A 68-year-old man with type 2 diabetes ­presented with progressive hyperpigmentation of the lower extremities and face over the past 3 years. Clinical examination revealed confluent, blue-black hyperpigmentation of the lower extremities (Figure), upper extremities, neck, and face. Laboratory tests and arterial studies were within normal ranges. The patient’s medication list included lisinopril 10 mg/d, metformin 1000 mg twice daily, minocycline 100 mg twice daily, and omeprazole 20 mg/d.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Hyperpigmentation is a rare but not uncommon adverse effect of long-term minocycline use. In this case, our patient had been taking minocycline for more than 5 years. When seen in our clinic, he said he could not remember why he was taking minocycline and incorrectly assumed it was for his diabetes. Chart review of outside records revealed that it had been prescribed, and refilled annually, by his primary physician for rosacea.

Minocycline hyperpigmentation is subdivided into 3 types:

• Type I manifests with blue-black discoloration in previously inflamed areas of skin.
• Type II manifests with blue-gray pigmentation in previously normal skin areas.
• Type III manifests diffusely with muddy-brown hyperpigmentation on photoexposed skin.

Furthermore, noncutaneous manifestations may occur on the sclera, nails, ear cartilage, bone, oral mucosa, teeth, and thyroid gland.¹

Diagnosis focuses on identifying the source

Minocycline is one of many drugs that can induce hyperpigmentation of the skin. In addition to history, examination, and review of the patient’s medication list, there are some clues on exam that may suggest a certain type of medication at play.

Continue to: Antimalarials

Antimalarials. Chloroquine, hydroxychloroquine, and quinacrine can cause blue-black skin hyperpigmentation in as many as 25% of patients. Common locations include the shins, face, oral mucosa, and subungual skin. This hyperpigmentation rarely fully resolves.²

Amiodarone. Hyperpigmentation secondary to amiodarone use typically is slate-gray in color and involves photoexposed skin. Patients should be counseled that pigmentation may—but does not always—fade with time after discontinuation of the drug.²

Heavy metals. Argyria results from exposure to silver, either ingested orally or applied externally. A common cause of argyria is ingestion of excessive amounts of silver-­containing supplements.³ Affected patients present with diffuse slate-gray discoloration of the skin.

This case underscores the importance of routinely reassessing patients’ understanding of their medications and treatment plans.

Other metals implicated in skin hyperpigmentation include arsenic, gold, mercury, and iron. Review of all supplements and herbal remedies in patients presenting with skin hyperpigmentation is crucial.

Bleomycin is a chemotherapeutic agent with a rare but unique adverse effect of inducing flagellate hyperpigmentation that favors the chest, abdomen, or back. This may be induced by trauma or scratching and is often transient. Hyperpigmentation can occur secondary to either intravenous or intralesional injection of the medication.²

Continue to: In addition to medication...

In addition to medication- or supple­ment-­induced hyperpigmentation, there is a physiologic source that should be considered when a patient presents with ­lower-extremity hyperpigmentation:

Stasis hyperpigmentation. Patients with chronic venous insufficiency may present with hyperpigmentation of the lower extremities. Commonly due to dysfunctional venous valves or obstruction, stasis hyperpigmentation manifests with red-brown discoloration from dermal hemosiderin deposition.⁴

Unlike our patient, those with stasis hyperpigmentation may present symptomatically, with associated dry skin, pruritus, induration, and inflammation. Treatment involves management of the underlying venous insufficiency.⁴

When there’s no obvious cause, be prepared to dig deeper

At the time of initial assessment, a thorough review of systems and detailed medication history, including over-the-counter supplements, should be obtained. Physical examination revealing diffuse, generalized hyperpigmentation with no reliable culprit medication in the patient’s history warrants further laboratory evaluation. This includes ordering renal and liver studies and tests for thyroid-stimulating hormone and ferritin and cortisol levels to rule out metabolic or endocrine hyperpigmentation disorders.

Stopping the offending medication is the first step

Discontinuation of the offending medication may result in mild improvement in skin hyperpigmentation over time. Some patients may not experience any improvement. If improvement occurs, it is important to educate patients that it can take several months to years. Dermatology guidelines favor discontinuation of antibiotics for acne or rosacea after 3 to 6 months to avoid bacterial resistance.⁵ Worsening hyperpigmentation despite medication discontinuation warrants further work-up.

Patients who are distressed by persistent hyperpigmentation can be treated using picosecond or Q-switched lasers.⁶

Our patient was advised to discontinue the minocycline. Three test spots on his face were treated with pulsed-dye laser, carbon dioxide laser, and dermabrasion. The patient noted that the spots responded better to the carbon dioxide laser and dermabrasion compared to the pulsed-dye laser. He did not ­follow up for further treatment.

A 68-year-old man with type 2 diabetes ­presented with progressive hyperpigmentation of the lower extremities and face over the past 3 years. Clinical examination revealed confluent, blue-black hyperpigmentation of the lower extremities (Figure), upper extremities, neck, and face. Laboratory tests and arterial studies were within normal ranges. The patient’s medication list included lisinopril 10 mg/d, metformin 1000 mg twice daily, minocycline 100 mg twice daily, and omeprazole 20 mg/d.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Hyperpigmentation is a rare but not uncommon adverse effect of long-term minocycline use. In this case, our patient had been taking minocycline for more than 5 years. When seen in our clinic, he said he could not remember why he was taking minocycline and incorrectly assumed it was for his diabetes. Chart review of outside records revealed that it had been prescribed, and refilled annually, by his primary physician for rosacea.

Minocycline hyperpigmentation is subdivided into 3 types:

• Type I manifests with blue-black discoloration in previously inflamed areas of skin.
• Type II manifests with blue-gray pigmentation in previously normal skin areas.
• Type III manifests diffusely with muddy-brown hyperpigmentation on photoexposed skin.

