door, and the prisoner noticed that. He heated up some baby oil in a microwave, which was available to prisoners at the time. Then he walked into the office, threw the oil on my back, and came at me with a sharp pencil.”

Dr. Newman said the nurses fled to an adjoining office, locked the door, and wouldn’t let him in. He went into another office and collapsed in exhaustion. He was saved by an inmate who came on the scene, fended off the attacker, and called for help.

“I was taken to the burn unit,” Dr. Newman recalled. “I had second- and third-degree burns on 9% of my body. It was extremely painful. It took me 45 days to recover enough to get back to work.” The two nurses were fired.
 

Doctors take threats by patients more seriously now

It is rare that patients murder their doctors, but when it happens, the news tears through the whole medical community. When orthopedic surgeon Preston Phillips, MD, was killed by a patient in Tulsa, Okla., on June 1, Jennifer M. Weiss, MD, recognized the potential danger to physicians.

“The news left me feeling very shaken,” said Dr. Weiss, a pediatric orthopedic surgeon at Southern California Permanente Medical Group, Los Angeles. “Every orthopedic surgeon I talked to about it felt shaken.”

Dr. Weiss said the impact of that event prompted her to take a patient’s abuse more seriously than she might have previously. “Before the killing, my colleagues and I might have swept the incident under the rug, but we reported it to the authorities,” she said.

“What happened was I told a parent of a school-aged child that the child wasn’t ready to go back to sports,” Dr. Weiss says. “This parent was incredibly triggered – screaming and making verbal threats. The parent was standing between me and the door, so I couldn’t get out.”

Coworkers down the hall heard the yelling and helped Dr. Weiss get out of the room. “The parent was escorted out of the building, and the incident was reported to our risk management team,” she said.
 

Shooters/killers vs. agitated patients

Patients who shoot to kill are very different from agitated patients seen by many doctors on a regular basis – particularly in emergency departments (EDs), psychiatric units, and pain clinics, said Scott Zeller, MD, a psychiatrist who is vice president of Acute Psychiatric Medicine at Vituity, a multistate physician partnership based in Emeryville, California.

“Agitated patients have trouble communicating their needs and can become physically and verbally aggressive,” Dr. Zeller said. He reports that there are 1.7 million such incidents a year in this country, but most of the incidents of verbal aggression can be kept from exploding into physical violence.

Shooters, however, are very hard to stop because they usually plan the action in advance, Dr. Zeller said. He recalled the 2017 murder of Todd Graham, MD, a friend from medical school. Dr. Graham, an orthopedic surgeon in South Bend, Ind., was gunned down by the husband of one of his patients after Dr. Graham declined to prescribe opioids for her.
 

Playing down the risk of violence

Doctors may play down the risk of violence, even after they have experienced it personally. “Patients can get angry and may make threatening comments,” Dr. Weiss said. “A lot of doctors just brush it off.”

Simple remarks can set off violence-prone patients, as happened to James P. Phillips, MD, director of disaster and operational medicine at George Washington University, Washington. He recalled asking a prisoner who was visiting his hospital to “lower the volume,” and the man exploded. “Even though he was handcuffed to the bed, he heaved an oxygen tank into a window,” Dr. Phillips said. “He said he would be coming back to kill me.”

Sometimes threats or other types of verbal abuse can be as destructive as physical violence. Diann Krywko, MD, an emergency physician at the Medical University of South Carolina (MUSC) Health, Charleston, has had some tough assignments. She worked in EDs in Detroit and Flint, Mich., for a decade before coming to MUSC, where she serves as director of wellness, health, and resilience. One of the incidents that has bothered her the most involved a threat.

It happened when Dr. Krywko denied a patient’s request for narcotics. “She was very angry and said she’d come to my home and cut my children’s heads off,” Dr. Krywko said. “To this day, what she said horrifies me. I still see her smile as she said that.”

Dr. Krywko considered filing for a restraining order against the patient but didn’t because the patient could have learned her address. Dr. Phillips said fear of retaliation is one reason many doctors don’t report threats from patients. “The patient you report knows where you work and may come there to take revenge,” he said. “Also, you may have to continue caring for the person who punched you.”

Online threats also may cause a great deal of angst. Dr. Phillips said he received many online threats when was a medical analyst for CNN in 2020. “Someone sent my address to his Twitter followers, and they shared it with others, so now the whole world knows where I live,” he said. “I had to upgrade security at my home.”
 

How to deal with volatile patients

Being nice may not always work, but in many cases, it can keep a volatile situation from exploding, according to Dr. Krywko.

“When patients begin to show signs of agitation or are already there, we always try to verbally deescalate the situation, which involves listening,” Dr. Krywko said. “They want someone to hear them out.”

Doctors speak to patients from a position of authority, but Dr. Krywko advises that they should not be too blunt. “Don’t tell patients they’re wrong,” she said. “Even if they may be incorrect, they feel their viewpoint is valid. Encourage a dialogue with words like, ‘Tell me more,’ ” Dr. Krywko said.
 

Defending yourself

Doctors may have little warning of an impending attack because a patient’s mood can change quickly. This happened several years ago to Jennifer Casaletto, MD, an emergency physician in Charlotte, N.C.

