The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

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

The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

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

The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

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

In a time of tremendous uncertainty, there is one trend that seems consistent year over year – the undisputed value of hospitalists. In the 2020 State of Hospital Medicine (SoHM) Report, the Society of Hospital Medicine partnered with the Medical Group Management Association (MGMA) to provide data on hospitalist compensation and productivity. The Report provides resounding evidence that hospitalists continue to be compensated at rising rates. This may be driven by both the continued demand-supply mismatch and a recognition of the overall value they generate rather than strictly the volume of their productivity.

In 2020, the median total compensation nationally for adult hospitalists (internal medicine and family medicine) was $307,633, representing an increase of over 6% from the 2018 Survey (see Figure 1).

Source: 2020 State of Hospital Medicine Report

Source: 2020 State of Hospital Medicine Report

However, the total compensation continues to be lower for academic hospitalists, with a median compensation difference of approximately $70,000 compared to their non-academic colleagues. Some of this sizable variance is offset by the fact that academic HMGs receive more in employee benefits packages than non-academic groups – a difference in median value of $10,500. Ideally, academic hospitalist compensation models should appropriately reflect and value their work efforts toward the tripartite academic mission of clinical care, education, and research. It would be valuable for future surveys to define and measure academic production in order to develop national standards for compensation models that recognize these non-billable forms of productivity.

While it’s important to review compensation benchmarks to remain competitive, it’s difficult to put a price on some factors that many may consider more valuable – group culture, opportunities for professional growth, and schedules that afford better work-life integration. Indirect measures of such benefits include paid time off, paid sick days, CME allowances and time, and retirement benefits programs. In 2020, the median employer contribution to retirement plans was reported to be $13,955, with respondents in the Midwest receiving the highest retirement benefit of $33,771.

It’s encouraging to see that hospitalist compensation continues to rise compared to previous years, despite relatively flat trends in wRVUs and total patient encounters. Another continued trend over the past years is the rising amount of financial support per physician that hospitals or other organizations provide HMGs (see Figure 3).

Source: 2020 State of Hospital Medicine Report

In 2020, the median financial support per FTE (full time equivalent) physician serving adult patients increased by 12% over 2018, to $198,750. Collectively these trends indicate hospitals are willing to compensate hospitalists for more than just their clinical volume.

There’s no doubt that the COVID-19 pandemic had some financial impact on hospital medicine groups in 2020. To assess this impact, SHM conducted a follow-up survey and compiled a COVID-19 Addendum to the SoHM Report. While 20.5% of HMG group respondents from the East reported providing hazard pay to clinicians caring for COVID-19 patients, nationally only 9.8% of groups said they offered this benefit. Of the 121 HMGs responding from across the country, 42% reported reductions in compensation, which included measures such as reductions in pay level and elimination or delays to bonus payments. The degree of reductions was not quantified, but fortunately the vast majority of these groups reported that these changes were likely to be temporary. To access all data in the 2020 SoHM Report and COVID-19 Addendum, visit hospitalmedicine.org/sohm to purchase your copy.

It’s certainly unclear what the future holds, but despite any transient changes observed during the COVID-19 pandemic, I believe that historical trends in hospitalist compensation will continue. If 2020 has taught us anything, it’s that hospitalists are essential, not only during an acute care crisis but for daily operations of any hospital.
 

Dr. Kurian is chief of the Division of Hospital Medicine at Northwell Health in New York. She is a member of SHM’s Practice Analysis Committee.

In a time of tremendous uncertainty, there is one trend that seems consistent year over year – the undisputed value of hospitalists. In the 2020 State of Hospital Medicine (SoHM) Report, the Society of Hospital Medicine partnered with the Medical Group Management Association (MGMA) to provide data on hospitalist compensation and productivity. The Report provides resounding evidence that hospitalists continue to be compensated at rising rates. This may be driven by both the continued demand-supply mismatch and a recognition of the overall value they generate rather than strictly the volume of their productivity.

In 2020, the median total compensation nationally for adult hospitalists (internal medicine and family medicine) was $307,633, representing an increase of over 6% from the 2018 Survey (see Figure 1).

Source: 2020 State of Hospital Medicine Report

Source: 2020 State of Hospital Medicine Report

However, the total compensation continues to be lower for academic hospitalists, with a median compensation difference of approximately $70,000 compared to their non-academic colleagues. Some of this sizable variance is offset by the fact that academic HMGs receive more in employee benefits packages than non-academic groups – a difference in median value of $10,500. Ideally, academic hospitalist compensation models should appropriately reflect and value their work efforts toward the tripartite academic mission of clinical care, education, and research. It would be valuable for future surveys to define and measure academic production in order to develop national standards for compensation models that recognize these non-billable forms of productivity.

While it’s important to review compensation benchmarks to remain competitive, it’s difficult to put a price on some factors that many may consider more valuable – group culture, opportunities for professional growth, and schedules that afford better work-life integration. Indirect measures of such benefits include paid time off, paid sick days, CME allowances and time, and retirement benefits programs. In 2020, the median employer contribution to retirement plans was reported to be $13,955, with respondents in the Midwest receiving the highest retirement benefit of $33,771.

It’s encouraging to see that hospitalist compensation continues to rise compared to previous years, despite relatively flat trends in wRVUs and total patient encounters. Another continued trend over the past years is the rising amount of financial support per physician that hospitals or other organizations provide HMGs (see Figure 3).

Source: 2020 State of Hospital Medicine Report

In 2020, the median financial support per FTE (full time equivalent) physician serving adult patients increased by 12% over 2018, to $198,750. Collectively these trends indicate hospitals are willing to compensate hospitalists for more than just their clinical volume.

There’s no doubt that the COVID-19 pandemic had some financial impact on hospital medicine groups in 2020. To assess this impact, SHM conducted a follow-up survey and compiled a COVID-19 Addendum to the SoHM Report. While 20.5% of HMG group respondents from the East reported providing hazard pay to clinicians caring for COVID-19 patients, nationally only 9.8% of groups said they offered this benefit. Of the 121 HMGs responding from across the country, 42% reported reductions in compensation, which included measures such as reductions in pay level and elimination or delays to bonus payments. The degree of reductions was not quantified, but fortunately the vast majority of these groups reported that these changes were likely to be temporary. To access all data in the 2020 SoHM Report and COVID-19 Addendum, visit hospitalmedicine.org/sohm to purchase your copy.

It’s certainly unclear what the future holds, but despite any transient changes observed during the COVID-19 pandemic, I believe that historical trends in hospitalist compensation will continue. If 2020 has taught us anything, it’s that hospitalists are essential, not only during an acute care crisis but for daily operations of any hospital.
 

Dr. Kurian is chief of the Division of Hospital Medicine at Northwell Health in New York. She is a member of SHM’s Practice Analysis Committee.

In a time of tremendous uncertainty, there is one trend that seems consistent year over year – the undisputed value of hospitalists. In the 2020 State of Hospital Medicine (SoHM) Report, the Society of Hospital Medicine partnered with the Medical Group Management Association (MGMA) to provide data on hospitalist compensation and productivity. The Report provides resounding evidence that hospitalists continue to be compensated at rising rates. This may be driven by both the continued demand-supply mismatch and a recognition of the overall value they generate rather than strictly the volume of their productivity.

In 2020, the median total compensation nationally for adult hospitalists (internal medicine and family medicine) was $307,633, representing an increase of over 6% from the 2018 Survey (see Figure 1).

Source: 2020 State of Hospital Medicine Report

Source: 2020 State of Hospital Medicine Report

However, the total compensation continues to be lower for academic hospitalists, with a median compensation difference of approximately $70,000 compared to their non-academic colleagues. Some of this sizable variance is offset by the fact that academic HMGs receive more in employee benefits packages than non-academic groups – a difference in median value of $10,500. Ideally, academic hospitalist compensation models should appropriately reflect and value their work efforts toward the tripartite academic mission of clinical care, education, and research. It would be valuable for future surveys to define and measure academic production in order to develop national standards for compensation models that recognize these non-billable forms of productivity.

While it’s important to review compensation benchmarks to remain competitive, it’s difficult to put a price on some factors that many may consider more valuable – group culture, opportunities for professional growth, and schedules that afford better work-life integration. Indirect measures of such benefits include paid time off, paid sick days, CME allowances and time, and retirement benefits programs. In 2020, the median employer contribution to retirement plans was reported to be $13,955, with respondents in the Midwest receiving the highest retirement benefit of $33,771.

It’s encouraging to see that hospitalist compensation continues to rise compared to previous years, despite relatively flat trends in wRVUs and total patient encounters. Another continued trend over the past years is the rising amount of financial support per physician that hospitals or other organizations provide HMGs (see Figure 3).

Source: 2020 State of Hospital Medicine Report

In 2020, the median financial support per FTE (full time equivalent) physician serving adult patients increased by 12% over 2018, to $198,750. Collectively these trends indicate hospitals are willing to compensate hospitalists for more than just their clinical volume.

There’s no doubt that the COVID-19 pandemic had some financial impact on hospital medicine groups in 2020. To assess this impact, SHM conducted a follow-up survey and compiled a COVID-19 Addendum to the SoHM Report. While 20.5% of HMG group respondents from the East reported providing hazard pay to clinicians caring for COVID-19 patients, nationally only 9.8% of groups said they offered this benefit. Of the 121 HMGs responding from across the country, 42% reported reductions in compensation, which included measures such as reductions in pay level and elimination or delays to bonus payments. The degree of reductions was not quantified, but fortunately the vast majority of these groups reported that these changes were likely to be temporary. To access all data in the 2020 SoHM Report and COVID-19 Addendum, visit hospitalmedicine.org/sohm to purchase your copy.

It’s certainly unclear what the future holds, but despite any transient changes observed during the COVID-19 pandemic, I believe that historical trends in hospitalist compensation will continue. If 2020 has taught us anything, it’s that hospitalists are essential, not only during an acute care crisis but for daily operations of any hospital.
 

Dr. Kurian is chief of the Division of Hospital Medicine at Northwell Health in New York. She is a member of SHM’s Practice Analysis Committee.

To the Editor:

The transient and generic appearance of exercise-induced vasculitis (EIV) makes it a commonly misdiagnosed condition. The lesion often is only encountered through photographs brought by the patient or by taking a thorough history. The lack of findings on clinical inspection and the generic appearance of EIV may lead to misdiagnosis as stasis dermatitis due to its presentation as erythematous lesions on the medial lower legs.

A 68-year-old woman with no notable medical history was referred to our clinic for suspected stasis dermatitis. At presentation, no lesions were identified on the legs, but she brought photographs of an erythematous urticarial eruption on the medial lower legs, extending from just above the sock line to the mid-calves (Figure). The eruptions had occurred over the last 16 years, typically presenting suddenly after playing tennis or an extended period of walking and spontaneously resolving in 4 days. The lesions were painless, restricted to the calves, and were not pruritic, though the initial presentation 16 years prior included pruritic pigmented patches on the anterior thighs. Because the condition spontaneously improved within days, no treatment was attempted. An ultrasound venous reflux study ruled out venous reflux and stasis dermatitis.