Furthermore, noncutaneous manifestations may occur on the sclera, nails, ear cartilage, bone, oral mucosa, teeth, and thyroid gland.¹

Diagnosis focuses on identifying the source

Minocycline is one of many drugs that can induce hyperpigmentation of the skin. In addition to history, examination, and review of the patient’s medication list, there are some clues on exam that may suggest a certain type of medication at play.

Continue to: Antimalarials

Antimalarials. Chloroquine, hydroxychloroquine, and quinacrine can cause blue-black skin hyperpigmentation in as many as 25% of patients. Common locations include the shins, face, oral mucosa, and subungual skin. This hyperpigmentation rarely fully resolves.²

Amiodarone. Hyperpigmentation secondary to amiodarone use typically is slate-gray in color and involves photoexposed skin. Patients should be counseled that pigmentation may—but does not always—fade with time after discontinuation of the drug.²

Heavy metals. Argyria results from exposure to silver, either ingested orally or applied externally. A common cause of argyria is ingestion of excessive amounts of silver-­containing supplements.³ Affected patients present with diffuse slate-gray discoloration of the skin.

This case underscores the importance of routinely reassessing patients’ understanding of their medications and treatment plans.

Other metals implicated in skin hyperpigmentation include arsenic, gold, mercury, and iron. Review of all supplements and herbal remedies in patients presenting with skin hyperpigmentation is crucial.

Bleomycin is a chemotherapeutic agent with a rare but unique adverse effect of inducing flagellate hyperpigmentation that favors the chest, abdomen, or back. This may be induced by trauma or scratching and is often transient. Hyperpigmentation can occur secondary to either intravenous or intralesional injection of the medication.²

Continue to: In addition to medication...

In addition to medication- or supple­ment-­induced hyperpigmentation, there is a physiologic source that should be considered when a patient presents with ­lower-extremity hyperpigmentation:

Stasis hyperpigmentation. Patients with chronic venous insufficiency may present with hyperpigmentation of the lower extremities. Commonly due to dysfunctional venous valves or obstruction, stasis hyperpigmentation manifests with red-brown discoloration from dermal hemosiderin deposition.⁴

Unlike our patient, those with stasis hyperpigmentation may present symptomatically, with associated dry skin, pruritus, induration, and inflammation. Treatment involves management of the underlying venous insufficiency.⁴

When there’s no obvious cause, be prepared to dig deeper

At the time of initial assessment, a thorough review of systems and detailed medication history, including over-the-counter supplements, should be obtained. Physical examination revealing diffuse, generalized hyperpigmentation with no reliable culprit medication in the patient’s history warrants further laboratory evaluation. This includes ordering renal and liver studies and tests for thyroid-stimulating hormone and ferritin and cortisol levels to rule out metabolic or endocrine hyperpigmentation disorders.

Stopping the offending medication is the first step

Discontinuation of the offending medication may result in mild improvement in skin hyperpigmentation over time. Some patients may not experience any improvement. If improvement occurs, it is important to educate patients that it can take several months to years. Dermatology guidelines favor discontinuation of antibiotics for acne or rosacea after 3 to 6 months to avoid bacterial resistance.⁵ Worsening hyperpigmentation despite medication discontinuation warrants further work-up.

Patients who are distressed by persistent hyperpigmentation can be treated using picosecond or Q-switched lasers.⁶

Our patient was advised to discontinue the minocycline. Three test spots on his face were treated with pulsed-dye laser, carbon dioxide laser, and dermabrasion. The patient noted that the spots responded better to the carbon dioxide laser and dermabrasion compared to the pulsed-dye laser. He did not ­follow up for further treatment.

A 68-year-old man with type 2 diabetes ­presented with progressive hyperpigmentation of the lower extremities and face over the past 3 years. Clinical examination revealed confluent, blue-black hyperpigmentation of the lower extremities (Figure), upper extremities, neck, and face. Laboratory tests and arterial studies were within normal ranges. The patient’s medication list included lisinopril 10 mg/d, metformin 1000 mg twice daily, minocycline 100 mg twice daily, and omeprazole 20 mg/d.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Hyperpigmentation is a rare but not uncommon adverse effect of long-term minocycline use. In this case, our patient had been taking minocycline for more than 5 years. When seen in our clinic, he said he could not remember why he was taking minocycline and incorrectly assumed it was for his diabetes. Chart review of outside records revealed that it had been prescribed, and refilled annually, by his primary physician for rosacea.

Minocycline hyperpigmentation is subdivided into 3 types:

• Type I manifests with blue-black discoloration in previously inflamed areas of skin.
• Type II manifests with blue-gray pigmentation in previously normal skin areas.
• Type III manifests diffusely with muddy-brown hyperpigmentation on photoexposed skin.

Furthermore, noncutaneous manifestations may occur on the sclera, nails, ear cartilage, bone, oral mucosa, teeth, and thyroid gland.¹

Diagnosis focuses on identifying the source

Minocycline is one of many drugs that can induce hyperpigmentation of the skin. In addition to history, examination, and review of the patient’s medication list, there are some clues on exam that may suggest a certain type of medication at play.

Continue to: Antimalarials

Antimalarials. Chloroquine, hydroxychloroquine, and quinacrine can cause blue-black skin hyperpigmentation in as many as 25% of patients. Common locations include the shins, face, oral mucosa, and subungual skin. This hyperpigmentation rarely fully resolves.²

Amiodarone. Hyperpigmentation secondary to amiodarone use typically is slate-gray in color and involves photoexposed skin. Patients should be counseled that pigmentation may—but does not always—fade with time after discontinuation of the drug.²

Heavy metals. Argyria results from exposure to silver, either ingested orally or applied externally. A common cause of argyria is ingestion of excessive amounts of silver-­containing supplements.³ Affected patients present with diffuse slate-gray discoloration of the skin.

This case underscores the importance of routinely reassessing patients’ understanding of their medications and treatment plans.

Other metals implicated in skin hyperpigmentation include arsenic, gold, mercury, and iron. Review of all supplements and herbal remedies in patients presenting with skin hyperpigmentation is crucial.