“A man was brought into my ED by ambulance,” she said. “He seemed very calm for a long while, but then he became completely unhinged. A male nurse placed himself between the patient and others and was attacked. He got hurt but was able to continue working.”

Dr. Zeller said health care teams sometimes overreact when patients lash out. “The old-fashioned way to deal with an agitated patient is to call in the cavalry – everyone does a group takedown,” he said. “The patient is put in restraints and heavily sedated. This is not good for anybody. Not only is it likely to injure and traumatize the patient, it can also injure the care team.”

Many hospital EDs have security guards. “I feel safer when a hospital has armed security guards, but they need to be well trained,” Dr. Casaletto said. “Many small hospitals and freestanding EDs do not have security officers at all, or the guards are undertrained or told not to touch anybody.”

In many electronic health record systems, doctors can flag violent patients so future caregivers can be forewarned. However, Dr. Zeller advises against writing about patients’ violence or rudeness in the medical record, because patients can have access to it and might take revenge.
 

Rising violence from patients

“It feels like it has become much more dangerous to work in the ED,” said Hasan Gokal, MD, an emergency physician working in EDs at the Texas Medical Center. “Just last week, a woman pulled out a gun and fired it in an ED near Houston.”

The statistics back up Dr. Gokal’s assessment. Injuries caused by violent attacks against medical professionals grew by 67% from 2011 to 2018, according to the U.S. Bureau of Labor Statistics. Those levels rose even more during the COVID-19 pandemic – the assault rate in hospitals rose 23% just in 2020.

Dr. Krywko said she had “a patient who said she wanted to hurt the next person who irritated her, and that happened to me. She jumped out of her bed swinging and punching, and I wasn’t ready for it. I yelled for help and the care team came.”

“The rise in violence has to do with a decline in respect for authority,” Dr. Phillips said. “Some people now believe doctors are lying to them about the need for COVID precautions because they are taking money from the vaccine companies. The pandemic has exacerbated violence in every way.”

Dr. Phillips said that a growing lack of resources had led to more anger among patients. “There are fewer nurses and reduced physician coverage,” he said. “That means longer wait times for patients, which increases patients’ frustrations.”

Dr. Weiss said patients have higher expectations. “In sports medicine, the expectations are incredible,” she said. “Parents want their kids to get back to playing as soon as possible.”

“Hospitals in particular are soft targets for violence,” Dr. Phillips said. “People know you can’t assault a flight attendant, because it’s a federal offense, but there is no such federal offense for violence against health care personnel.”

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

Ralph Newman, MD, got a taste of how dangerous medicine could be at age 10, when he witnessed a physician being shot by a patient.

“I was visiting a friend whose father was a psychiatrist,” Dr. Newman recalled. “We were playing in the living room when the doorbell rang. My friend went to the door and opened it. Then I heard a shot. I ran to the front hall and saw my friend’s father slumped at the bottom of the stairs. He had come down the stairs to see who was there. It was a patient armed with a shotgun.”

As a result of the shooting, a large portion of the psychiatrist’s intestines was removed. In spite of this traumatic incident, Dr. Newman went on to become a psychiatrist – who treated many violent prisoners. “I knew it was dangerous,” he said, “but I rationalized that I wouldn’t be attacked because I would be nicer.”

That attitude seemed to work until 2002, when a prisoner threw boiling oil on him. Dr. Newman was working at the Federal Medical Center Butner, a facility for prisoners in North Carolina. “A prisoner I had been treating was denied parole, based on my recommendation,” he said. “From then on, he was looking for a way to exact revenge.”

“One day I was sitting in the nursing station, typing up notes,” Dr. Newman said. “Two new nurses, who were also there, had forgotten to lock the door, and the prisoner noticed that. He heated up some baby oil in a microwave, which was available to prisoners at the time. Then he walked into the office, threw the oil on my back, and came at me with a sharp pencil.”

Dr. Newman said the nurses fled to an adjoining office, locked the door, and wouldn’t let him in. He went into another office and collapsed in exhaustion. He was saved by an inmate who came on the scene, fended off the attacker, and called for help.

“I was taken to the burn unit,” Dr. Newman recalled. “I had second- and third-degree burns on 9% of my body. It was extremely painful. It took me 45 days to recover enough to get back to work.” The two nurses were fired.
 

Doctors take threats by patients more seriously now

It is rare that patients murder their doctors, but when it happens, the news tears through the whole medical community. When orthopedic surgeon Preston Phillips, MD, was killed by a patient in Tulsa, Okla., on June 1, Jennifer M. Weiss, MD, recognized the potential danger to physicians.

“The news left me feeling very shaken,” said Dr. Weiss, a pediatric orthopedic surgeon at Southern California Permanente Medical Group, Los Angeles. “Every orthopedic surgeon I talked to about it felt shaken.”

Dr. Weiss said the impact of that event prompted her to take a patient’s abuse more seriously than she might have previously. “Before the killing, my colleagues and I might have swept the incident under the rug, but we reported it to the authorities,” she said.

“What happened was I told a parent of a school-aged child that the child wasn’t ready to go back to sports,” Dr. Weiss says. “This parent was incredibly triggered – screaming and making verbal threats. The parent was standing between me and the door, so I couldn’t get out.”