Histologic examination demonstrates features of leukocytoclastic vasculitis with perivascular lymphocytic and neutrophilic infiltrates.² Erythrocyte extravasation, IgM deposits, and identification of C3 also have been reported.^8,9 The spontaneous resolution of EIV has led to treatment efforts being focused on preventative measures. Several cases have reported some degree of success in preventing EIV with compression therapy, venoactive drugs, systemic steroids, and application of topical steroids before exercise.³

The clinical morphology and lower leg location of EIV leads to a common misdiagnosis of stasis dermatitis. Clinical history of a transient nature is the mainstay in the diagnosis of EIV, and ultrasound venous reflux study may be required in some cases. Preventative measures are superior to treatment and mainly include compression therapy.

To the Editor:

The transient and generic appearance of exercise-induced vasculitis (EIV) makes it a commonly misdiagnosed condition. The lesion often is only encountered through photographs brought by the patient or by taking a thorough history. The lack of findings on clinical inspection and the generic appearance of EIV may lead to misdiagnosis as stasis dermatitis due to its presentation as erythematous lesions on the medial lower legs.

A 68-year-old woman with no notable medical history was referred to our clinic for suspected stasis dermatitis. At presentation, no lesions were identified on the legs, but she brought photographs of an erythematous urticarial eruption on the medial lower legs, extending from just above the sock line to the mid-calves (Figure). The eruptions had occurred over the last 16 years, typically presenting suddenly after playing tennis or an extended period of walking and spontaneously resolving in 4 days. The lesions were painless, restricted to the calves, and were not pruritic, though the initial presentation 16 years prior included pruritic pigmented patches on the anterior thighs. Because the condition spontaneously improved within days, no treatment was attempted. An ultrasound venous reflux study ruled out venous reflux and stasis dermatitis.

Histologic examination demonstrates features of leukocytoclastic vasculitis with perivascular lymphocytic and neutrophilic infiltrates.² Erythrocyte extravasation, IgM deposits, and identification of C3 also have been reported.^8,9 The spontaneous resolution of EIV has led to treatment efforts being focused on preventative measures. Several cases have reported some degree of success in preventing EIV with compression therapy, venoactive drugs, systemic steroids, and application of topical steroids before exercise.³

The clinical morphology and lower leg location of EIV leads to a common misdiagnosis of stasis dermatitis. Clinical history of a transient nature is the mainstay in the diagnosis of EIV, and ultrasound venous reflux study may be required in some cases. Preventative measures are superior to treatment and mainly include compression therapy.

To the Editor:

The transient and generic appearance of exercise-induced vasculitis (EIV) makes it a commonly misdiagnosed condition. The lesion often is only encountered through photographs brought by the patient or by taking a thorough history. The lack of findings on clinical inspection and the generic appearance of EIV may lead to misdiagnosis as stasis dermatitis due to its presentation as erythematous lesions on the medial lower legs.

A 68-year-old woman with no notable medical history was referred to our clinic for suspected stasis dermatitis. At presentation, no lesions were identified on the legs, but she brought photographs of an erythematous urticarial eruption on the medial lower legs, extending from just above the sock line to the mid-calves (Figure). The eruptions had occurred over the last 16 years, typically presenting suddenly after playing tennis or an extended period of walking and spontaneously resolving in 4 days. The lesions were painless, restricted to the calves, and were not pruritic, though the initial presentation 16 years prior included pruritic pigmented patches on the anterior thighs. Because the condition spontaneously improved within days, no treatment was attempted. An ultrasound venous reflux study ruled out venous reflux and stasis dermatitis.

Histologic examination demonstrates features of leukocytoclastic vasculitis with perivascular lymphocytic and neutrophilic infiltrates.² Erythrocyte extravasation, IgM deposits, and identification of C3 also have been reported.^8,9 The spontaneous resolution of EIV has led to treatment efforts being focused on preventative measures. Several cases have reported some degree of success in preventing EIV with compression therapy, venoactive drugs, systemic steroids, and application of topical steroids before exercise.³

The clinical morphology and lower leg location of EIV leads to a common misdiagnosis of stasis dermatitis. Clinical history of a transient nature is the mainstay in the diagnosis of EIV, and ultrasound venous reflux study may be required in some cases. Preventative measures are superior to treatment and mainly include compression therapy.

To the Editor:

Few cases of unilateral nail changes affecting only the hemiplegic side after a stroke have been reported. We present a case of acquired unilateral nail clubbing and longitudinal melanonychia in a hemiparetic patient.

A 79-year-old Black man with a history of smoking and stroke presented with concerns of discoloration of the fingernails. His medical history was notable for congestive heart failure; hypertension; diabetes mellitus; hypercholesterolemia; and stroke 11 years prior, which resulted in right-sided hemiparesis. Physical examination revealed longitudinal, even hyperpigmentation of several fingernails on the hands, in addition to whitening of the nail beds, sparing the tips (Terry nails). Clubbing was noted only on the fingernails of the right hand; the fingernails of the left hand exhibited normal curvature (Figure). Pulse oximetry was conducted and demonstrated the following readings: unaffected left index finger, 98%; unaffected left middle finger, 100%; affected right index finger, 95%; and affected right middle finger, 97%. The patient was diagnosed with benign longitudinal melanonychia secondary to ethnic variation, Terry nails without underlying anemia or hypoalbuminemic state, and unilateral right-sided clubbing of the fingernails in the setting of right-sided hemiparesis.

Digital clubbing describes an exaggerated nail curvature and bulbous overgrowth of the fingertips due to an expansion of connective tissue between the nail plate and the nail bed.^3,5 Clubbed fingers are found in various chronic conditions affecting the heart, lungs, and liver. Although the pathogenesis of clubbing remains unknown, many hypothesize that it is a state of proliferation in response to digital hypoxia.⁵ Fittingly, our patient exhibited a relative hypoperfusion of the clubbed fingers in comparison to the unaffected side.

This case provides additional support for the phenomenon of unilateral nail changes limited to hemiplegic or hemiparetic limbs. The unique presentation of longitudinal melanonychia, clubbing, and a lowered pulse oximetry reading only affecting the hemiparetic side demonstrates the possible connection between hypoxia and nail clubbing in this patient population.

To the Editor:

Few cases of unilateral nail changes affecting only the hemiplegic side after a stroke have been reported. We present a case of acquired unilateral nail clubbing and longitudinal melanonychia in a hemiparetic patient.

A 79-year-old Black man with a history of smoking and stroke presented with concerns of discoloration of the fingernails. His medical history was notable for congestive heart failure; hypertension; diabetes mellitus; hypercholesterolemia; and stroke 11 years prior, which resulted in right-sided hemiparesis. Physical examination revealed longitudinal, even hyperpigmentation of several fingernails on the hands, in addition to whitening of the nail beds, sparing the tips (Terry nails). Clubbing was noted only on the fingernails of the right hand; the fingernails of the left hand exhibited normal curvature (Figure). Pulse oximetry was conducted and demonstrated the following readings: unaffected left index finger, 98%; unaffected left middle finger, 100%; affected right index finger, 95%; and affected right middle finger, 97%. The patient was diagnosed with benign longitudinal melanonychia secondary to ethnic variation, Terry nails without underlying anemia or hypoalbuminemic state, and unilateral right-sided clubbing of the fingernails in the setting of right-sided hemiparesis.

Digital clubbing describes an exaggerated nail curvature and bulbous overgrowth of the fingertips due to an expansion of connective tissue between the nail plate and the nail bed.^3,5 Clubbed fingers are found in various chronic conditions affecting the heart, lungs, and liver. Although the pathogenesis of clubbing remains unknown, many hypothesize that it is a state of proliferation in response to digital hypoxia.⁵ Fittingly, our patient exhibited a relative hypoperfusion of the clubbed fingers in comparison to the unaffected side.

This case provides additional support for the phenomenon of unilateral nail changes limited to hemiplegic or hemiparetic limbs. The unique presentation of longitudinal melanonychia, clubbing, and a lowered pulse oximetry reading only affecting the hemiparetic side demonstrates the possible connection between hypoxia and nail clubbing in this patient population.

To the Editor:

Few cases of unilateral nail changes affecting only the hemiplegic side after a stroke have been reported. We present a case of acquired unilateral nail clubbing and longitudinal melanonychia in a hemiparetic patient.

A 79-year-old Black man with a history of smoking and stroke presented with concerns of discoloration of the fingernails. His medical history was notable for congestive heart failure; hypertension; diabetes mellitus; hypercholesterolemia; and stroke 11 years prior, which resulted in right-sided hemiparesis. Physical examination revealed longitudinal, even hyperpigmentation of several fingernails on the hands, in addition to whitening of the nail beds, sparing the tips (Terry nails). Clubbing was noted only on the fingernails of the right hand; the fingernails of the left hand exhibited normal curvature (Figure). Pulse oximetry was conducted and demonstrated the following readings: unaffected left index finger, 98%; unaffected left middle finger, 100%; affected right index finger, 95%; and affected right middle finger, 97%. The patient was diagnosed with benign longitudinal melanonychia secondary to ethnic variation, Terry nails without underlying anemia or hypoalbuminemic state, and unilateral right-sided clubbing of the fingernails in the setting of right-sided hemiparesis.

Digital clubbing describes an exaggerated nail curvature and bulbous overgrowth of the fingertips due to an expansion of connective tissue between the nail plate and the nail bed.^3,5 Clubbed fingers are found in various chronic conditions affecting the heart, lungs, and liver. Although the pathogenesis of clubbing remains unknown, many hypothesize that it is a state of proliferation in response to digital hypoxia.⁵ Fittingly, our patient exhibited a relative hypoperfusion of the clubbed fingers in comparison to the unaffected side.

This case provides additional support for the phenomenon of unilateral nail changes limited to hemiplegic or hemiparetic limbs. The unique presentation of longitudinal melanonychia, clubbing, and a lowered pulse oximetry reading only affecting the hemiparetic side demonstrates the possible connection between hypoxia and nail clubbing in this patient population.

An androgen annihilation strategy using apalutamide significantly slows progression in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), according to final results from the phase 3 ACIS trial.

Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.

Courtesy of Memorial Sloan Kettering Cancer Center

“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.

Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.

With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.

Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.

Study outcomes

The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).

Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.

For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.

The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).

Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.

Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.

“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.

“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
 

Practice changing?

To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.

However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.

Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.

“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”

The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.

An androgen annihilation strategy using apalutamide significantly slows progression in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), according to final results from the phase 3 ACIS trial.

Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.

Courtesy of Memorial Sloan Kettering Cancer Center

“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.

Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.

With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.

Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.

Study outcomes

The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).

Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.

For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.

The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).

Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.

Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.

“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.

“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
 

Practice changing?

To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.

However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.

Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.

“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”

The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.

An androgen annihilation strategy using apalutamide significantly slows progression in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), according to final results from the phase 3 ACIS trial.

Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.

Courtesy of Memorial Sloan Kettering Cancer Center

“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.

Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.

With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.

Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.

Study outcomes

The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).

Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.

For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.

The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).

Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.

Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.

“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.

“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
 

Practice changing?

To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.

However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.

Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.