Bleomycin is a chemotherapeutic agent with a rare but unique adverse effect of inducing flagellate hyperpigmentation that favors the chest, abdomen, or back. This may be induced by trauma or scratching and is often transient. Hyperpigmentation can occur secondary to either intravenous or intralesional injection of the medication.²

Continue to: In addition to medication...

In addition to medication- or supple­ment-­induced hyperpigmentation, there is a physiologic source that should be considered when a patient presents with ­lower-extremity hyperpigmentation:

Stasis hyperpigmentation. Patients with chronic venous insufficiency may present with hyperpigmentation of the lower extremities. Commonly due to dysfunctional venous valves or obstruction, stasis hyperpigmentation manifests with red-brown discoloration from dermal hemosiderin deposition.⁴

Unlike our patient, those with stasis hyperpigmentation may present symptomatically, with associated dry skin, pruritus, induration, and inflammation. Treatment involves management of the underlying venous insufficiency.⁴

When there’s no obvious cause, be prepared to dig deeper

At the time of initial assessment, a thorough review of systems and detailed medication history, including over-the-counter supplements, should be obtained. Physical examination revealing diffuse, generalized hyperpigmentation with no reliable culprit medication in the patient’s history warrants further laboratory evaluation. This includes ordering renal and liver studies and tests for thyroid-stimulating hormone and ferritin and cortisol levels to rule out metabolic or endocrine hyperpigmentation disorders.

Stopping the offending medication is the first step

Discontinuation of the offending medication may result in mild improvement in skin hyperpigmentation over time. Some patients may not experience any improvement. If improvement occurs, it is important to educate patients that it can take several months to years. Dermatology guidelines favor discontinuation of antibiotics for acne or rosacea after 3 to 6 months to avoid bacterial resistance.⁵ Worsening hyperpigmentation despite medication discontinuation warrants further work-up.

Patients who are distressed by persistent hyperpigmentation can be treated using picosecond or Q-switched lasers.⁶

Our patient was advised to discontinue the minocycline. Three test spots on his face were treated with pulsed-dye laser, carbon dioxide laser, and dermabrasion. The patient noted that the spots responded better to the carbon dioxide laser and dermabrasion compared to the pulsed-dye laser. He did not ­follow up for further treatment.

ILLUSTRATIVE CASE

A 72-year-old man with a history of hypertension, permanent atrial fibrillation, and heart failure (HF) comes into your clinic for follow-up. He was hospitalized a few months ago for HF requiring diuresis. His echocardiogram at that time showed an EF of 50% and no significant valvular disease. He does not have a history of diabetes or tobacco use. His medication regimen includes metoprolol, lisinopril-hydrochlorothiazide, apixaban, and atorvastatin. The patient is still symptomatic from his HF and asks you if there is anything else he can do to prevent another hospitalization for HF.

HFpEF was first defined as HF in patients with a left ventricular ejection fraction (LVEF) > 40%. However, HF with an LVEF between 41% and 49% has been reclassified as its own category: heart failure with mildly reduced ejection fraction (HFmrEF).² HFpEF is now diagnosed when the patient has HF symptoms and an LVEF ≥ 50%, mimickers (lung disease, pulmonary embolism, pulmonary hypertension, and renal disease) have been excluded, and there is evidence of elevated left ventricular filling pressure or noninvasive correlates such as elevated natriuretic peptides. It is estimated that HFpEF comprises half of all patients with HF.³

In comparison with HF with reduced ejection fraction (HFrEF), there are limited proven treatment options with cardiovascular (CV) benefit in HFpEF.⁴ Spironolactone is associated with a slight decrease in HF-­related hospitalizations but not with a reduction in CV or all-cause mortality for patients with HFpEF.^4,5 Angiotensin-­converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers have not been shown to reduce morbidity or mortality in HFpEF when not indicated for another reason.^6,7 Sodium-glucose cotransporter 2 (SGLT2) inhibitors are known to decrease the development and progression of HFrEF⁸; however, the effect of SGLT2 inhibition in patients with HFpEF remains unclear. Post hoc analyses of a multicenter trial of dapagliflozin in type 2 diabetes indicated no reduction in CV death, hospitalization, or all-cause mortality in HFpEF.⁹ Another study found improved CV mortality and decreased HF-related urgent visits and hospitalizations with sotagliflozin, but the number of events was too small to estimate a treatment effect.¹⁰ Given this uncertainty, the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-­Preserved) was conducted to evaluate the effects of SGLT2 inhibition with empagliflozin in patients with HFpEF.¹

STUDY SUMMARY

Confirmation of benefit of empagliflozin for patients with HFpEF

The EMPEROR-Preserved study was a ­double-blind, placebo-controlled trial that randomized adult patients with HFpEF (defined by an LVEF > 40%) to either placebo or empagliflozin 10 mg/d, in addition to usual therapy. Patients were randomized in a 1:1 ratio stratified by geographic region, diabetes status, renal function (estimated glomerular filtration rate [eGFR] either < 60 or ≥ 60 mL/min/1.73 m²), and LVEF > 40% to < 50% or LVEF ≥ 50%.

For patients with HFpEF, empagliflozin added to usual care significantly reduced the risk of hospitalization for heart failure, regardless of whether patients had diabetes.

Included patients were 18 years or older and had an NT-proBNP level > 300 pg/mL (or > 900 pg/mL if the patient had atrial fibrillation at baseline), an LVEF > 40%, and New York Heart Association (NYHA) class II-IV symptoms at baseline. Patients with a CV event in the preceding 90 days, systolic blood pressure ≥ 180 mm Hg, or significant valvular disease were excluded from the study.

The primary outcome was a composite of CV death or first hospitalization for HF. The secondary outcomes were all hospitalizations for HF and the rate of decline in eGFR.