Coworkers down the hall heard the yelling and helped Dr. Weiss get out of the room. “The parent was escorted out of the building, and the incident was reported to our risk management team,” she said.
 

Shooters/killers vs. agitated patients

Patients who shoot to kill are very different from agitated patients seen by many doctors on a regular basis – particularly in emergency departments (EDs), psychiatric units, and pain clinics, said Scott Zeller, MD, a psychiatrist who is vice president of Acute Psychiatric Medicine at Vituity, a multistate physician partnership based in Emeryville, California.

“Agitated patients have trouble communicating their needs and can become physically and verbally aggressive,” Dr. Zeller said. He reports that there are 1.7 million such incidents a year in this country, but most of the incidents of verbal aggression can be kept from exploding into physical violence.

Shooters, however, are very hard to stop because they usually plan the action in advance, Dr. Zeller said. He recalled the 2017 murder of Todd Graham, MD, a friend from medical school. Dr. Graham, an orthopedic surgeon in South Bend, Ind., was gunned down by the husband of one of his patients after Dr. Graham declined to prescribe opioids for her.
 

Playing down the risk of violence

Doctors may play down the risk of violence, even after they have experienced it personally. “Patients can get angry and may make threatening comments,” Dr. Weiss said. “A lot of doctors just brush it off.”

Simple remarks can set off violence-prone patients, as happened to James P. Phillips, MD, director of disaster and operational medicine at George Washington University, Washington. He recalled asking a prisoner who was visiting his hospital to “lower the volume,” and the man exploded. “Even though he was handcuffed to the bed, he heaved an oxygen tank into a window,” Dr. Phillips said. “He said he would be coming back to kill me.”

Sometimes threats or other types of verbal abuse can be as destructive as physical violence. Diann Krywko, MD, an emergency physician at the Medical University of South Carolina (MUSC) Health, Charleston, has had some tough assignments. She worked in EDs in Detroit and Flint, Mich., for a decade before coming to MUSC, where she serves as director of wellness, health, and resilience. One of the incidents that has bothered her the most involved a threat.

It happened when Dr. Krywko denied a patient’s request for narcotics. “She was very angry and said she’d come to my home and cut my children’s heads off,” Dr. Krywko said. “To this day, what she said horrifies me. I still see her smile as she said that.”

Dr. Krywko considered filing for a restraining order against the patient but didn’t because the patient could have learned her address. Dr. Phillips said fear of retaliation is one reason many doctors don’t report threats from patients. “The patient you report knows where you work and may come there to take revenge,” he said. “Also, you may have to continue caring for the person who punched you.”

Online threats also may cause a great deal of angst. Dr. Phillips said he received many online threats when was a medical analyst for CNN in 2020. “Someone sent my address to his Twitter followers, and they shared it with others, so now the whole world knows where I live,” he said. “I had to upgrade security at my home.”
 

How to deal with volatile patients

Being nice may not always work, but in many cases, it can keep a volatile situation from exploding, according to Dr. Krywko.

“When patients begin to show signs of agitation or are already there, we always try to verbally deescalate the situation, which involves listening,” Dr. Krywko said. “They want someone to hear them out.”

Doctors speak to patients from a position of authority, but Dr. Krywko advises that they should not be too blunt. “Don’t tell patients they’re wrong,” she said. “Even if they may be incorrect, they feel their viewpoint is valid. Encourage a dialogue with words like, ‘Tell me more,’ ” Dr. Krywko said.
 

Defending yourself

Doctors may have little warning of an impending attack because a patient’s mood can change quickly. This happened several years ago to Jennifer Casaletto, MD, an emergency physician in Charlotte, N.C.

“A man was brought into my ED by ambulance,” she said. “He seemed very calm for a long while, but then he became completely unhinged. A male nurse placed himself between the patient and others and was attacked. He got hurt but was able to continue working.”

Dr. Zeller said health care teams sometimes overreact when patients lash out. “The old-fashioned way to deal with an agitated patient is to call in the cavalry – everyone does a group takedown,” he said. “The patient is put in restraints and heavily sedated. This is not good for anybody. Not only is it likely to injure and traumatize the patient, it can also injure the care team.”

Many hospital EDs have security guards. “I feel safer when a hospital has armed security guards, but they need to be well trained,” Dr. Casaletto said. “Many small hospitals and freestanding EDs do not have security officers at all, or the guards are undertrained or told not to touch anybody.”

In many electronic health record systems, doctors can flag violent patients so future caregivers can be forewarned. However, Dr. Zeller advises against writing about patients’ violence or rudeness in the medical record, because patients can have access to it and might take revenge.
 

Rising violence from patients

“It feels like it has become much more dangerous to work in the ED,” said Hasan Gokal, MD, an emergency physician working in EDs at the Texas Medical Center. “Just last week, a woman pulled out a gun and fired it in an ED near Houston.”

The statistics back up Dr. Gokal’s assessment. Injuries caused by violent attacks against medical professionals grew by 67% from 2011 to 2018, according to the U.S. Bureau of Labor Statistics. Those levels rose even more during the COVID-19 pandemic – the assault rate in hospitals rose 23% just in 2020.