“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”

The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

With the exception of clozapine, the selection of an antipsychotic medication for acute treatment is driven by side effects.

That’s a key pearl of wisdom that Stephen R. Marder, MD, shared during a discussion of key criteria for choosing an antipsychotic for patients with schizophrenia.

“It’s a decision that can have huge consequences, both to an individual’s mental health and their physical health,” Dr. Marder said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “If a patient did well and liked a prior antipsychotic, that’s usually evidence that they’ll respond again. That’s been shown numerous times. Aside from that, the largest consideration is usually adverse effects.”

In a multiple-treatments meta-analysis that compared the efficacy and tolerability of 15 antipsychotic drugs in schizophrenia, researchers found that an overall positive change in symptoms occurred with clozapine, compared with any other drug.

“Clozapine is not just the most effective antipsychotic for patients who are treatment resistant; it’s also the most effective antipsychotic in general populations,” said Dr. Marder, the Daniel X. Freedman Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles. “The next most effective antipsychotic is amisulpride, which is not available in the U.S., although there’s a company that’s developing a formulation of amisulpride. After that, the 95% confidence intervals overlap, and the differences are probably related not to their true effectiveness but to other circumstances.”

For example, he continued, risperidone and olanzapine were developed in the 1990s. They were always compared with haloperidol and they tended to work a little bit better. “The drugs developed later on in clinical trials tended to be used in patients who were more treatment resistant,” he said. “Aside from clozapine, the differences in effectiveness are relatively small. But the differences in side effects are large.”

The meta-analysis found that haloperidol stood out as the antipsychotic most likely to cause extrapyramidal side effects. Olanzapine and clozapine stood out as causing the most weight gain, while ziprasidone and lurasidone were less likely to cause weight gain. In addition, risperidone, paliperidone, and haloperidol tended to cause the greatest elevation of prolactin levels, while aripiprazole was found to reduce prolactin levels.

“This becomes an important issue, particularly in young people when one is worried about galactorrhea in women or gynecomastia in men, which sometimes happens with risperidone or haloperidol, and to a lesser extent, sexual dysfunction,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education, and Clinical Center for the Department of Veterans Affairs. “Sedation is a major consideration for clozapine and chlorpromazine, but less for other antipsychotics.”

When do you know if you’ve selected the right medication for your patient? According to a meta-analysis of 42 studies involving 7,450 patients, improvement tends to occur within the first 2 weeks of treatment. “Which means if you put someone on an adequate dose of an antipsychotic and they haven’t improved in 2 weeks, there’s very little chance that they’re going to continue to improve,” Dr. Marder said. “This has been consequential because it provides guidance for clinicians to make decisions.”

Symptoms that are likely to improve in the first couple of days include agitation and psychomotor excitement. Improvement in psychotic symptoms typically occurs in the following order: those with thought disorder symptoms tend to develop more organized thinking, those with hallucinations tend to experience a decrease the intensity and frequency of their episodes, and those with well-ingrained delusions “tend to experience fewer misinterpretations,” Dr. Marder said. “They may feel less suspicious and they may talk less about delusions.”

Dr. Marder makes it a point to evaluate the antipsychotic response of patients in 2-3 weeks. “If it’s a partial response, continue a bit longer,” he advised. “It it’s no response, switch. And, of course, if the drug isn’t tolerated well, switch.”

He advised against thinking that patients can easily be categorized as being strong responders or nonresponders. Instead, he favors viewing responsiveness to an antipsychotic along a continuum. “Ten to fifteen percent of patients will fail to remit even at first exposure to an antipsychotic medication, but it’s more common that patients will be partial responders,” Dr. Marder said. “One will have to determine whether that response is adequate or not. There’s also the idea that patients sometimes respond vigorously to an antipsychotic early on. For example, first-episode patients tend to respond very well, and they respond at substantially lower doses. But I set a high criteria that we really want patients on an antipsychotic to respond well, to being in a remission that they can live with, not just to be partially remitted.”

In an analysis of response rates, 244 patients with first-episode schizophrenia moved through two antipsychotic trials, followed by a trial with clozapine. For the first two trials, treatment consisted of risperidone followed by olanzapine, or vice versa. About 75% of patients on either drug showed an initial response. “Among those who did not respond in the first trial but were switched to either drug, the response rate was very low, averaging about 16%,” Dr. Marder said. “In other words, if somebody responds poorly to risperidone, they’re not likely to respond to olanzapine, or vice versa. I think this is true among nearly all of the antipsychotic drugs that are available. Patients tend to have sort of an idiosyncratic ability to respond to a nonclozapine antipsychotic. They may respond to one better than the other, but oftentimes they won’t respond well.” When patients in the trial were switched to clozapine, 75% showed an adequate response.

Based on the study findings and on his own clinical practice, Dr. Marder recommends trying one or two antipsychotics before prescribing clozapine. “If they haven’t responded in a couple of weeks, it’s probably good to change them to another antipsychotic,” he said. “If the patient is responding poorly they should go on to clozapine, which I think is very underutilized.”

In late 2019, the Food and Drug Administration approved lumateperone, a presynaptic D2 partial agonist and a postsynaptic D2 antagonist, for the treatment of schizophrenia in adults. “Its dopamine blockage doesn’t lead to increased dopamine, so it seems to work differently than other antipsychotics,” Dr. Marder said. “It’s effective at lower D2 affinity, which is similar to drugs like clozapine, and it has greater 5 HT2A:D2 antagonism.” It appears to have a relatively benign safety profile, including minimal weight gain, minimal metabolic adverse effects, and minimal extrapyramidal effects. “However, I think the jury’s out,” he added. “There is very little information about head-to-head comparisons between lumateperone and other antipsychotics.”

The new kid on the block is the Alkermes agent AKLS 3831, a combination drug of olanzapine-samidorphan, for the treatment of adults with schizophrenia and adults with bipolar I disorder. In December 2020, the FDA accepted the company’s New Drug Application and set the Prescription Drug User Fee Act target action date of June 1, 2021. Results from a phase 2 trial demonstrated mitigation of olanzapine-induced weight gain with the opioid antagonist samidorphan. “This is not a weight-loss drug,” Dr. Marder said. “It’s just a formulation that causes less weight gain. For patients who do well on olanzapine, putting them on this combination may be helpful in preventing weight gain.”

Dr. Marder disclosed that he has served as a consultant for AbbVie, Allergan, Boehringer Ingelheim, Forum, Genentech, Lundbeck, Neurocrine, Otsuka, Roche, Sunovion, Takeda, Targacept, and Teva. He has also received research support from Boehringer Ingelheim, Neurocrine, and Takeda, and is a section editor for UpToDate.

[email protected]

With the exception of clozapine, the selection of an antipsychotic medication for acute treatment is driven by side effects.

That’s a key pearl of wisdom that Stephen R. Marder, MD, shared during a discussion of key criteria for choosing an antipsychotic for patients with schizophrenia.

“It’s a decision that can have huge consequences, both to an individual’s mental health and their physical health,” Dr. Marder said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “If a patient did well and liked a prior antipsychotic, that’s usually evidence that they’ll respond again. That’s been shown numerous times. Aside from that, the largest consideration is usually adverse effects.”

In a multiple-treatments meta-analysis that compared the efficacy and tolerability of 15 antipsychotic drugs in schizophrenia, researchers found that an overall positive change in symptoms occurred with clozapine, compared with any other drug.

“Clozapine is not just the most effective antipsychotic for patients who are treatment resistant; it’s also the most effective antipsychotic in general populations,” said Dr. Marder, the Daniel X. Freedman Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles. “The next most effective antipsychotic is amisulpride, which is not available in the U.S., although there’s a company that’s developing a formulation of amisulpride. After that, the 95% confidence intervals overlap, and the differences are probably related not to their true effectiveness but to other circumstances.”

For example, he continued, risperidone and olanzapine were developed in the 1990s. They were always compared with haloperidol and they tended to work a little bit better. “The drugs developed later on in clinical trials tended to be used in patients who were more treatment resistant,” he said. “Aside from clozapine, the differences in effectiveness are relatively small. But the differences in side effects are large.”

The meta-analysis found that haloperidol stood out as the antipsychotic most likely to cause extrapyramidal side effects. Olanzapine and clozapine stood out as causing the most weight gain, while ziprasidone and lurasidone were less likely to cause weight gain. In addition, risperidone, paliperidone, and haloperidol tended to cause the greatest elevation of prolactin levels, while aripiprazole was found to reduce prolactin levels.

“This becomes an important issue, particularly in young people when one is worried about galactorrhea in women or gynecomastia in men, which sometimes happens with risperidone or haloperidol, and to a lesser extent, sexual dysfunction,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education, and Clinical Center for the Department of Veterans Affairs. “Sedation is a major consideration for clozapine and chlorpromazine, but less for other antipsychotics.”

When do you know if you’ve selected the right medication for your patient? According to a meta-analysis of 42 studies involving 7,450 patients, improvement tends to occur within the first 2 weeks of treatment. “Which means if you put someone on an adequate dose of an antipsychotic and they haven’t improved in 2 weeks, there’s very little chance that they’re going to continue to improve,” Dr. Marder said. “This has been consequential because it provides guidance for clinicians to make decisions.”

Symptoms that are likely to improve in the first couple of days include agitation and psychomotor excitement. Improvement in psychotic symptoms typically occurs in the following order: those with thought disorder symptoms tend to develop more organized thinking, those with hallucinations tend to experience a decrease the intensity and frequency of their episodes, and those with well-ingrained delusions “tend to experience fewer misinterpretations,” Dr. Marder said. “They may feel less suspicious and they may talk less about delusions.”

Dr. Marder makes it a point to evaluate the antipsychotic response of patients in 2-3 weeks. “If it’s a partial response, continue a bit longer,” he advised. “It it’s no response, switch. And, of course, if the drug isn’t tolerated well, switch.”

He advised against thinking that patients can easily be categorized as being strong responders or nonresponders. Instead, he favors viewing responsiveness to an antipsychotic along a continuum. “Ten to fifteen percent of patients will fail to remit even at first exposure to an antipsychotic medication, but it’s more common that patients will be partial responders,” Dr. Marder said. “One will have to determine whether that response is adequate or not. There’s also the idea that patients sometimes respond vigorously to an antipsychotic early on. For example, first-episode patients tend to respond very well, and they respond at substantially lower doses. But I set a high criteria that we really want patients on an antipsychotic to respond well, to being in a remission that they can live with, not just to be partially remitted.”

In an analysis of response rates, 244 patients with first-episode schizophrenia moved through two antipsychotic trials, followed by a trial with clozapine. For the first two trials, treatment consisted of risperidone followed by olanzapine, or vice versa. About 75% of patients on either drug showed an initial response. “Among those who did not respond in the first trial but were switched to either drug, the response rate was very low, averaging about 16%,” Dr. Marder said. “In other words, if somebody responds poorly to risperidone, they’re not likely to respond to olanzapine, or vice versa. I think this is true among nearly all of the antipsychotic drugs that are available. Patients tend to have sort of an idiosyncratic ability to respond to a nonclozapine antipsychotic. They may respond to one better than the other, but oftentimes they won’t respond well.” When patients in the trial were switched to clozapine, 75% showed an adequate response.