Of the 5988 patients in the trial, 2997 were randomized to receive empagliflozin and 2991 were randomized to placebo. The average age was 72 years in each group, 45% of patients were women, about 76% were White, and 12% were from North America. About 81% of patients were classified as NYHA class II, nearly half had diabetes, and half had an eGFR < 60 mL/min/1.73 m². The median body mass index (BMI) was 30, and the median LVEF was 54%. At baseline, the groups were similar in BMI, history of HF hospitalization in the past 12 months, history of common risk factors for HFpEF (atrial fibrillation, diabetes, and hypertension), and prescribed CV medications (ACE inhibitor or ARB with or without a neprilysin inhibitor, spironolactone, beta-blocker, digitalis glycosides, aspirin, and statins). Patients were followed for a median of 26.2 months.

Continue to: The primary composite...

The primary composite outcome of death from CV causes or HF-related hospitalization occurred in 415 patients (13.8%) in the empagliflozin group and in 511 patients (17.1%) in the placebo group (hazard ratio [HR] = 0.79; 95% CI, 0.69-0.90; P < .001). The number needed to treat to prevent 1 primary outcome event was 31 (95% CI, 20-69). Hospitalization for HF occurred in 259 patients (8.6%) with empagliflozin vs 352 patients (11.8%) with placebo (HR = 0.71; 95% CI, 0.60-0.83), and CV death occurred in 219 patients (7.3%) with empagliflozin vs 244 patients (8.2%) with placebo (HR = 0.91; 95% CI, 0.76-1.09). The effect was consistent in patients with or without diabetes at baseline; however, the largest reduction in the primary composite outcome was seen in those with an LVEF < 50%, age ≥ 70 years old, BMI < 30, and NYHA class II status.

The secondary outcome of total number of hospitalizations for HF was 407 with empagliflozin vs 541 with placebo (HR = 0.73; 95% CI, 0.61-0.88; P < .001). The rate of decline in the eGFR per year was –1.25 in the empagliflozin group vs –2.62 in the placebo group (P < .001), indicating that those taking empagliflozin had preserved renal function compared with those taking placebo.

Death from any cause occurred in 422 patients (14.1%) in the empagliflozin group and 427 patients (14.3%) in the placebo group (HR = 1.00; 95% CI, 0.87-1.15). Empagliflozin treatment was associated with higher rates of genital infections (2.2% vs 0.7%; P value not provided), urinary tract infections (9.9% vs 8.1%; P value not provided), and hypotension (10.4% vs 8.6%; P value not provided), compared to placebo.

WHAT’S NEW

Risk of hospitalization significantly reduced for patients with HFpEF

In the EMPEROR-Preserved study, empagliflozin led to a lower incidence of hospitalization for HF in patients with HFpEF but did not significantly reduce the number of deaths from CV disease or other causes. In comparison, in the similarly designed EMPEROR-Reduced trial, treatment with empagliflozin reduced CV and all-cause mortality in individuals with HFrEF.⁸

CAVEATS

HF criteria, study population may limit generalizability

The reduction in the primary outcome of CV death or first hospitalization was most pronounced in patients with an LVEF > 40% to < 50%, typically defined as HFmrEF, who often have clinical features similar to those with HFrEF. This raises the question of how generalizable these results are for all patients with HFpEF.

Continue to: The study's generalizability...

Empagliflozin treatment, however, was associated with higher rates of genital infections, urinary tract infections, and hypotension, compared to placebo.

The study’s generalizability was further limited by its significant exclusion criteria, which included elevated blood pressure, chronic obstructive pulmonary disease on home oxygen, liver disease, renal disease with an eGFR < 20 mL/min/1.73 m² or requiring dialysis, and BMI ≥ 45.

Finally, only 12% of patients were from North America, and results were not significant for this subgroup (HR = 0.72; 95% CI, 0.52-1.00), which may challenge its external validity. The authors noted that 23% of patients discontinued treatment for reasons other than death, which may have driven the null effect.

CHALLENGES TO IMPLEMENTATION

Empagliflozin is expensive,but coverage may improve

Cost could be a major barrier to implementation. Retail pricing for empagliflozin is estimated to be more than $550 per month, which may be prohibitive for patients with no insurance or with higher-deductible plans.¹¹ However, the US Food and Drug Administration has approved empagliflozin to reduce the risk of CV death and hospitalization for HF in adults,¹² which may help to improve insurance coverage.

ILLUSTRATIVE CASE

A 72-year-old man with a history of hypertension, permanent atrial fibrillation, and heart failure (HF) comes into your clinic for follow-up. He was hospitalized a few months ago for HF requiring diuresis. His echocardiogram at that time showed an EF of 50% and no significant valvular disease. He does not have a history of diabetes or tobacco use. His medication regimen includes metoprolol, lisinopril-hydrochlorothiazide, apixaban, and atorvastatin. The patient is still symptomatic from his HF and asks you if there is anything else he can do to prevent another hospitalization for HF.

HFpEF was first defined as HF in patients with a left ventricular ejection fraction (LVEF) > 40%. However, HF with an LVEF between 41% and 49% has been reclassified as its own category: heart failure with mildly reduced ejection fraction (HFmrEF).² HFpEF is now diagnosed when the patient has HF symptoms and an LVEF ≥ 50%, mimickers (lung disease, pulmonary embolism, pulmonary hypertension, and renal disease) have been excluded, and there is evidence of elevated left ventricular filling pressure or noninvasive correlates such as elevated natriuretic peptides. It is estimated that HFpEF comprises half of all patients with HF.³

In comparison with HF with reduced ejection fraction (HFrEF), there are limited proven treatment options with cardiovascular (CV) benefit in HFpEF.⁴ Spironolactone is associated with a slight decrease in HF-­related hospitalizations but not with a reduction in CV or all-cause mortality for patients with HFpEF.^4,5 Angiotensin-­converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers have not been shown to reduce morbidity or mortality in HFpEF when not indicated for another reason.^6,7 Sodium-glucose cotransporter 2 (SGLT2) inhibitors are known to decrease the development and progression of HFrEF⁸; however, the effect of SGLT2 inhibition in patients with HFpEF remains unclear. Post hoc analyses of a multicenter trial of dapagliflozin in type 2 diabetes indicated no reduction in CV death, hospitalization, or all-cause mortality in HFpEF.⁹ Another study found improved CV mortality and decreased HF-related urgent visits and hospitalizations with sotagliflozin, but the number of events was too small to estimate a treatment effect.¹⁰ Given this uncertainty, the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-­Preserved) was conducted to evaluate the effects of SGLT2 inhibition with empagliflozin in patients with HFpEF.¹