Dr. Krywko said she had “a patient who said she wanted to hurt the next person who irritated her, and that happened to me. She jumped out of her bed swinging and punching, and I wasn’t ready for it. I yelled for help and the care team came.”

“The rise in violence has to do with a decline in respect for authority,” Dr. Phillips said. “Some people now believe doctors are lying to them about the need for COVID precautions because they are taking money from the vaccine companies. The pandemic has exacerbated violence in every way.”

Dr. Phillips said that a growing lack of resources had led to more anger among patients. “There are fewer nurses and reduced physician coverage,” he said. “That means longer wait times for patients, which increases patients’ frustrations.”

Dr. Weiss said patients have higher expectations. “In sports medicine, the expectations are incredible,” she said. “Parents want their kids to get back to playing as soon as possible.”

“Hospitals in particular are soft targets for violence,” Dr. Phillips said. “People know you can’t assault a flight attendant, because it’s a federal offense, but there is no such federal offense for violence against health care personnel.”

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

The No. 1 issue I have dealt with in my over 40 years of practicing medicine is racism.

As a Black man who grew up in this country, I can tell you first-hand what it does to you. The scars never go away, and your status is always in question, no matter your title or uniforms of respect. Eventually it wears you down.

I was born into poverty and the segregation of southwest Louisiana. I experienced the dehumanization intended for me: separate drinking fountains and poor foundational education. I was lucky to attend a historically Black college or university (Southern University, Baton Rouge, La.), that gave me my bearings. I then went to some of the very best, predominantly White institutions.

When I looked for a job after training, there were few integrated medical groups, so I started my own. It included practitioners who were White, Black, Jewish, Asian, Middle Eastern, Muslim, Christian, etc. We cross covered and treated patients from every corner of the globe.

In medicine, we treat human beings with disease. The disease should be the only difference that sets us apart. There is absolutely no place for racism.

It is difficult to be called a racist, and I have met only a handful of people in health care whom I would label as such. But racism is structural and institutionalized so that it is often hidden.

One way to overcome this is to make every effort possible to get to know people as individuals. Only then can we see that there are few real differences between us. I would often seek out a colleague from a different culture or race to have lunch with so I could learn more about them.

We all strive for the same things – validation, happiness, love, family, and a future. We all grieve over the same things.

What some caregivers may not realize is that, just as clinicians have been trained to recognize subtle signs and symptoms of disease, minorities can recognize racism immediately during a medical encounter. Our past experiences make us skilled at picking up a lack of eye contact or body language and tone of voice that are dismissive and disrespectful.

A patient who has felt racism may still return for care because of insurance coverage limitations, location, or a lack of alternatives. But trust and loyalty will never develop on the part of this patient, and empathy will be absent on the part of their caregiver.

To counter this in my own practice, I developed the Francis Commitment to avoid any hint of racism or bias toward my patients.

I commit to the following:

1. I see you.

2. I hear you.

3. I accept who you are.

4. I will try to understand how you must feel (empathy).

5. Treating you is very important to me.

6. I would like to gain your trust that I will do my very best to make you better.

7. I value you as a human being and will treat you as if you are family.

8. I care about what happens to you.

9. I want us to work together to fight this disease.

10. I am grateful that you chose me as your caregiver.

The INOVA health care system where I work has undertaken an initiative called What Matters Most to better understand the needs of every patient. We are currently working on a strategy of patient personalization to not only learn about their medical needs but also to discover who they are as a person. We incorporate Social Determinants of Health in our dealings with patients. We also have participated in a program called “A Long Talk”, where we learned that those of us who remain silent when we see or hear racism are responsible for its persistence and growth.

But we must do more. Racism will propagate if we live in silos surrounded by people whose ideas reflect our own. As long as we have nondiversified board rooms, departments, and staff, the problem will persist.

A lot of the biases that we unconsciously carry in our heads and hearts have no basis in reality and were placed there without our permission by parents, society, and friends. But we can replace these divisive thoughts and impulses.

What’s in your heart can only be known and controlled by you. How tolerant we are of racism is up to us: Do you call out racism; do you challenge any inkling of racism from friends or acquaintances; do you put pressure on institutions where you work to diversify in recruiting and hiring?

Think of all the advances in medicine that were achieved by people from different cultures and races. Racism has no place in what we have all devoted our lives to do – take care of our fellow humans.

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

The No. 1 issue I have dealt with in my over 40 years of practicing medicine is racism.

As a Black man who grew up in this country, I can tell you first-hand what it does to you. The scars never go away, and your status is always in question, no matter your title or uniforms of respect. Eventually it wears you down.

I was born into poverty and the segregation of southwest Louisiana. I experienced the dehumanization intended for me: separate drinking fountains and poor foundational education. I was lucky to attend a historically Black college or university (Southern University, Baton Rouge, La.), that gave me my bearings. I then went to some of the very best, predominantly White institutions.

When I looked for a job after training, there were few integrated medical groups, so I started my own. It included practitioners who were White, Black, Jewish, Asian, Middle Eastern, Muslim, Christian, etc. We cross covered and treated patients from every corner of the globe.

In medicine, we treat human beings with disease. The disease should be the only difference that sets us apart. There is absolutely no place for racism.