Based on the study findings and on his own clinical practice, Dr. Marder recommends trying one or two antipsychotics before prescribing clozapine. “If they haven’t responded in a couple of weeks, it’s probably good to change them to another antipsychotic,” he said. “If the patient is responding poorly they should go on to clozapine, which I think is very underutilized.”

In late 2019, the Food and Drug Administration approved lumateperone, a presynaptic D2 partial agonist and a postsynaptic D2 antagonist, for the treatment of schizophrenia in adults. “Its dopamine blockage doesn’t lead to increased dopamine, so it seems to work differently than other antipsychotics,” Dr. Marder said. “It’s effective at lower D2 affinity, which is similar to drugs like clozapine, and it has greater 5 HT2A:D2 antagonism.” It appears to have a relatively benign safety profile, including minimal weight gain, minimal metabolic adverse effects, and minimal extrapyramidal effects. “However, I think the jury’s out,” he added. “There is very little information about head-to-head comparisons between lumateperone and other antipsychotics.”

The new kid on the block is the Alkermes agent AKLS 3831, a combination drug of olanzapine-samidorphan, for the treatment of adults with schizophrenia and adults with bipolar I disorder. In December 2020, the FDA accepted the company’s New Drug Application and set the Prescription Drug User Fee Act target action date of June 1, 2021. Results from a phase 2 trial demonstrated mitigation of olanzapine-induced weight gain with the opioid antagonist samidorphan. “This is not a weight-loss drug,” Dr. Marder said. “It’s just a formulation that causes less weight gain. For patients who do well on olanzapine, putting them on this combination may be helpful in preventing weight gain.”

Dr. Marder disclosed that he has served as a consultant for AbbVie, Allergan, Boehringer Ingelheim, Forum, Genentech, Lundbeck, Neurocrine, Otsuka, Roche, Sunovion, Takeda, Targacept, and Teva. He has also received research support from Boehringer Ingelheim, Neurocrine, and Takeda, and is a section editor for UpToDate.

[email protected]

With the exception of clozapine, the selection of an antipsychotic medication for acute treatment is driven by side effects.

That’s a key pearl of wisdom that Stephen R. Marder, MD, shared during a discussion of key criteria for choosing an antipsychotic for patients with schizophrenia.

“It’s a decision that can have huge consequences, both to an individual’s mental health and their physical health,” Dr. Marder said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “If a patient did well and liked a prior antipsychotic, that’s usually evidence that they’ll respond again. That’s been shown numerous times. Aside from that, the largest consideration is usually adverse effects.”

In a multiple-treatments meta-analysis that compared the efficacy and tolerability of 15 antipsychotic drugs in schizophrenia, researchers found that an overall positive change in symptoms occurred with clozapine, compared with any other drug.

“Clozapine is not just the most effective antipsychotic for patients who are treatment resistant; it’s also the most effective antipsychotic in general populations,” said Dr. Marder, the Daniel X. Freedman Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles. “The next most effective antipsychotic is amisulpride, which is not available in the U.S., although there’s a company that’s developing a formulation of amisulpride. After that, the 95% confidence intervals overlap, and the differences are probably related not to their true effectiveness but to other circumstances.”

For example, he continued, risperidone and olanzapine were developed in the 1990s. They were always compared with haloperidol and they tended to work a little bit better. “The drugs developed later on in clinical trials tended to be used in patients who were more treatment resistant,” he said. “Aside from clozapine, the differences in effectiveness are relatively small. But the differences in side effects are large.”

The meta-analysis found that haloperidol stood out as the antipsychotic most likely to cause extrapyramidal side effects. Olanzapine and clozapine stood out as causing the most weight gain, while ziprasidone and lurasidone were less likely to cause weight gain. In addition, risperidone, paliperidone, and haloperidol tended to cause the greatest elevation of prolactin levels, while aripiprazole was found to reduce prolactin levels.

“This becomes an important issue, particularly in young people when one is worried about galactorrhea in women or gynecomastia in men, which sometimes happens with risperidone or haloperidol, and to a lesser extent, sexual dysfunction,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education, and Clinical Center for the Department of Veterans Affairs. “Sedation is a major consideration for clozapine and chlorpromazine, but less for other antipsychotics.”

When do you know if you’ve selected the right medication for your patient? According to a meta-analysis of 42 studies involving 7,450 patients, improvement tends to occur within the first 2 weeks of treatment. “Which means if you put someone on an adequate dose of an antipsychotic and they haven’t improved in 2 weeks, there’s very little chance that they’re going to continue to improve,” Dr. Marder said. “This has been consequential because it provides guidance for clinicians to make decisions.”

Symptoms that are likely to improve in the first couple of days include agitation and psychomotor excitement. Improvement in psychotic symptoms typically occurs in the following order: those with thought disorder symptoms tend to develop more organized thinking, those with hallucinations tend to experience a decrease the intensity and frequency of their episodes, and those with well-ingrained delusions “tend to experience fewer misinterpretations,” Dr. Marder said. “They may feel less suspicious and they may talk less about delusions.”

Dr. Marder makes it a point to evaluate the antipsychotic response of patients in 2-3 weeks. “If it’s a partial response, continue a bit longer,” he advised. “It it’s no response, switch. And, of course, if the drug isn’t tolerated well, switch.”

He advised against thinking that patients can easily be categorized as being strong responders or nonresponders. Instead, he favors viewing responsiveness to an antipsychotic along a continuum. “Ten to fifteen percent of patients will fail to remit even at first exposure to an antipsychotic medication, but it’s more common that patients will be partial responders,” Dr. Marder said. “One will have to determine whether that response is adequate or not. There’s also the idea that patients sometimes respond vigorously to an antipsychotic early on. For example, first-episode patients tend to respond very well, and they respond at substantially lower doses. But I set a high criteria that we really want patients on an antipsychotic to respond well, to being in a remission that they can live with, not just to be partially remitted.”

In an analysis of response rates, 244 patients with first-episode schizophrenia moved through two antipsychotic trials, followed by a trial with clozapine. For the first two trials, treatment consisted of risperidone followed by olanzapine, or vice versa. About 75% of patients on either drug showed an initial response. “Among those who did not respond in the first trial but were switched to either drug, the response rate was very low, averaging about 16%,” Dr. Marder said. “In other words, if somebody responds poorly to risperidone, they’re not likely to respond to olanzapine, or vice versa. I think this is true among nearly all of the antipsychotic drugs that are available. Patients tend to have sort of an idiosyncratic ability to respond to a nonclozapine antipsychotic. They may respond to one better than the other, but oftentimes they won’t respond well.” When patients in the trial were switched to clozapine, 75% showed an adequate response.

Based on the study findings and on his own clinical practice, Dr. Marder recommends trying one or two antipsychotics before prescribing clozapine. “If they haven’t responded in a couple of weeks, it’s probably good to change them to another antipsychotic,” he said. “If the patient is responding poorly they should go on to clozapine, which I think is very underutilized.”

In late 2019, the Food and Drug Administration approved lumateperone, a presynaptic D2 partial agonist and a postsynaptic D2 antagonist, for the treatment of schizophrenia in adults. “Its dopamine blockage doesn’t lead to increased dopamine, so it seems to work differently than other antipsychotics,” Dr. Marder said. “It’s effective at lower D2 affinity, which is similar to drugs like clozapine, and it has greater 5 HT2A:D2 antagonism.” It appears to have a relatively benign safety profile, including minimal weight gain, minimal metabolic adverse effects, and minimal extrapyramidal effects. “However, I think the jury’s out,” he added. “There is very little information about head-to-head comparisons between lumateperone and other antipsychotics.”

The new kid on the block is the Alkermes agent AKLS 3831, a combination drug of olanzapine-samidorphan, for the treatment of adults with schizophrenia and adults with bipolar I disorder. In December 2020, the FDA accepted the company’s New Drug Application and set the Prescription Drug User Fee Act target action date of June 1, 2021. Results from a phase 2 trial demonstrated mitigation of olanzapine-induced weight gain with the opioid antagonist samidorphan. “This is not a weight-loss drug,” Dr. Marder said. “It’s just a formulation that causes less weight gain. For patients who do well on olanzapine, putting them on this combination may be helpful in preventing weight gain.”

Dr. Marder disclosed that he has served as a consultant for AbbVie, Allergan, Boehringer Ingelheim, Forum, Genentech, Lundbeck, Neurocrine, Otsuka, Roche, Sunovion, Takeda, Targacept, and Teva. He has also received research support from Boehringer Ingelheim, Neurocrine, and Takeda, and is a section editor for UpToDate.

[email protected]

The combination of methylprednisolone and intravenous immunoglobulins works better than intravenous immunoglobulins alone for multisystem inflammatory syndrome in children (MIS-C), researchers say.

“I’m not sure it’s the best treatment because we have not studied every possible treatment,” François Angoulvant, MD, PhD, told this news organization, “but right now, it’s the standard of care.”

Dr. Angoulvant, a professor of pediatrics at University of Paris, and colleagues published a comparison of the two treatments in the Journal of the American Medical Association.

A small percentage of children infected with SARS-CoV-2 develop MIS-C about 2 to 4 weeks later. It is considered a separate disease entity from COVID-19 and is associated with persistent fever, digestive symptoms, rash, bilateral nonpurulent conjunctivitis, mucocutaneous inflammation signs, and frequent cardiovascular involvement. In more than 60% of cases, it leads to hemodynamic failure, with acute cardiac dysfunction.

Because MIS-C resembles Kawasaki disease, clinicians modeled their treatment on that condition and started with immunoglobulins alone, Dr. Angoulvant said.

Based on expert opinion, the National Health Service in the United Kingdom published a consensus statement in Sept. listing immunoglobulins alone as the first-line treatment.

But anecdotal reports have emerged that combining the immunoglobulins with a corticosteroid worked better. To investigate this possibility, Dr. Angoulvant and colleagues analyzed records of MIS-C cases in France, where physicians are required to report all suspected cases of MIS-C to the French National Public Health Agency.

Among the 181 cases they scrutinized, 111 fulfilled the World Health Organization criteria for MIS-C. Of these, the researchers were able to match 64 patients who had received immunoglobulins alone with 32 who had received the combined therapy and could be matched using propensity scores.

The researchers defined treatment failure as persistence of fever for 2 days after the start of therapy or recurrence of fever within a week. By this measure, the combination treatment failed in only 9% of cases while immunoglobulins alone failed in 38% of cases. The difference was statistically significant (P = .008). Most of those for whom these treatments failed received second-line treatments such as steroids or biological agents.

Patients treated with the combination therapy also had a lower risk of secondary acute left ventricular dysfunction (odds ratio, 0.20; 95% confidence interval, 0.06-0.66) and a lower risk of needing hemodynamic support (OR, 0.21; 95% CI, 0.06-0.76).

Those receiving the combination therapy spent a mean of 4 days in the pediatric intensive care unit compared with 6 days for those receiving immunoglobulins alone. (Difference in days, −2.4; 95% CI, −4.0 to −0.7; P = .005).