STUDY SUMMARY

Confirmation of benefit of empagliflozin for patients with HFpEF

The EMPEROR-Preserved study was a ­double-blind, placebo-controlled trial that randomized adult patients with HFpEF (defined by an LVEF > 40%) to either placebo or empagliflozin 10 mg/d, in addition to usual therapy. Patients were randomized in a 1:1 ratio stratified by geographic region, diabetes status, renal function (estimated glomerular filtration rate [eGFR] either < 60 or ≥ 60 mL/min/1.73 m²), and LVEF > 40% to < 50% or LVEF ≥ 50%.

For patients with HFpEF, empagliflozin added to usual care significantly reduced the risk of hospitalization for heart failure, regardless of whether patients had diabetes.

Included patients were 18 years or older and had an NT-proBNP level > 300 pg/mL (or > 900 pg/mL if the patient had atrial fibrillation at baseline), an LVEF > 40%, and New York Heart Association (NYHA) class II-IV symptoms at baseline. Patients with a CV event in the preceding 90 days, systolic blood pressure ≥ 180 mm Hg, or significant valvular disease were excluded from the study.

The primary outcome was a composite of CV death or first hospitalization for HF. The secondary outcomes were all hospitalizations for HF and the rate of decline in eGFR.

Of the 5988 patients in the trial, 2997 were randomized to receive empagliflozin and 2991 were randomized to placebo. The average age was 72 years in each group, 45% of patients were women, about 76% were White, and 12% were from North America. About 81% of patients were classified as NYHA class II, nearly half had diabetes, and half had an eGFR < 60 mL/min/1.73 m². The median body mass index (BMI) was 30, and the median LVEF was 54%. At baseline, the groups were similar in BMI, history of HF hospitalization in the past 12 months, history of common risk factors for HFpEF (atrial fibrillation, diabetes, and hypertension), and prescribed CV medications (ACE inhibitor or ARB with or without a neprilysin inhibitor, spironolactone, beta-blocker, digitalis glycosides, aspirin, and statins). Patients were followed for a median of 26.2 months.

Continue to: The primary composite...

The primary composite outcome of death from CV causes or HF-related hospitalization occurred in 415 patients (13.8%) in the empagliflozin group and in 511 patients (17.1%) in the placebo group (hazard ratio [HR] = 0.79; 95% CI, 0.69-0.90; P < .001). The number needed to treat to prevent 1 primary outcome event was 31 (95% CI, 20-69). Hospitalization for HF occurred in 259 patients (8.6%) with empagliflozin vs 352 patients (11.8%) with placebo (HR = 0.71; 95% CI, 0.60-0.83), and CV death occurred in 219 patients (7.3%) with empagliflozin vs 244 patients (8.2%) with placebo (HR = 0.91; 95% CI, 0.76-1.09). The effect was consistent in patients with or without diabetes at baseline; however, the largest reduction in the primary composite outcome was seen in those with an LVEF < 50%, age ≥ 70 years old, BMI < 30, and NYHA class II status.

The secondary outcome of total number of hospitalizations for HF was 407 with empagliflozin vs 541 with placebo (HR = 0.73; 95% CI, 0.61-0.88; P < .001). The rate of decline in the eGFR per year was –1.25 in the empagliflozin group vs –2.62 in the placebo group (P < .001), indicating that those taking empagliflozin had preserved renal function compared with those taking placebo.

Death from any cause occurred in 422 patients (14.1%) in the empagliflozin group and 427 patients (14.3%) in the placebo group (HR = 1.00; 95% CI, 0.87-1.15). Empagliflozin treatment was associated with higher rates of genital infections (2.2% vs 0.7%; P value not provided), urinary tract infections (9.9% vs 8.1%; P value not provided), and hypotension (10.4% vs 8.6%; P value not provided), compared to placebo.

WHAT’S NEW

Risk of hospitalization significantly reduced for patients with HFpEF

In the EMPEROR-Preserved study, empagliflozin led to a lower incidence of hospitalization for HF in patients with HFpEF but did not significantly reduce the number of deaths from CV disease or other causes. In comparison, in the similarly designed EMPEROR-Reduced trial, treatment with empagliflozin reduced CV and all-cause mortality in individuals with HFrEF.⁸

CAVEATS

HF criteria, study population may limit generalizability

The reduction in the primary outcome of CV death or first hospitalization was most pronounced in patients with an LVEF > 40% to < 50%, typically defined as HFmrEF, who often have clinical features similar to those with HFrEF. This raises the question of how generalizable these results are for all patients with HFpEF.

Continue to: The study's generalizability...

Empagliflozin treatment, however, was associated with higher rates of genital infections, urinary tract infections, and hypotension, compared to placebo.

The study’s generalizability was further limited by its significant exclusion criteria, which included elevated blood pressure, chronic obstructive pulmonary disease on home oxygen, liver disease, renal disease with an eGFR < 20 mL/min/1.73 m² or requiring dialysis, and BMI ≥ 45.

Finally, only 12% of patients were from North America, and results were not significant for this subgroup (HR = 0.72; 95% CI, 0.52-1.00), which may challenge its external validity. The authors noted that 23% of patients discontinued treatment for reasons other than death, which may have driven the null effect.

CHALLENGES TO IMPLEMENTATION

Empagliflozin is expensive,but coverage may improve

Cost could be a major barrier to implementation. Retail pricing for empagliflozin is estimated to be more than $550 per month, which may be prohibitive for patients with no insurance or with higher-deductible plans.¹¹ However, the US Food and Drug Administration has approved empagliflozin to reduce the risk of CV death and hospitalization for HF in adults,¹² which may help to improve insurance coverage.