It is difficult to be called a racist, and I have met only a handful of people in health care whom I would label as such. But racism is structural and institutionalized so that it is often hidden.

One way to overcome this is to make every effort possible to get to know people as individuals. Only then can we see that there are few real differences between us. I would often seek out a colleague from a different culture or race to have lunch with so I could learn more about them.

We all strive for the same things – validation, happiness, love, family, and a future. We all grieve over the same things.

What some caregivers may not realize is that, just as clinicians have been trained to recognize subtle signs and symptoms of disease, minorities can recognize racism immediately during a medical encounter. Our past experiences make us skilled at picking up a lack of eye contact or body language and tone of voice that are dismissive and disrespectful.

A patient who has felt racism may still return for care because of insurance coverage limitations, location, or a lack of alternatives. But trust and loyalty will never develop on the part of this patient, and empathy will be absent on the part of their caregiver.

To counter this in my own practice, I developed the Francis Commitment to avoid any hint of racism or bias toward my patients.

I commit to the following:

1. I see you.

2. I hear you.

3. I accept who you are.

4. I will try to understand how you must feel (empathy).

5. Treating you is very important to me.

6. I would like to gain your trust that I will do my very best to make you better.

7. I value you as a human being and will treat you as if you are family.

8. I care about what happens to you.

9. I want us to work together to fight this disease.

10. I am grateful that you chose me as your caregiver.

The INOVA health care system where I work has undertaken an initiative called What Matters Most to better understand the needs of every patient. We are currently working on a strategy of patient personalization to not only learn about their medical needs but also to discover who they are as a person. We incorporate Social Determinants of Health in our dealings with patients. We also have participated in a program called “A Long Talk”, where we learned that those of us who remain silent when we see or hear racism are responsible for its persistence and growth.

But we must do more. Racism will propagate if we live in silos surrounded by people whose ideas reflect our own. As long as we have nondiversified board rooms, departments, and staff, the problem will persist.

A lot of the biases that we unconsciously carry in our heads and hearts have no basis in reality and were placed there without our permission by parents, society, and friends. But we can replace these divisive thoughts and impulses.

What’s in your heart can only be known and controlled by you. How tolerant we are of racism is up to us: Do you call out racism; do you challenge any inkling of racism from friends or acquaintances; do you put pressure on institutions where you work to diversify in recruiting and hiring?

Think of all the advances in medicine that were achieved by people from different cultures and races. Racism has no place in what we have all devoted our lives to do – take care of our fellow humans.

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

The No. 1 issue I have dealt with in my over 40 years of practicing medicine is racism.

As a Black man who grew up in this country, I can tell you first-hand what it does to you. The scars never go away, and your status is always in question, no matter your title or uniforms of respect. Eventually it wears you down.

I was born into poverty and the segregation of southwest Louisiana. I experienced the dehumanization intended for me: separate drinking fountains and poor foundational education. I was lucky to attend a historically Black college or university (Southern University, Baton Rouge, La.), that gave me my bearings. I then went to some of the very best, predominantly White institutions.

When I looked for a job after training, there were few integrated medical groups, so I started my own. It included practitioners who were White, Black, Jewish, Asian, Middle Eastern, Muslim, Christian, etc. We cross covered and treated patients from every corner of the globe.

In medicine, we treat human beings with disease. The disease should be the only difference that sets us apart. There is absolutely no place for racism.

It is difficult to be called a racist, and I have met only a handful of people in health care whom I would label as such. But racism is structural and institutionalized so that it is often hidden.

One way to overcome this is to make every effort possible to get to know people as individuals. Only then can we see that there are few real differences between us. I would often seek out a colleague from a different culture or race to have lunch with so I could learn more about them.

We all strive for the same things – validation, happiness, love, family, and a future. We all grieve over the same things.

What some caregivers may not realize is that, just as clinicians have been trained to recognize subtle signs and symptoms of disease, minorities can recognize racism immediately during a medical encounter. Our past experiences make us skilled at picking up a lack of eye contact or body language and tone of voice that are dismissive and disrespectful.

A patient who has felt racism may still return for care because of insurance coverage limitations, location, or a lack of alternatives. But trust and loyalty will never develop on the part of this patient, and empathy will be absent on the part of their caregiver.

To counter this in my own practice, I developed the Francis Commitment to avoid any hint of racism or bias toward my patients.

I commit to the following:

1. I see you.

2. I hear you.

3. I accept who you are.

4. I will try to understand how you must feel (empathy).

5. Treating you is very important to me.

6. I would like to gain your trust that I will do my very best to make you better.

7. I value you as a human being and will treat you as if you are family.

8. I care about what happens to you.

9. I want us to work together to fight this disease.

10. I am grateful that you chose me as your caregiver.

The INOVA health care system where I work has undertaken an initiative called What Matters Most to better understand the needs of every patient. We are currently working on a strategy of patient personalization to not only learn about their medical needs but also to discover who they are as a person. We incorporate Social Determinants of Health in our dealings with patients. We also have participated in a program called “A Long Talk”, where we learned that those of us who remain silent when we see or hear racism are responsible for its persistence and growth.

But we must do more. Racism will propagate if we live in silos surrounded by people whose ideas reflect our own. As long as we have nondiversified board rooms, departments, and staff, the problem will persist.