There are few drawbacks to the combination approach, Dr. Angoulvant said, as the side effects of corticosteroids are generally not severe and they can be anticipated because this class of medications has been used for many years.

The study raises the question of whether corticosteroids might work as well by themselves, but it could not be answered with this database as no one is using that approach in France, Dr. Angoulvant said. “I hope other teams around the world could bring us the answer.”

In the United States, most physicians appear to already be using the combination therapy, said David Teachey, MD, an associate professor of pediatrics at the Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia.

The reduction in time in pediatric intensive care and the reduced risk of cardiac dysfunction are important findings, he said.

This retrospective study falls short of the evidence provided by a randomized clinical trial, Dr. Teachey noted. But he acknowledged that few families would agree to participate in such a trial as they would have to take a chance that the sick children would receive a less effective therapy than what they would otherwise get. “It’s hard to [talk] about a therapy reduction,” he told this news organization.

Given that impediment, he agreed with Dr. Angoulvant that the current study and others like it may provide the best data available pointing to a treatment approach for MIS-C.

The study received an unrestricted grant from Pfizer. The French COVID-19 Paediatric Inflammation Consortium received an unrestricted grant from the Square Foundation (Grandir–Fonds de Solidarité pour L’Enfance). Dr. Angoulvant and Dr. Teachey have disclosed no relevant financial relationships.

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

The combination of methylprednisolone and intravenous immunoglobulins works better than intravenous immunoglobulins alone for multisystem inflammatory syndrome in children (MIS-C), researchers say.

“I’m not sure it’s the best treatment because we have not studied every possible treatment,” François Angoulvant, MD, PhD, told this news organization, “but right now, it’s the standard of care.”

Dr. Angoulvant, a professor of pediatrics at University of Paris, and colleagues published a comparison of the two treatments in the Journal of the American Medical Association.

A small percentage of children infected with SARS-CoV-2 develop MIS-C about 2 to 4 weeks later. It is considered a separate disease entity from COVID-19 and is associated with persistent fever, digestive symptoms, rash, bilateral nonpurulent conjunctivitis, mucocutaneous inflammation signs, and frequent cardiovascular involvement. In more than 60% of cases, it leads to hemodynamic failure, with acute cardiac dysfunction.

Because MIS-C resembles Kawasaki disease, clinicians modeled their treatment on that condition and started with immunoglobulins alone, Dr. Angoulvant said.

Based on expert opinion, the National Health Service in the United Kingdom published a consensus statement in Sept. listing immunoglobulins alone as the first-line treatment.

But anecdotal reports have emerged that combining the immunoglobulins with a corticosteroid worked better. To investigate this possibility, Dr. Angoulvant and colleagues analyzed records of MIS-C cases in France, where physicians are required to report all suspected cases of MIS-C to the French National Public Health Agency.

Among the 181 cases they scrutinized, 111 fulfilled the World Health Organization criteria for MIS-C. Of these, the researchers were able to match 64 patients who had received immunoglobulins alone with 32 who had received the combined therapy and could be matched using propensity scores.

The researchers defined treatment failure as persistence of fever for 2 days after the start of therapy or recurrence of fever within a week. By this measure, the combination treatment failed in only 9% of cases while immunoglobulins alone failed in 38% of cases. The difference was statistically significant (P = .008). Most of those for whom these treatments failed received second-line treatments such as steroids or biological agents.

Patients treated with the combination therapy also had a lower risk of secondary acute left ventricular dysfunction (odds ratio, 0.20; 95% confidence interval, 0.06-0.66) and a lower risk of needing hemodynamic support (OR, 0.21; 95% CI, 0.06-0.76).

Those receiving the combination therapy spent a mean of 4 days in the pediatric intensive care unit compared with 6 days for those receiving immunoglobulins alone. (Difference in days, −2.4; 95% CI, −4.0 to −0.7; P = .005).

There are few drawbacks to the combination approach, Dr. Angoulvant said, as the side effects of corticosteroids are generally not severe and they can be anticipated because this class of medications has been used for many years.

The study raises the question of whether corticosteroids might work as well by themselves, but it could not be answered with this database as no one is using that approach in France, Dr. Angoulvant said. “I hope other teams around the world could bring us the answer.”

In the United States, most physicians appear to already be using the combination therapy, said David Teachey, MD, an associate professor of pediatrics at the Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia.

The reduction in time in pediatric intensive care and the reduced risk of cardiac dysfunction are important findings, he said.

This retrospective study falls short of the evidence provided by a randomized clinical trial, Dr. Teachey noted. But he acknowledged that few families would agree to participate in such a trial as they would have to take a chance that the sick children would receive a less effective therapy than what they would otherwise get. “It’s hard to [talk] about a therapy reduction,” he told this news organization.

Given that impediment, he agreed with Dr. Angoulvant that the current study and others like it may provide the best data available pointing to a treatment approach for MIS-C.

The study received an unrestricted grant from Pfizer. The French COVID-19 Paediatric Inflammation Consortium received an unrestricted grant from the Square Foundation (Grandir–Fonds de Solidarité pour L’Enfance). Dr. Angoulvant and Dr. Teachey have disclosed no relevant financial relationships.

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

The combination of methylprednisolone and intravenous immunoglobulins works better than intravenous immunoglobulins alone for multisystem inflammatory syndrome in children (MIS-C), researchers say.

“I’m not sure it’s the best treatment because we have not studied every possible treatment,” François Angoulvant, MD, PhD, told this news organization, “but right now, it’s the standard of care.”

Dr. Angoulvant, a professor of pediatrics at University of Paris, and colleagues published a comparison of the two treatments in the Journal of the American Medical Association.

A small percentage of children infected with SARS-CoV-2 develop MIS-C about 2 to 4 weeks later. It is considered a separate disease entity from COVID-19 and is associated with persistent fever, digestive symptoms, rash, bilateral nonpurulent conjunctivitis, mucocutaneous inflammation signs, and frequent cardiovascular involvement. In more than 60% of cases, it leads to hemodynamic failure, with acute cardiac dysfunction.

Because MIS-C resembles Kawasaki disease, clinicians modeled their treatment on that condition and started with immunoglobulins alone, Dr. Angoulvant said.

Based on expert opinion, the National Health Service in the United Kingdom published a consensus statement in Sept. listing immunoglobulins alone as the first-line treatment.

But anecdotal reports have emerged that combining the immunoglobulins with a corticosteroid worked better. To investigate this possibility, Dr. Angoulvant and colleagues analyzed records of MIS-C cases in France, where physicians are required to report all suspected cases of MIS-C to the French National Public Health Agency.

Among the 181 cases they scrutinized, 111 fulfilled the World Health Organization criteria for MIS-C. Of these, the researchers were able to match 64 patients who had received immunoglobulins alone with 32 who had received the combined therapy and could be matched using propensity scores.

The researchers defined treatment failure as persistence of fever for 2 days after the start of therapy or recurrence of fever within a week. By this measure, the combination treatment failed in only 9% of cases while immunoglobulins alone failed in 38% of cases. The difference was statistically significant (P = .008). Most of those for whom these treatments failed received second-line treatments such as steroids or biological agents.

Patients treated with the combination therapy also had a lower risk of secondary acute left ventricular dysfunction (odds ratio, 0.20; 95% confidence interval, 0.06-0.66) and a lower risk of needing hemodynamic support (OR, 0.21; 95% CI, 0.06-0.76).

Those receiving the combination therapy spent a mean of 4 days in the pediatric intensive care unit compared with 6 days for those receiving immunoglobulins alone. (Difference in days, −2.4; 95% CI, −4.0 to −0.7; P = .005).

There are few drawbacks to the combination approach, Dr. Angoulvant said, as the side effects of corticosteroids are generally not severe and they can be anticipated because this class of medications has been used for many years.

The study raises the question of whether corticosteroids might work as well by themselves, but it could not be answered with this database as no one is using that approach in France, Dr. Angoulvant said. “I hope other teams around the world could bring us the answer.”

In the United States, most physicians appear to already be using the combination therapy, said David Teachey, MD, an associate professor of pediatrics at the Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia.

The reduction in time in pediatric intensive care and the reduced risk of cardiac dysfunction are important findings, he said.

This retrospective study falls short of the evidence provided by a randomized clinical trial, Dr. Teachey noted. But he acknowledged that few families would agree to participate in such a trial as they would have to take a chance that the sick children would receive a less effective therapy than what they would otherwise get. “It’s hard to [talk] about a therapy reduction,” he told this news organization.

Given that impediment, he agreed with Dr. Angoulvant that the current study and others like it may provide the best data available pointing to a treatment approach for MIS-C.

The study received an unrestricted grant from Pfizer. The French COVID-19 Paediatric Inflammation Consortium received an unrestricted grant from the Square Foundation (Grandir–Fonds de Solidarité pour L’Enfance). Dr. Angoulvant and Dr. Teachey have disclosed no relevant financial relationships.

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

To the Editor:

Bullous pemphigoid (BP) is a rare complication of lower limb amputation. Termed stump pemphigoid, it previously was described as a late complication arising on the stumps of leg amputees and tends to remain localized. We describe a case of stump pemphigoid presenting with an urticarial prodromal phase without generalized progression, confirmed by serum assay for circulating anti–basement membrane antibodies.

A 62-year-old man with a history of a right above-knee amputation initially presented with erythema as well as coalescing erosions and ulcers with fluid-filled vesicles and bullae on the amputation stump (Figure 1). The amputation was performed 15 years prior after a motorcycle accident. A skin biopsy of a vesicle on the amputation stump revealed subepidermal and focal intraepidermal clefting with hemorrhage and rare inflammatory cells composed of neutrophils and eosinophils (Figure 2). A tissue direct immunofluorescence test demonstrated linear C3 and IgG deposition along the dermoepidermal junction. Serum enzyme-linked immunosorbent assay (ELISA) demonstrated an anti-BP180 IgG of 50.90 U/mL and anti-BP230 IgG of 129.40 U/mL (reference range, <9.00 U/mL [for both]).

Amputees experience a high rate of skin complications on their stump,¹ including friction blisters, shear injury, contact dermatitis, infections, and autoimmune blistering disorders (ie, BP, epidermolysis bullosa acquisita). The etiology of stump pemphigoid is not entirely understood but could be related to exposure of structural components of the hemidesmosome (eg, BP230, BP180), leading to autoantibody production as a consequence of either the underlying limb injury or from recurrent trauma related to limb prosthetics.²

Two previously reported cases of stump pemphigoid demonstrated a positive direct immunofluorescence antibody test.^3,4 Another case demonstrated the presence of circulating IgG antibodies on indirect immunofluorescence to salt-split skin.⁵ We report a case of stump pemphigoid confirmed by presence of circulating anti–basement membrane antibodies on ELISA, supporting its use in the diagnostic workup and monitoring treatment response.

To the Editor:

Bullous pemphigoid (BP) is a rare complication of lower limb amputation. Termed stump pemphigoid, it previously was described as a late complication arising on the stumps of leg amputees and tends to remain localized. We describe a case of stump pemphigoid presenting with an urticarial prodromal phase without generalized progression, confirmed by serum assay for circulating anti–basement membrane antibodies.