ILLUSTRATIVE CASE

A 72-year-old man with a history of hypertension, permanent atrial fibrillation, and heart failure (HF) comes into your clinic for follow-up. He was hospitalized a few months ago for HF requiring diuresis. His echocardiogram at that time showed an EF of 50% and no significant valvular disease. He does not have a history of diabetes or tobacco use. His medication regimen includes metoprolol, lisinopril-hydrochlorothiazide, apixaban, and atorvastatin. The patient is still symptomatic from his HF and asks you if there is anything else he can do to prevent another hospitalization for HF.

HFpEF was first defined as HF in patients with a left ventricular ejection fraction (LVEF) > 40%. However, HF with an LVEF between 41% and 49% has been reclassified as its own category: heart failure with mildly reduced ejection fraction (HFmrEF).² HFpEF is now diagnosed when the patient has HF symptoms and an LVEF ≥ 50%, mimickers (lung disease, pulmonary embolism, pulmonary hypertension, and renal disease) have been excluded, and there is evidence of elevated left ventricular filling pressure or noninvasive correlates such as elevated natriuretic peptides. It is estimated that HFpEF comprises half of all patients with HF.³

In comparison with HF with reduced ejection fraction (HFrEF), there are limited proven treatment options with cardiovascular (CV) benefit in HFpEF.⁴ Spironolactone is associated with a slight decrease in HF-­related hospitalizations but not with a reduction in CV or all-cause mortality for patients with HFpEF.^4,5 Angiotensin-­converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers have not been shown to reduce morbidity or mortality in HFpEF when not indicated for another reason.^6,7 Sodium-glucose cotransporter 2 (SGLT2) inhibitors are known to decrease the development and progression of HFrEF⁸; however, the effect of SGLT2 inhibition in patients with HFpEF remains unclear. Post hoc analyses of a multicenter trial of dapagliflozin in type 2 diabetes indicated no reduction in CV death, hospitalization, or all-cause mortality in HFpEF.⁹ Another study found improved CV mortality and decreased HF-related urgent visits and hospitalizations with sotagliflozin, but the number of events was too small to estimate a treatment effect.¹⁰ Given this uncertainty, the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-­Preserved) was conducted to evaluate the effects of SGLT2 inhibition with empagliflozin in patients with HFpEF.¹

STUDY SUMMARY

Confirmation of benefit of empagliflozin for patients with HFpEF

The EMPEROR-Preserved study was a ­double-blind, placebo-controlled trial that randomized adult patients with HFpEF (defined by an LVEF > 40%) to either placebo or empagliflozin 10 mg/d, in addition to usual therapy. Patients were randomized in a 1:1 ratio stratified by geographic region, diabetes status, renal function (estimated glomerular filtration rate [eGFR] either < 60 or ≥ 60 mL/min/1.73 m²), and LVEF > 40% to < 50% or LVEF ≥ 50%.

For patients with HFpEF, empagliflozin added to usual care significantly reduced the risk of hospitalization for heart failure, regardless of whether patients had diabetes.

Included patients were 18 years or older and had an NT-proBNP level > 300 pg/mL (or > 900 pg/mL if the patient had atrial fibrillation at baseline), an LVEF > 40%, and New York Heart Association (NYHA) class II-IV symptoms at baseline. Patients with a CV event in the preceding 90 days, systolic blood pressure ≥ 180 mm Hg, or significant valvular disease were excluded from the study.

The primary outcome was a composite of CV death or first hospitalization for HF. The secondary outcomes were all hospitalizations for HF and the rate of decline in eGFR.

Of the 5988 patients in the trial, 2997 were randomized to receive empagliflozin and 2991 were randomized to placebo. The average age was 72 years in each group, 45% of patients were women, about 76% were White, and 12% were from North America. About 81% of patients were classified as NYHA class II, nearly half had diabetes, and half had an eGFR < 60 mL/min/1.73 m². The median body mass index (BMI) was 30, and the median LVEF was 54%. At baseline, the groups were similar in BMI, history of HF hospitalization in the past 12 months, history of common risk factors for HFpEF (atrial fibrillation, diabetes, and hypertension), and prescribed CV medications (ACE inhibitor or ARB with or without a neprilysin inhibitor, spironolactone, beta-blocker, digitalis glycosides, aspirin, and statins). Patients were followed for a median of 26.2 months.

Continue to: The primary composite...

The primary composite outcome of death from CV causes or HF-related hospitalization occurred in 415 patients (13.8%) in the empagliflozin group and in 511 patients (17.1%) in the placebo group (hazard ratio [HR] = 0.79; 95% CI, 0.69-0.90; P < .001). The number needed to treat to prevent 1 primary outcome event was 31 (95% CI, 20-69). Hospitalization for HF occurred in 259 patients (8.6%) with empagliflozin vs 352 patients (11.8%) with placebo (HR = 0.71; 95% CI, 0.60-0.83), and CV death occurred in 219 patients (7.3%) with empagliflozin vs 244 patients (8.2%) with placebo (HR = 0.91; 95% CI, 0.76-1.09). The effect was consistent in patients with or without diabetes at baseline; however, the largest reduction in the primary composite outcome was seen in those with an LVEF < 50%, age ≥ 70 years old, BMI < 30, and NYHA class II status.

The secondary outcome of total number of hospitalizations for HF was 407 with empagliflozin vs 541 with placebo (HR = 0.73; 95% CI, 0.61-0.88; P < .001). The rate of decline in the eGFR per year was –1.25 in the empagliflozin group vs –2.62 in the placebo group (P < .001), indicating that those taking empagliflozin had preserved renal function compared with those taking placebo.

Death from any cause occurred in 422 patients (14.1%) in the empagliflozin group and 427 patients (14.3%) in the placebo group (HR = 1.00; 95% CI, 0.87-1.15). Empagliflozin treatment was associated with higher rates of genital infections (2.2% vs 0.7%; P value not provided), urinary tract infections (9.9% vs 8.1%; P value not provided), and hypotension (10.4% vs 8.6%; P value not provided), compared to placebo.