A lot of the biases that we unconsciously carry in our heads and hearts have no basis in reality and were placed there without our permission by parents, society, and friends. But we can replace these divisive thoughts and impulses.

What’s in your heart can only be known and controlled by you. How tolerant we are of racism is up to us: Do you call out racism; do you challenge any inkling of racism from friends or acquaintances; do you put pressure on institutions where you work to diversify in recruiting and hiring?

Think of all the advances in medicine that were achieved by people from different cultures and races. Racism has no place in what we have all devoted our lives to do – take care of our fellow humans.

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

NEW YORK – An algorithm in development for psoriatic arthritis (PsA) is showing promise for directing patients to the biologic with the greatest likelihood of producing disease control, according to a proof-of-concept study presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our technique involves a more precise functional assay showing exact T-cell behavior, compared to the previous assessments that only analyzed cellular phenotypes,” reported Gizem Ayan, MD, a fellow in rheumatology at Hacettepe University Faculty of Medicine, Ankara, Turkey.

Ted Bosworth/MDedge News

The concept of precision medicine in PsA as well as other autoimmune diseases is not new. Phenotypes and biomarkers have already shown potential for guiding treatment, according to Dr. Ayan, but she said none are yet guideline recommended or proven to improve patient outcomes.

The principle of the new algorithm that she and her coinvestigators are pursing is based on immunophenotype analysis conducted with a flow-cytometric cytokine secretion assay (FCCSA). In the protocol, monocytes obtained from peripheral blood undergo activation before an FCCSA to distinguish patients by their T-cell behavior.

The treatment decision tree is based on median ratios of tumor necrosis factor (TNF)-alpha, interleukin (IL)–22, IL-17, and interferon-gamma expression among CD4+ and CD8+ cells. Based on a yes-or-no response to specific immune patterns, the patient is funneled to a biologic that inhibits a dominant cytokine.

The proof-of-concept study, which enrolled 8 patients with PsA who were naive to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and 11 patients with PsA who were naive to biologic DMARDs (bDMARDs), was designed to demonstrate feasibility. It did not test clinical benefit, but it did show that immunophenotyping with this methodology can be performed efficiently.

“From the time a blood sample is obtained, the method provided results within 24 hours,” according to Dr. Ayan, who is now planning a randomized trial to test the ability of the algorithm to improve clinical outcomes.

In the decision tree, there are five yes-no pathways to a treatment choice. The first step of the algorithm is to test the ratio of TNF-alpha to interferon-gamma CD4+ T cells. A “yes’ response is produced if the ratio is greater than or equal to 2. These patients are then evaluated for the ratio of TNF-alpha to interferon-gamma CD8+ T cells. A yes response is produced if the ratio is greater than or equal to 0.5. If yes, they are candidates for a TNF-alpha inhibitor. If no, they are directed to an IL-12/23 inhibitor.

If the answer at the first decision point in the algorithm is a “no,” meaning they do not have a TNF-alpha to interferon-gamma CD4+ ratio of 2 or higher, they are evaluated for percentage of CD4+ T cells expressing IL-22 or IL-17. Is it greater than or equal to 2%? If the answer is “no,” they are candidates for an IL-12/23 inhibitor.

If “yes,” they are evaluated for percentage of IL-22 to IL-17 CD4+. If the IL-22 CD4+ percentage is lower than the IL-17 CD4+ percentage, meaning a “yes” to this decision point, they are directed to an IL-17 inhibitor. If the answer at this decision point is “no,” they are directed to an IL-12/23 inhibitor.

Prior to enrollment in this proof-of-concept study, 10 of the bDMARD patients were scheduled to receive an anti-TNF drug and 1 was scheduled to receive an IL-12/23 inhibitor. On the basis of this algorithm, only 5 patients were directed to an anti-TNF drug. Of the remaining, 5 were directed to an IL-17 inhibitor, and 1 was directed to an IL-12/23 inhibitor.

All 19 participants in the proof-of-concept study had peripheral arthritis; their median age was 45 years. Approximately 90% had skin lesions. Axial involvement was present in only one patient. Based on these and other characteristics and the median ratios of the cytokines measured, Dr. Ayan called this a representative population.

Based on the feasibility of this method for subtyping patients by T-cell behavior to guide drug selection, Dr. Ayan anticipates pursuing the additional steps that would show the algorithm makes a difference to patient care, including such adjunctive benefits as more cost-effective treatment selection.

“We aim to develop a treatment decision algorithm that can be implemented in daily practice,” Dr. Ayan said.

Is peripheral blood sampling adequate?

In addition to saying that the algorithm will need to prove that it alters outcomes, Samuel Tzen-yue Hwang, MD, PhD, professor and chair of the department of dermatology at the University of California, Davis, Sacramento, pointed out some potential practical issues.

“Flow cytometry is not typically available as a rapid throughput, and the cost is high,” he said. Moreover, he remains skeptical about performing this algorithm on the basis of peripheral blood samples.

“It is debatable that looking at peripheral cells would provide adequate information about what is taking place at sites of inflammation,” he said. Although it would “be fantastic” to develop an algorithm that required only a peripheral blood sample, he pointed out that “only a fraction of these cells is relevant” to disease activity.