A 62-year-old man with a history of a right above-knee amputation initially presented with erythema as well as coalescing erosions and ulcers with fluid-filled vesicles and bullae on the amputation stump (Figure 1). The amputation was performed 15 years prior after a motorcycle accident. A skin biopsy of a vesicle on the amputation stump revealed subepidermal and focal intraepidermal clefting with hemorrhage and rare inflammatory cells composed of neutrophils and eosinophils (Figure 2). A tissue direct immunofluorescence test demonstrated linear C3 and IgG deposition along the dermoepidermal junction. Serum enzyme-linked immunosorbent assay (ELISA) demonstrated an anti-BP180 IgG of 50.90 U/mL and anti-BP230 IgG of 129.40 U/mL (reference range, <9.00 U/mL [for both]).

Amputees experience a high rate of skin complications on their stump,¹ including friction blisters, shear injury, contact dermatitis, infections, and autoimmune blistering disorders (ie, BP, epidermolysis bullosa acquisita). The etiology of stump pemphigoid is not entirely understood but could be related to exposure of structural components of the hemidesmosome (eg, BP230, BP180), leading to autoantibody production as a consequence of either the underlying limb injury or from recurrent trauma related to limb prosthetics.²

Two previously reported cases of stump pemphigoid demonstrated a positive direct immunofluorescence antibody test.^3,4 Another case demonstrated the presence of circulating IgG antibodies on indirect immunofluorescence to salt-split skin.⁵ We report a case of stump pemphigoid confirmed by presence of circulating anti–basement membrane antibodies on ELISA, supporting its use in the diagnostic workup and monitoring treatment response.

To the Editor:

Bullous pemphigoid (BP) is a rare complication of lower limb amputation. Termed stump pemphigoid, it previously was described as a late complication arising on the stumps of leg amputees and tends to remain localized. We describe a case of stump pemphigoid presenting with an urticarial prodromal phase without generalized progression, confirmed by serum assay for circulating anti–basement membrane antibodies.

A 62-year-old man with a history of a right above-knee amputation initially presented with erythema as well as coalescing erosions and ulcers with fluid-filled vesicles and bullae on the amputation stump (Figure 1). The amputation was performed 15 years prior after a motorcycle accident. A skin biopsy of a vesicle on the amputation stump revealed subepidermal and focal intraepidermal clefting with hemorrhage and rare inflammatory cells composed of neutrophils and eosinophils (Figure 2). A tissue direct immunofluorescence test demonstrated linear C3 and IgG deposition along the dermoepidermal junction. Serum enzyme-linked immunosorbent assay (ELISA) demonstrated an anti-BP180 IgG of 50.90 U/mL and anti-BP230 IgG of 129.40 U/mL (reference range, <9.00 U/mL [for both]).

Amputees experience a high rate of skin complications on their stump,¹ including friction blisters, shear injury, contact dermatitis, infections, and autoimmune blistering disorders (ie, BP, epidermolysis bullosa acquisita). The etiology of stump pemphigoid is not entirely understood but could be related to exposure of structural components of the hemidesmosome (eg, BP230, BP180), leading to autoantibody production as a consequence of either the underlying limb injury or from recurrent trauma related to limb prosthetics.²

Two previously reported cases of stump pemphigoid demonstrated a positive direct immunofluorescence antibody test.^3,4 Another case demonstrated the presence of circulating IgG antibodies on indirect immunofluorescence to salt-split skin.⁵ We report a case of stump pemphigoid confirmed by presence of circulating anti–basement membrane antibodies on ELISA, supporting its use in the diagnostic workup and monitoring treatment response.

To the Editor:

Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi (genus Rickettsia), which is transmitted by the larvae of trombiculid mites, commonly called chiggers. The disease mainly has been described in Asia in an area known as the Tsutsugamushi Triangle, delineated by Pakistan, eastern Russia, and northern Australia. Although this classic distribution remains, recent reports have documented 1 case in the Arabian Peninsula¹ and more than 16 cases in southern Chile.^2-4 The first case in Chile was published in 2011 from Chiloé Island.² To date, no other cases have been reported in the Americas.^1-6

We describe a new case of ST from Chiloé Island and compare it to the first case reported in Chile in 2011.² Both patients showed the typical clinical manifestation, but because ST has become an increasingly suspected disease in southern regions of Chile, new cases are now easily diagnosed. This infection is diagnosed mainly by skin lesions; therefore, dermatologists should be aware of this diagnosis when presented with a febrile rash.

A 67-year-old man from the city of Punta Arenas presented to the emergency department with a dark necrotic lesion on the right foot of 1 week’s duration. The patient later developed a generalized pruritic rash and fever. He also reported muscle pain, headache, cough, night sweats, and odynophagia. He reported recent travel to a rural area in the northern part of Chiloé Island, where he came into contact with firewood and participated in outdoor activities. He had no other relevant medical history.

Physical examination revealed a temperature of 38 °C and a macular rash, with some papules distributed mainly on the face, trunk, and proximal extremities (Figure 1). He had a necrotic eschar on the dorsum of the right foot, with an erythematous halo (tache noire)(Figure 2).

Scrub typhus is a high-impact disease in Asia, described mainly in an area known as the Tsutsugamushi Triangle. Recent reports show important epidemiologic changes in the distribution of the disease, with new published reports of cases outside this endemic area—1 in the Arabian peninsula¹ and more than 16 in southern Chile.^2-4

The disease begins with a painless, erythematous, and usually unnoticed papule at the site of the bite. After 48 to 72 hours, the papule changes to a necrotic form (tache noire), surrounded by a red halo that often is small, similar to a cigarette burn. This lesion is described in 20% to 90% of infected patients in different series.⁷ Two or 3 days later (1 to 3 weeks after exposure), high fever suddenly develops. Along with fever, a maculopapular rash distributed centrifugally develops, without compromise of the palms or soles. Patients frequently report headache and night sweating. Sometimes, ST is accompanied by muscle or joint pain, red eye, cough, and abdominal pain. Hearing loss and altered mental status less frequently have been reported.^5,8

Common laboratory tests can be of use in diagnosis. An elevated C-reactive protein level and a slight to moderate increase in hepatic transaminases should be expected. Thrombocytopenia, leukopenia, and elevation of the lactate dehydrogenase level less frequently are present.^5,9

Our case de1monstrated a typical presentation. The patient developed a febrile syndrome with a generalized rash and a tache noire–type eschar associated with muscle pain, headache, cough, night sweats, and odynophagia. Because of epidemiologic changes in the area, the familiar clinical findings, and laboratory confirmation, histologic studies were unnecessary. In cases in which the diagnosis is not evident, skin biopsy could be useful, as in the first case reported in Chile.²

In that first case, the patient initially was hospitalized because of a febrile syndrome; eventually, a necrotic eschar was noticed on his leg. He had been staying on Chiloé Island and reported being bitten by leeches on multiple occasions. Laboratory findings revealed only slightly raised levels of hepatic transaminases and alkaline phosphatase. After a more precise dermatologic evaluation, the eschar of a tache noire, combined with other clinical and laboratory findings, raised suspicion of ST. Because this entity had never been described in Chile, biopsy of the eschar was taken to consider other entities in the differential diagnosis. Biopsy showed necrotizing leukocytoclastic vasculitis in the dermis and subcutaneous tissue, perivascular inflammatory infiltrates comprising lymphocytes and macrophages, and rickettsial microorganisms inside endothelial cells under electron microscopic examination. The specimen was tested for the 16S ribosomal RNA Orientia gene; its presence confirmed the diagnosis.²

Classically, histology from the eschar shows signs of vasculitis and rickettsial microorganisms inside endothelial cells on electron microscopy.^2,10 More recent publications describe important necrotic changes within keratinocytes as well as an inflammatory infiltrate comprising antigen-presenting cells, monocytes, macrophages, and dendritic cells. Using high-resolution thin sections with confocal laser scanning microscopy and staining of specific monoclonal antibodies against 56 kDa type-specific surface antigens, the bacteria were found inside antigen-presenting cells, many of them located perivascularly or passing through the endothelium.¹¹

The causal agent in Asia is O tsutsugamushi, an obligate intracellular bacterium (genus Rickettsia). Orientia species are transmitted by larvae of trombiculid mites, commonly called chiggers. The reservoir is believed to be the same as with chiggers, in which some vertebrates become infected and trombiculid mites feed on them.¹² Recent studies of Chilean cases have revealed the presence of a novel Orientia species, Candidatus Orientia chiloensis and its vector, trombiculid mites from the Herpetacarus species, Quadraseta species, and Paratrombicula species genera.^13,14

A high seroprevalence of Orientia species in dogs was reported in the main cities of Chiloé Island. Rates were higher in rural settings and older dogs. Of 202 specimens, 21.3% were positive for IgG against Orientia species.¹⁵

In Chile, most cases of ST came from Chiloé Island; some reports of cases from continental Chilean regions have been published.⁶ Most cases have occurred in the context of activities that brought the patients in contact with plants and firewood in rural areas during the summer.^3-6

The diagnosis of ST is eminently clinical, based on the triad of fever, macular or papular rash, and an inoculation necrotic eschar. The diagnosis is supported by epidemiologic facts and fast recovery after treatment is initiated.¹⁶ Although the diagnosis can be established based on a quick recovery in endemic countries, in areas such as Chile where incidence and distribution are not completely known, it is better to confirm the diagnosis with laboratory tests without delaying treatment. Several testing options exist, including serologic techniques (immunofluorescence or enzyme-linked immunosorbent assay), culture, and detection of the genetic material of Orientia species by PCR. Usually, IgM titers initially are negative, and IgG testing requires paired samples (acute and convalescent) to demonstrate seroconversion and therefore acute infection.¹⁷ Because culture requires a highly specialized laboratory, it is not frequently used. Polymerase chain reaction is recognized as the best confirmation method due to its high sensitivity and because it remains positive for a few days after treatment has been initiated. The specimen of choice is the eschar because of its high bacterial load. The base of the scar and the buffy coat are useful specimens when the eschar is unavailable.^5,17-19

Due to potential complications of ST, empirical treatment with an antibiotic should be started based on clinical facts and never delayed because of diagnostic tests.¹⁸ Classically, ST is treated with a member of the tetracycline family, such as doxycycline, which provides a cure rate of 63% to 100% in ST.⁵

A 2017 systematic review of treatment options for this infection examined 11 studies from Southeast Asia, China, and South Korea (N=957).¹⁶ The review mainly compared doxycycline with azithromycin, chloramphenicol, and tetracycline. No significant difference in cure rate was noted in comparing doxycycline with any of the other 3 antibiotics; most of the studies examined were characterized by a moderate level of evidence. Regarding adverse effects, doxycycline showed a few more cases of gastrointestinal intolerance, and in 2 of 4 studies with chloramphenicol, patients presented with leukopenia.¹⁶ Several studies compared standard treatment (doxycycline) with rifampicin, telithromycin, erythromycin, and levofloxacin individually; similar cure rates were noted between doxycycline and each of those 4 agents.