WHAT’S NEW

Risk of hospitalization significantly reduced for patients with HFpEF

In the EMPEROR-Preserved study, empagliflozin led to a lower incidence of hospitalization for HF in patients with HFpEF but did not significantly reduce the number of deaths from CV disease or other causes. In comparison, in the similarly designed EMPEROR-Reduced trial, treatment with empagliflozin reduced CV and all-cause mortality in individuals with HFrEF.⁸

CAVEATS

HF criteria, study population may limit generalizability

The reduction in the primary outcome of CV death or first hospitalization was most pronounced in patients with an LVEF > 40% to < 50%, typically defined as HFmrEF, who often have clinical features similar to those with HFrEF. This raises the question of how generalizable these results are for all patients with HFpEF.

Continue to: The study's generalizability...

Empagliflozin treatment, however, was associated with higher rates of genital infections, urinary tract infections, and hypotension, compared to placebo.

The study’s generalizability was further limited by its significant exclusion criteria, which included elevated blood pressure, chronic obstructive pulmonary disease on home oxygen, liver disease, renal disease with an eGFR < 20 mL/min/1.73 m² or requiring dialysis, and BMI ≥ 45.

Finally, only 12% of patients were from North America, and results were not significant for this subgroup (HR = 0.72; 95% CI, 0.52-1.00), which may challenge its external validity. The authors noted that 23% of patients discontinued treatment for reasons other than death, which may have driven the null effect.

CHALLENGES TO IMPLEMENTATION

Empagliflozin is expensive,but coverage may improve

Cost could be a major barrier to implementation. Retail pricing for empagliflozin is estimated to be more than $550 per month, which may be prohibitive for patients with no insurance or with higher-deductible plans.¹¹ However, the US Food and Drug Administration has approved empagliflozin to reduce the risk of CV death and hospitalization for HF in adults,¹² which may help to improve insurance coverage.

THE CASE

A 40-year-old woman with no significant medical history sought care at the emergency department for a fever, rash, and arthralgia. On admission, she had worsening bilateral ankle pain and was having difficulty walking. During the previous 3 months, she’d had 3 episodes of tonsillitis, all of which were presumed to be caused by Streptococcus, although no swabs were obtained. Her primary care physician treated her with antibiotics each time: 1 round of amoxicillin 500 mg twice daily for 10 days and 2 rounds of amoxicillin/clavulanate 875 mg twice daily for 7 to 10 days. During the previous month, she’d experienced intermittent fevers ranging from 100.2 °F to 100.8 °F, with no distinct pattern.

The patient said that 2 weeks prior to her admission to the hospital, she’d developed a rash on her right arm, which was papular, nondraining, nonpruritic, and not painful (FIGURE 1). Six days later, the rash spread to her left arm, chest, and back, with a few lesions on her legs (FIGURE 2). A few days later, she developed arthralgias in her hips, knees, and ankles. These were associated with the appearance of large, flat, erythematous lesions on her anterior lower extremities (FIGURE 2). About 5 days before she was admitted to our hospital, the patient was seen at another hospital and treated for possible cellulitis with cephalexin (500 mg 4 times daily for 5-7 days), but her symptoms persisted.

At this point, she sought care at our hospital for her worsening lower extremity arthralgia, difficulty walking, and the persistent rash. An initial lab report showed a white blood cell (WBC) count of 12.6 × 10³/µL (normal range, 4.0-10.0 × 10³/µL) with an absolute neutrophil count of 9.7 × 10³/µL ­(normal, 1.7-7.0 × 10³/µL). Her C-reactive protein (CRP) level was elevated (194.7 mg/L; normal, 0.0-5.0 mg/L), as was her erythrocyte sedimentation rate (ESR) (102.0 mm/h; normal, 0.0-20.0 mm/h). A rapid pharyngeal strep test was negative. Her anti-­streptolysin O (ASO) titer was elevated (2092.0 IU/mL; normal, < 250.0 IU/mL), and her rheumatic factor was mildly elevated (19.0 IU/mL; normal, 0.0-14.0 IU/mL). An antinuclear antibody panel was positive at 1:80. Further testing was performed, and the patient was found to be negative for Sjögren syndrome A, Sjögren syndrome B, anti-Smith, scleroderma-70, double-stranded DNA, and chromatin AB—making an autoimmune disease unlikely.

THE DIAGNOSIS

The patient met the American Heart Association’s revised Jones criteria for the diagnosis of rheumatic fever: She had a positive ASO titer; polyarthritis and subcutaneous nodules (2 major criteria); and ESR > 60 mm/h and CRP > 3 mg/L (1 minor criterion).¹ She started taking naproxen 500 mg twice per day and was given a penicillin G 1.5-million-unit injection. A transthoracic echocardiogram also was performed during her admission to rule out endocarditis; no abnormalities were found.

A few days after starting treatment for rheumatic fever, the patient’s WBC count returned to within normal limits and her joint swelling and pain improved; however, her rash did not go away, leading us to wonder if there was a second disease at work. Dermatology was consulted, and a punch biopsy was obtained. The results showed acute febrile neutrophilic dermatosis, or Sweet syndrome.

DISCUSSION

Sweet syndrome is considered rare, and incidence numbers are elusive.² It has a worldwide distribution and no racial bias.³ Sweet syndrome usually occurs in women ages 30 to 50 years, although it may also occur in younger adults and children.³ The differentialdiagnosis for Sweet syndrome is broad and includes infectious and inflammatory disorders, neoplastic conditions, reactive erythemas, vasculitis, other cutaneous conditions, and other systemic diseases.³

Three subtypes have been defined based on etiology: (1) classical (or idiopathic) Sweet syndrome; (2) malignancy-associated Sweet syndrome, which is most often related to acute myelogenous leukemia; and (3) drug-induced Sweet syndrome, which is usually associated with granulocyte colony–­stimulating factor treatment.⁴ Our patient had the most common subtype: classical Sweet syndrome.