Aspirating fluid from an involved joint “might be more useful,” but it is more work, he added. Yet, Dr. Hwang acknowledged that this approach is intriguing. He agreed that there is considerable heterogeneity among patients with PsA in their response to specific biologics, and a method to better direct patients to the treatment most likely to elicit a response is needed.

Dr. Ayan and Dr. Hwang reported no potential conflicts of interest.

NEW YORK – An algorithm in development for psoriatic arthritis (PsA) is showing promise for directing patients to the biologic with the greatest likelihood of producing disease control, according to a proof-of-concept study presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our technique involves a more precise functional assay showing exact T-cell behavior, compared to the previous assessments that only analyzed cellular phenotypes,” reported Gizem Ayan, MD, a fellow in rheumatology at Hacettepe University Faculty of Medicine, Ankara, Turkey.

Ted Bosworth/MDedge News

The concept of precision medicine in PsA as well as other autoimmune diseases is not new. Phenotypes and biomarkers have already shown potential for guiding treatment, according to Dr. Ayan, but she said none are yet guideline recommended or proven to improve patient outcomes.

The principle of the new algorithm that she and her coinvestigators are pursing is based on immunophenotype analysis conducted with a flow-cytometric cytokine secretion assay (FCCSA). In the protocol, monocytes obtained from peripheral blood undergo activation before an FCCSA to distinguish patients by their T-cell behavior.

The treatment decision tree is based on median ratios of tumor necrosis factor (TNF)-alpha, interleukin (IL)–22, IL-17, and interferon-gamma expression among CD4+ and CD8+ cells. Based on a yes-or-no response to specific immune patterns, the patient is funneled to a biologic that inhibits a dominant cytokine.

The proof-of-concept study, which enrolled 8 patients with PsA who were naive to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and 11 patients with PsA who were naive to biologic DMARDs (bDMARDs), was designed to demonstrate feasibility. It did not test clinical benefit, but it did show that immunophenotyping with this methodology can be performed efficiently.

“From the time a blood sample is obtained, the method provided results within 24 hours,” according to Dr. Ayan, who is now planning a randomized trial to test the ability of the algorithm to improve clinical outcomes.

In the decision tree, there are five yes-no pathways to a treatment choice. The first step of the algorithm is to test the ratio of TNF-alpha to interferon-gamma CD4+ T cells. A “yes’ response is produced if the ratio is greater than or equal to 2. These patients are then evaluated for the ratio of TNF-alpha to interferon-gamma CD8+ T cells. A yes response is produced if the ratio is greater than or equal to 0.5. If yes, they are candidates for a TNF-alpha inhibitor. If no, they are directed to an IL-12/23 inhibitor.

If the answer at the first decision point in the algorithm is a “no,” meaning they do not have a TNF-alpha to interferon-gamma CD4+ ratio of 2 or higher, they are evaluated for percentage of CD4+ T cells expressing IL-22 or IL-17. Is it greater than or equal to 2%? If the answer is “no,” they are candidates for an IL-12/23 inhibitor.

If “yes,” they are evaluated for percentage of IL-22 to IL-17 CD4+. If the IL-22 CD4+ percentage is lower than the IL-17 CD4+ percentage, meaning a “yes” to this decision point, they are directed to an IL-17 inhibitor. If the answer at this decision point is “no,” they are directed to an IL-12/23 inhibitor.

Prior to enrollment in this proof-of-concept study, 10 of the bDMARD patients were scheduled to receive an anti-TNF drug and 1 was scheduled to receive an IL-12/23 inhibitor. On the basis of this algorithm, only 5 patients were directed to an anti-TNF drug. Of the remaining, 5 were directed to an IL-17 inhibitor, and 1 was directed to an IL-12/23 inhibitor.

All 19 participants in the proof-of-concept study had peripheral arthritis; their median age was 45 years. Approximately 90% had skin lesions. Axial involvement was present in only one patient. Based on these and other characteristics and the median ratios of the cytokines measured, Dr. Ayan called this a representative population.

Based on the feasibility of this method for subtyping patients by T-cell behavior to guide drug selection, Dr. Ayan anticipates pursuing the additional steps that would show the algorithm makes a difference to patient care, including such adjunctive benefits as more cost-effective treatment selection.

“We aim to develop a treatment decision algorithm that can be implemented in daily practice,” Dr. Ayan said.

Is peripheral blood sampling adequate?

In addition to saying that the algorithm will need to prove that it alters outcomes, Samuel Tzen-yue Hwang, MD, PhD, professor and chair of the department of dermatology at the University of California, Davis, Sacramento, pointed out some potential practical issues.

“Flow cytometry is not typically available as a rapid throughput, and the cost is high,” he said. Moreover, he remains skeptical about performing this algorithm on the basis of peripheral blood samples.

“It is debatable that looking at peripheral cells would provide adequate information about what is taking place at sites of inflammation,” he said. Although it would “be fantastic” to develop an algorithm that required only a peripheral blood sample, he pointed out that “only a fraction of these cells is relevant” to disease activity.

Aspirating fluid from an involved joint “might be more useful,” but it is more work, he added. Yet, Dr. Hwang acknowledged that this approach is intriguing. He agreed that there is considerable heterogeneity among patients with PsA in their response to specific biologics, and a method to better direct patients to the treatment most likely to elicit a response is needed.