Therapeutic failure in ST has been reported in several cases with the use of levofloxacin.²⁰ Evidence for this novel antibiotic is still insufficient. Further studies are needed before rifampicin, telithromycin, erythromycin, or levofloxacin can be considered as options.Scrub typhus usually resolves within a few weeks. Left untreated, the disease can cause complications such as pneumonia, meningoencephalitis, renal failure, and even multiorgan failure and death. Without treatment, mortality is variable. A 2015 systematic review of mortality from untreated ST showed, on average, mortality of 6% (range, 0%–70%).²¹ When ST is treated, mortality falls to 0% to 30%.²² Cases reported in Chile have neither been lethal nor presented with severe complications.^4,5

Scrub typhus is an infectious disease common in Asia, caused by O tsutsugamushi and transmitted by chiggers. It should be suspected when a febrile macular or papular rash and a tache noire appear. The diagnosis can be supported by laboratory findings, such as an elevated C-reactive protein level or a slight increase in the levels of hepatic transaminases, and response to treatment. The diagnosis is confirmed by serology or PCR of a specimen of the eschar. Empiric therapy with antibiotics is mandatory; doxycycline is the first option.

First described in Chile in 2011,² ST was seen in a patient in whom disease was suspected because of clinical characteristics, laboratory and histologic findings, absence of prior reporting in South America, and confirmation with PCR targeting the 16S ribosomal RNA Orientia gene from specimens of the eschar. By 2020, 60 cases have been confirmed in Chile, not all of them published; there are no other reported cases in South America.

When comparing the first case in Chile² with our case, we noted that both described classic clinical findings; however, the management approach and diagnostic challenges have evolved over time. Nowadays, ST is highly suspected, so it can be largely recognized and treated, which also provides better understanding of the nature of this disease in Chile. Because this infection is diagnosed mainly by characteristic cutaneous lesions, dermatologists should be aware of its epidemiology, clinical features, and transmission, and they should stay open to the possibility of this (until now) unusual diagnosis in South America.

Acknowledgments
The authors would like to thank the Chilean Rickettsia & Zoonosis Research Group (Thomas Weitzel, MD [Santiago, Chile]; Constanza Martínez-Valdebenito [Santiago, Chile]; and Gerardo Acosta-Jammet, DSc [Valdivia, Chile]), whose study in execution in the country allowed the detection of the case and confirmation by PCR. The authors also thank Juan Carlos Román, MD (Chiloé, Chile) who was part of the team that detected this case.

To the Editor:

Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi (genus Rickettsia), which is transmitted by the larvae of trombiculid mites, commonly called chiggers. The disease mainly has been described in Asia in an area known as the Tsutsugamushi Triangle, delineated by Pakistan, eastern Russia, and northern Australia. Although this classic distribution remains, recent reports have documented 1 case in the Arabian Peninsula¹ and more than 16 cases in southern Chile.^2-4 The first case in Chile was published in 2011 from Chiloé Island.² To date, no other cases have been reported in the Americas.^1-6

We describe a new case of ST from Chiloé Island and compare it to the first case reported in Chile in 2011.² Both patients showed the typical clinical manifestation, but because ST has become an increasingly suspected disease in southern regions of Chile, new cases are now easily diagnosed. This infection is diagnosed mainly by skin lesions; therefore, dermatologists should be aware of this diagnosis when presented with a febrile rash.

A 67-year-old man from the city of Punta Arenas presented to the emergency department with a dark necrotic lesion on the right foot of 1 week’s duration. The patient later developed a generalized pruritic rash and fever. He also reported muscle pain, headache, cough, night sweats, and odynophagia. He reported recent travel to a rural area in the northern part of Chiloé Island, where he came into contact with firewood and participated in outdoor activities. He had no other relevant medical history.

Physical examination revealed a temperature of 38 °C and a macular rash, with some papules distributed mainly on the face, trunk, and proximal extremities (Figure 1). He had a necrotic eschar on the dorsum of the right foot, with an erythematous halo (tache noire)(Figure 2).

Scrub typhus is a high-impact disease in Asia, described mainly in an area known as the Tsutsugamushi Triangle. Recent reports show important epidemiologic changes in the distribution of the disease, with new published reports of cases outside this endemic area—1 in the Arabian peninsula¹ and more than 16 in southern Chile.^2-4

The disease begins with a painless, erythematous, and usually unnoticed papule at the site of the bite. After 48 to 72 hours, the papule changes to a necrotic form (tache noire), surrounded by a red halo that often is small, similar to a cigarette burn. This lesion is described in 20% to 90% of infected patients in different series.⁷ Two or 3 days later (1 to 3 weeks after exposure), high fever suddenly develops. Along with fever, a maculopapular rash distributed centrifugally develops, without compromise of the palms or soles. Patients frequently report headache and night sweating. Sometimes, ST is accompanied by muscle or joint pain, red eye, cough, and abdominal pain. Hearing loss and altered mental status less frequently have been reported.^5,8

Common laboratory tests can be of use in diagnosis. An elevated C-reactive protein level and a slight to moderate increase in hepatic transaminases should be expected. Thrombocytopenia, leukopenia, and elevation of the lactate dehydrogenase level less frequently are present.^5,9

Our case de1monstrated a typical presentation. The patient developed a febrile syndrome with a generalized rash and a tache noire–type eschar associated with muscle pain, headache, cough, night sweats, and odynophagia. Because of epidemiologic changes in the area, the familiar clinical findings, and laboratory confirmation, histologic studies were unnecessary. In cases in which the diagnosis is not evident, skin biopsy could be useful, as in the first case reported in Chile.²

In that first case, the patient initially was hospitalized because of a febrile syndrome; eventually, a necrotic eschar was noticed on his leg. He had been staying on Chiloé Island and reported being bitten by leeches on multiple occasions. Laboratory findings revealed only slightly raised levels of hepatic transaminases and alkaline phosphatase. After a more precise dermatologic evaluation, the eschar of a tache noire, combined with other clinical and laboratory findings, raised suspicion of ST. Because this entity had never been described in Chile, biopsy of the eschar was taken to consider other entities in the differential diagnosis. Biopsy showed necrotizing leukocytoclastic vasculitis in the dermis and subcutaneous tissue, perivascular inflammatory infiltrates comprising lymphocytes and macrophages, and rickettsial microorganisms inside endothelial cells under electron microscopic examination. The specimen was tested for the 16S ribosomal RNA Orientia gene; its presence confirmed the diagnosis.²

Classically, histology from the eschar shows signs of vasculitis and rickettsial microorganisms inside endothelial cells on electron microscopy.^2,10 More recent publications describe important necrotic changes within keratinocytes as well as an inflammatory infiltrate comprising antigen-presenting cells, monocytes, macrophages, and dendritic cells. Using high-resolution thin sections with confocal laser scanning microscopy and staining of specific monoclonal antibodies against 56 kDa type-specific surface antigens, the bacteria were found inside antigen-presenting cells, many of them located perivascularly or passing through the endothelium.¹¹

The causal agent in Asia is O tsutsugamushi, an obligate intracellular bacterium (genus Rickettsia). Orientia species are transmitted by larvae of trombiculid mites, commonly called chiggers. The reservoir is believed to be the same as with chiggers, in which some vertebrates become infected and trombiculid mites feed on them.¹² Recent studies of Chilean cases have revealed the presence of a novel Orientia species, Candidatus Orientia chiloensis and its vector, trombiculid mites from the Herpetacarus species, Quadraseta species, and Paratrombicula species genera.^13,14

A high seroprevalence of Orientia species in dogs was reported in the main cities of Chiloé Island. Rates were higher in rural settings and older dogs. Of 202 specimens, 21.3% were positive for IgG against Orientia species.¹⁵

In Chile, most cases of ST came from Chiloé Island; some reports of cases from continental Chilean regions have been published.⁶ Most cases have occurred in the context of activities that brought the patients in contact with plants and firewood in rural areas during the summer.^3-6

The diagnosis of ST is eminently clinical, based on the triad of fever, macular or papular rash, and an inoculation necrotic eschar. The diagnosis is supported by epidemiologic facts and fast recovery after treatment is initiated.¹⁶ Although the diagnosis can be established based on a quick recovery in endemic countries, in areas such as Chile where incidence and distribution are not completely known, it is better to confirm the diagnosis with laboratory tests without delaying treatment. Several testing options exist, including serologic techniques (immunofluorescence or enzyme-linked immunosorbent assay), culture, and detection of the genetic material of Orientia species by PCR. Usually, IgM titers initially are negative, and IgG testing requires paired samples (acute and convalescent) to demonstrate seroconversion and therefore acute infection.¹⁷ Because culture requires a highly specialized laboratory, it is not frequently used. Polymerase chain reaction is recognized as the best confirmation method due to its high sensitivity and because it remains positive for a few days after treatment has been initiated. The specimen of choice is the eschar because of its high bacterial load. The base of the scar and the buffy coat are useful specimens when the eschar is unavailable.^5,17-19

Due to potential complications of ST, empirical treatment with an antibiotic should be started based on clinical facts and never delayed because of diagnostic tests.¹⁸ Classically, ST is treated with a member of the tetracycline family, such as doxycycline, which provides a cure rate of 63% to 100% in ST.⁵

A 2017 systematic review of treatment options for this infection examined 11 studies from Southeast Asia, China, and South Korea (N=957).¹⁶ The review mainly compared doxycycline with azithromycin, chloramphenicol, and tetracycline. No significant difference in cure rate was noted in comparing doxycycline with any of the other 3 antibiotics; most of the studies examined were characterized by a moderate level of evidence. Regarding adverse effects, doxycycline showed a few more cases of gastrointestinal intolerance, and in 2 of 4 studies with chloramphenicol, patients presented with leukopenia.¹⁶ Several studies compared standard treatment (doxycycline) with rifampicin, telithromycin, erythromycin, and levofloxacin individually; similar cure rates were noted between doxycycline and each of those 4 agents.

Therapeutic failure in ST has been reported in several cases with the use of levofloxacin.²⁰ Evidence for this novel antibiotic is still insufficient. Further studies are needed before rifampicin, telithromycin, erythromycin, or levofloxacin can be considered as options.Scrub typhus usually resolves within a few weeks. Left untreated, the disease can cause complications such as pneumonia, meningoencephalitis, renal failure, and even multiorgan failure and death. Without treatment, mortality is variable. A 2015 systematic review of mortality from untreated ST showed, on average, mortality of 6% (range, 0%–70%).²¹ When ST is treated, mortality falls to 0% to 30%.²² Cases reported in Chile have neither been lethal nor presented with severe complications.^4,5

Scrub typhus is an infectious disease common in Asia, caused by O tsutsugamushi and transmitted by chiggers. It should be suspected when a febrile macular or papular rash and a tache noire appear. The diagnosis can be supported by laboratory findings, such as an elevated C-reactive protein level or a slight increase in the levels of hepatic transaminases, and response to treatment. The diagnosis is confirmed by serology or PCR of a specimen of the eschar. Empiric therapy with antibiotics is mandatory; doxycycline is the first option.

First described in Chile in 2011,² ST was seen in a patient in whom disease was suspected because of clinical characteristics, laboratory and histologic findings, absence of prior reporting in South America, and confirmation with PCR targeting the 16S ribosomal RNA Orientia gene from specimens of the eschar. By 2020, 60 cases have been confirmed in Chile, not all of them published; there are no other reported cases in South America.

When comparing the first case in Chile² with our case, we noted that both described classic clinical findings; however, the management approach and diagnostic challenges have evolved over time. Nowadays, ST is highly suspected, so it can be largely recognized and treated, which also provides better understanding of the nature of this disease in Chile. Because this infection is diagnosed mainly by characteristic cutaneous lesions, dermatologists should be aware of its epidemiology, clinical features, and transmission, and they should stay open to the possibility of this (until now) unusual diagnosis in South America.

Acknowledgments
The authors would like to thank the Chilean Rickettsia & Zoonosis Research Group (Thomas Weitzel, MD [Santiago, Chile]; Constanza Martínez-Valdebenito [Santiago, Chile]; and Gerardo Acosta-Jammet, DSc [Valdivia, Chile]), whose study in execution in the country allowed the detection of the case and confirmation by PCR. The authors also thank Juan Carlos Román, MD (Chiloé, Chile) who was part of the team that detected this case.

To the Editor:

Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi (genus Rickettsia), which is transmitted by the larvae of trombiculid mites, commonly called chiggers. The disease mainly has been described in Asia in an area known as the Tsutsugamushi Triangle, delineated by Pakistan, eastern Russia, and northern Australia. Although this classic distribution remains, recent reports have documented 1 case in the Arabian Peninsula¹ and more than 16 cases in southern Chile.^2-4 The first case in Chile was published in 2011 from Chiloé Island.² To date, no other cases have been reported in the Americas.^1-6

We describe a new case of ST from Chiloé Island and compare it to the first case reported in Chile in 2011.² Both patients showed the typical clinical manifestation, but because ST has become an increasingly suspected disease in southern regions of Chile, new cases are now easily diagnosed. This infection is diagnosed mainly by skin lesions; therefore, dermatologists should be aware of this diagnosis when presented with a febrile rash.

A 67-year-old man from the city of Punta Arenas presented to the emergency department with a dark necrotic lesion on the right foot of 1 week’s duration. The patient later developed a generalized pruritic rash and fever. He also reported muscle pain, headache, cough, night sweats, and odynophagia. He reported recent travel to a rural area in the northern part of Chiloé Island, where he came into contact with firewood and participated in outdoor activities. He had no other relevant medical history.

Physical examination revealed a temperature of 38 °C and a macular rash, with some papules distributed mainly on the face, trunk, and proximal extremities (Figure 1). He had a necrotic eschar on the dorsum of the right foot, with an erythematous halo (tache noire)(Figure 2).

Scrub typhus is a high-impact disease in Asia, described mainly in an area known as the Tsutsugamushi Triangle. Recent reports show important epidemiologic changes in the distribution of the disease, with new published reports of cases outside this endemic area—1 in the Arabian peninsula¹ and more than 16 in southern Chile.^2-4

The disease begins with a painless, erythematous, and usually unnoticed papule at the site of the bite. After 48 to 72 hours, the papule changes to a necrotic form (tache noire), surrounded by a red halo that often is small, similar to a cigarette burn. This lesion is described in 20% to 90% of infected patients in different series.⁷ Two or 3 days later (1 to 3 weeks after exposure), high fever suddenly develops. Along with fever, a maculopapular rash distributed centrifugally develops, without compromise of the palms or soles. Patients frequently report headache and night sweating. Sometimes, ST is accompanied by muscle or joint pain, red eye, cough, and abdominal pain. Hearing loss and altered mental status less frequently have been reported.^5,8

Common laboratory tests can be of use in diagnosis. An elevated C-reactive protein level and a slight to moderate increase in hepatic transaminases should be expected. Thrombocytopenia, leukopenia, and elevation of the lactate dehydrogenase level less frequently are present.^5,9

Our case de1monstrated a typical presentation. The patient developed a febrile syndrome with a generalized rash and a tache noire–type eschar associated with muscle pain, headache, cough, night sweats, and odynophagia. Because of epidemiologic changes in the area, the familiar clinical findings, and laboratory confirmation, histologic studies were unnecessary. In cases in which the diagnosis is not evident, skin biopsy could be useful, as in the first case reported in Chile.²

In that first case, the patient initially was hospitalized because of a febrile syndrome; eventually, a necrotic eschar was noticed on his leg. He had been staying on Chiloé Island and reported being bitten by leeches on multiple occasions. Laboratory findings revealed only slightly raised levels of hepatic transaminases and alkaline phosphatase. After a more precise dermatologic evaluation, the eschar of a tache noire, combined with other clinical and laboratory findings, raised suspicion of ST. Because this entity had never been described in Chile, biopsy of the eschar was taken to consider other entities in the differential diagnosis. Biopsy showed necrotizing leukocytoclastic vasculitis in the dermis and subcutaneous tissue, perivascular inflammatory infiltrates comprising lymphocytes and macrophages, and rickettsial microorganisms inside endothelial cells under electron microscopic examination. The specimen was tested for the 16S ribosomal RNA Orientia gene; its presence confirmed the diagnosis.²

Classically, histology from the eschar shows signs of vasculitis and rickettsial microorganisms inside endothelial cells on electron microscopy.^2,10 More recent publications describe important necrotic changes within keratinocytes as well as an inflammatory infiltrate comprising antigen-presenting cells, monocytes, macrophages, and dendritic cells. Using high-resolution thin sections with confocal laser scanning microscopy and staining of specific monoclonal antibodies against 56 kDa type-specific surface antigens, the bacteria were found inside antigen-presenting cells, many of them located perivascularly or passing through the endothelium.¹¹

The causal agent in Asia is O tsutsugamushi, an obligate intracellular bacterium (genus Rickettsia). Orientia species are transmitted by larvae of trombiculid mites, commonly called chiggers. The reservoir is believed to be the same as with chiggers, in which some vertebrates become infected and trombiculid mites feed on them.¹² Recent studies of Chilean cases have revealed the presence of a novel Orientia species, Candidatus Orientia chiloensis and its vector, trombiculid mites from the Herpetacarus species, Quadraseta species, and Paratrombicula species genera.^13,14

A high seroprevalence of Orientia species in dogs was reported in the main cities of Chiloé Island. Rates were higher in rural settings and older dogs. Of 202 specimens, 21.3% were positive for IgG against Orientia species.¹⁵

In Chile, most cases of ST came from Chiloé Island; some reports of cases from continental Chilean regions have been published.⁶ Most cases have occurred in the context of activities that brought the patients in contact with plants and firewood in rural areas during the summer.^3-6

The diagnosis of ST is eminently clinical, based on the triad of fever, macular or papular rash, and an inoculation necrotic eschar. The diagnosis is supported by epidemiologic facts and fast recovery after treatment is initiated.¹⁶ Although the diagnosis can be established based on a quick recovery in endemic countries, in areas such as Chile where incidence and distribution are not completely known, it is better to confirm the diagnosis with laboratory tests without delaying treatment. Several testing options exist, including serologic techniques (immunofluorescence or enzyme-linked immunosorbent assay), culture, and detection of the genetic material of Orientia species by PCR. Usually, IgM titers initially are negative, and IgG testing requires paired samples (acute and convalescent) to demonstrate seroconversion and therefore acute infection.¹⁷ Because culture requires a highly specialized laboratory, it is not frequently used. Polymerase chain reaction is recognized as the best confirmation method due to its high sensitivity and because it remains positive for a few days after treatment has been initiated. The specimen of choice is the eschar because of its high bacterial load. The base of the scar and the buffy coat are useful specimens when the eschar is unavailable.^5,17-19

Due to potential complications of ST, empirical treatment with an antibiotic should be started based on clinical facts and never delayed because of diagnostic tests.¹⁸ Classically, ST is treated with a member of the tetracycline family, such as doxycycline, which provides a cure rate of 63% to 100% in ST.⁵

A 2017 systematic review of treatment options for this infection examined 11 studies from Southeast Asia, China, and South Korea (N=957).¹⁶ The review mainly compared doxycycline with azithromycin, chloramphenicol, and tetracycline. No significant difference in cure rate was noted in comparing doxycycline with any of the other 3 antibiotics; most of the studies examined were characterized by a moderate level of evidence. Regarding adverse effects, doxycycline showed a few more cases of gastrointestinal intolerance, and in 2 of 4 studies with chloramphenicol, patients presented with leukopenia.¹⁶ Several studies compared standard treatment (doxycycline) with rifampicin, telithromycin, erythromycin, and levofloxacin individually; similar cure rates were noted between doxycycline and each of those 4 agents.

Therapeutic failure in ST has been reported in several cases with the use of levofloxacin.²⁰ Evidence for this novel antibiotic is still insufficient. Further studies are needed before rifampicin, telithromycin, erythromycin, or levofloxacin can be considered as options.Scrub typhus usually resolves within a few weeks. Left untreated, the disease can cause complications such as pneumonia, meningoencephalitis, renal failure, and even multiorgan failure and death. Without treatment, mortality is variable. A 2015 systematic review of mortality from untreated ST showed, on average, mortality of 6% (range, 0%–70%).²¹ When ST is treated, mortality falls to 0% to 30%.²² Cases reported in Chile have neither been lethal nor presented with severe complications.^4,5

Scrub typhus is an infectious disease common in Asia, caused by O tsutsugamushi and transmitted by chiggers. It should be suspected when a febrile macular or papular rash and a tache noire appear. The diagnosis can be supported by laboratory findings, such as an elevated C-reactive protein level or a slight increase in the levels of hepatic transaminases, and response to treatment. The diagnosis is confirmed by serology or PCR of a specimen of the eschar. Empiric therapy with antibiotics is mandatory; doxycycline is the first option.

First described in Chile in 2011,² ST was seen in a patient in whom disease was suspected because of clinical characteristics, laboratory and histologic findings, absence of prior reporting in South America, and confirmation with PCR targeting the 16S ribosomal RNA Orientia gene from specimens of the eschar. By 2020, 60 cases have been confirmed in Chile, not all of them published; there are no other reported cases in South America.

When comparing the first case in Chile² with our case, we noted that both described classic clinical findings; however, the management approach and diagnostic challenges have evolved over time. Nowadays, ST is highly suspected, so it can be largely recognized and treated, which also provides better understanding of the nature of this disease in Chile. Because this infection is diagnosed mainly by characteristic cutaneous lesions, dermatologists should be aware of its epidemiology, clinical features, and transmission, and they should stay open to the possibility of this (until now) unusual diagnosis in South America.

Acknowledgments
The authors would like to thank the Chilean Rickettsia & Zoonosis Research Group (Thomas Weitzel, MD [Santiago, Chile]; Constanza Martínez-Valdebenito [Santiago, Chile]; and Gerardo Acosta-Jammet, DSc [Valdivia, Chile]), whose study in execution in the country allowed the detection of the case and confirmation by PCR. The authors also thank Juan Carlos Román, MD (Chiloé, Chile) who was part of the team that detected this case.