Dr. Ayan and Dr. Hwang reported no potential conflicts of interest.

NEW YORK – An algorithm in development for psoriatic arthritis (PsA) is showing promise for directing patients to the biologic with the greatest likelihood of producing disease control, according to a proof-of-concept study presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our technique involves a more precise functional assay showing exact T-cell behavior, compared to the previous assessments that only analyzed cellular phenotypes,” reported Gizem Ayan, MD, a fellow in rheumatology at Hacettepe University Faculty of Medicine, Ankara, Turkey.

Ted Bosworth/MDedge News

The concept of precision medicine in PsA as well as other autoimmune diseases is not new. Phenotypes and biomarkers have already shown potential for guiding treatment, according to Dr. Ayan, but she said none are yet guideline recommended or proven to improve patient outcomes.

The principle of the new algorithm that she and her coinvestigators are pursing is based on immunophenotype analysis conducted with a flow-cytometric cytokine secretion assay (FCCSA). In the protocol, monocytes obtained from peripheral blood undergo activation before an FCCSA to distinguish patients by their T-cell behavior.

The treatment decision tree is based on median ratios of tumor necrosis factor (TNF)-alpha, interleukin (IL)–22, IL-17, and interferon-gamma expression among CD4+ and CD8+ cells. Based on a yes-or-no response to specific immune patterns, the patient is funneled to a biologic that inhibits a dominant cytokine.

The proof-of-concept study, which enrolled 8 patients with PsA who were naive to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and 11 patients with PsA who were naive to biologic DMARDs (bDMARDs), was designed to demonstrate feasibility. It did not test clinical benefit, but it did show that immunophenotyping with this methodology can be performed efficiently.

“From the time a blood sample is obtained, the method provided results within 24 hours,” according to Dr. Ayan, who is now planning a randomized trial to test the ability of the algorithm to improve clinical outcomes.

In the decision tree, there are five yes-no pathways to a treatment choice. The first step of the algorithm is to test the ratio of TNF-alpha to interferon-gamma CD4+ T cells. A “yes’ response is produced if the ratio is greater than or equal to 2. These patients are then evaluated for the ratio of TNF-alpha to interferon-gamma CD8+ T cells. A yes response is produced if the ratio is greater than or equal to 0.5. If yes, they are candidates for a TNF-alpha inhibitor. If no, they are directed to an IL-12/23 inhibitor.

If the answer at the first decision point in the algorithm is a “no,” meaning they do not have a TNF-alpha to interferon-gamma CD4+ ratio of 2 or higher, they are evaluated for percentage of CD4+ T cells expressing IL-22 or IL-17. Is it greater than or equal to 2%? If the answer is “no,” they are candidates for an IL-12/23 inhibitor.

If “yes,” they are evaluated for percentage of IL-22 to IL-17 CD4+. If the IL-22 CD4+ percentage is lower than the IL-17 CD4+ percentage, meaning a “yes” to this decision point, they are directed to an IL-17 inhibitor. If the answer at this decision point is “no,” they are directed to an IL-12/23 inhibitor.

Prior to enrollment in this proof-of-concept study, 10 of the bDMARD patients were scheduled to receive an anti-TNF drug and 1 was scheduled to receive an IL-12/23 inhibitor. On the basis of this algorithm, only 5 patients were directed to an anti-TNF drug. Of the remaining, 5 were directed to an IL-17 inhibitor, and 1 was directed to an IL-12/23 inhibitor.

All 19 participants in the proof-of-concept study had peripheral arthritis; their median age was 45 years. Approximately 90% had skin lesions. Axial involvement was present in only one patient. Based on these and other characteristics and the median ratios of the cytokines measured, Dr. Ayan called this a representative population.

Based on the feasibility of this method for subtyping patients by T-cell behavior to guide drug selection, Dr. Ayan anticipates pursuing the additional steps that would show the algorithm makes a difference to patient care, including such adjunctive benefits as more cost-effective treatment selection.

“We aim to develop a treatment decision algorithm that can be implemented in daily practice,” Dr. Ayan said.

Is peripheral blood sampling adequate?

In addition to saying that the algorithm will need to prove that it alters outcomes, Samuel Tzen-yue Hwang, MD, PhD, professor and chair of the department of dermatology at the University of California, Davis, Sacramento, pointed out some potential practical issues.

“Flow cytometry is not typically available as a rapid throughput, and the cost is high,” he said. Moreover, he remains skeptical about performing this algorithm on the basis of peripheral blood samples.

“It is debatable that looking at peripheral cells would provide adequate information about what is taking place at sites of inflammation,” he said. Although it would “be fantastic” to develop an algorithm that required only a peripheral blood sample, he pointed out that “only a fraction of these cells is relevant” to disease activity.

Aspirating fluid from an involved joint “might be more useful,” but it is more work, he added. Yet, Dr. Hwang acknowledged that this approach is intriguing. He agreed that there is considerable heterogeneity among patients with PsA in their response to specific biologics, and a method to better direct patients to the treatment most likely to elicit a response is needed.

Dr. Ayan and Dr. Hwang reported no potential conflicts of interest.