Continue to: What you'll see

What you’ll see. Classical Sweet syndrome usually develops approximately 1 to 3 weeks after an infection—usually an upper respiratory tract or gastrointestinal infection.⁵ It may also be associated with inflammatory bowel disease or pregnancy.⁵ Potential symptoms include pyrexia; elevated neutrophil count; papules, nodules, or plaques; and a diffuse infiltrate of predominantly mature neutrophils located in the upper dermis.^1,5

Corticosteroid therapy is the gold standard for treatment of classical Sweet syndrome.Dosing usually starts with prednisone 1 mg/kg/d, which can be tapered to 10 mg/d within 4 to 6 weeks.⁵ If steroid treatment is contraindicated in the patient, alternative treatments are colchicine 0.5 mg 3 times daily for 10 to 21 days or enteric-coated potassium iodide 300 mg 3 times daily until the rash subsides.⁵ Without treatment, symptoms may resolve within weeks to months; with treatment, the rash usually resolves within 2 to 5 days. Some resistant forms may require 2 to 3 months of treatment.

There is a risk of recurrence in approximately one-third of patients after successful treatment of classical Sweet syndrome.⁵ Recurrence can be caused by another inciting factor (ie, irritable bowel disease, upper respiratory tract infection, malignancy, or a new medication), making a new investigation necessary. However, treatment would entail the same medications.⁵

The patient was placed on penicillin V 250 mg twice daily for 5 years due to the significant risk of carditis in the setting of rheumatic fever. She started an oral steroid regimen of a prednisone weekly taper, starting with 60 mg/d, for 4 to 6 weeks. Her papular rash improved soon after initiation of steroid therapy.

THE TAKEAWAY

On presentation, this patient’s symptoms met the Jones criteria for rheumatic fever, but she did not respond to treatment. This led us to revisit her case, order additional tests, and identify a second diagnosis—Sweet syndrome—that responded positively to treatment. This case is a reminder that sometimes the signs and symptoms we are looking at are the result of 2 underlying illnesses, with 1 possibly triggering the other. That was likely what occurred in this case.

CORRESPONDENCE
Farah Leclercq, DO, Department of Family Medicine, University of Florida, 12041 Southwest 1 Lane, Gainesville, FL 32607; [email protected]

THE CASE

A 40-year-old woman with no significant medical history sought care at the emergency department for a fever, rash, and arthralgia. On admission, she had worsening bilateral ankle pain and was having difficulty walking. During the previous 3 months, she’d had 3 episodes of tonsillitis, all of which were presumed to be caused by Streptococcus, although no swabs were obtained. Her primary care physician treated her with antibiotics each time: 1 round of amoxicillin 500 mg twice daily for 10 days and 2 rounds of amoxicillin/clavulanate 875 mg twice daily for 7 to 10 days. During the previous month, she’d experienced intermittent fevers ranging from 100.2 °F to 100.8 °F, with no distinct pattern.

The patient said that 2 weeks prior to her admission to the hospital, she’d developed a rash on her right arm, which was papular, nondraining, nonpruritic, and not painful (FIGURE 1). Six days later, the rash spread to her left arm, chest, and back, with a few lesions on her legs (FIGURE 2). A few days later, she developed arthralgias in her hips, knees, and ankles. These were associated with the appearance of large, flat, erythematous lesions on her anterior lower extremities (FIGURE 2). About 5 days before she was admitted to our hospital, the patient was seen at another hospital and treated for possible cellulitis with cephalexin (500 mg 4 times daily for 5-7 days), but her symptoms persisted.

At this point, she sought care at our hospital for her worsening lower extremity arthralgia, difficulty walking, and the persistent rash. An initial lab report showed a white blood cell (WBC) count of 12.6 × 10³/µL (normal range, 4.0-10.0 × 10³/µL) with an absolute neutrophil count of 9.7 × 10³/µL ­(normal, 1.7-7.0 × 10³/µL). Her C-reactive protein (CRP) level was elevated (194.7 mg/L; normal, 0.0-5.0 mg/L), as was her erythrocyte sedimentation rate (ESR) (102.0 mm/h; normal, 0.0-20.0 mm/h). A rapid pharyngeal strep test was negative. Her anti-­streptolysin O (ASO) titer was elevated (2092.0 IU/mL; normal, < 250.0 IU/mL), and her rheumatic factor was mildly elevated (19.0 IU/mL; normal, 0.0-14.0 IU/mL). An antinuclear antibody panel was positive at 1:80. Further testing was performed, and the patient was found to be negative for Sjögren syndrome A, Sjögren syndrome B, anti-Smith, scleroderma-70, double-stranded DNA, and chromatin AB—making an autoimmune disease unlikely.

THE DIAGNOSIS

The patient met the American Heart Association’s revised Jones criteria for the diagnosis of rheumatic fever: She had a positive ASO titer; polyarthritis and subcutaneous nodules (2 major criteria); and ESR > 60 mm/h and CRP > 3 mg/L (1 minor criterion).¹ She started taking naproxen 500 mg twice per day and was given a penicillin G 1.5-million-unit injection. A transthoracic echocardiogram also was performed during her admission to rule out endocarditis; no abnormalities were found.

A few days after starting treatment for rheumatic fever, the patient’s WBC count returned to within normal limits and her joint swelling and pain improved; however, her rash did not go away, leading us to wonder if there was a second disease at work. Dermatology was consulted, and a punch biopsy was obtained. The results showed acute febrile neutrophilic dermatosis, or Sweet syndrome.

DISCUSSION

Sweet syndrome is considered rare, and incidence numbers are elusive.² It has a worldwide distribution and no racial bias.³ Sweet syndrome usually occurs in women ages 30 to 50 years, although it may also occur in younger adults and children.³ The differentialdiagnosis for Sweet syndrome is broad and includes infectious and inflammatory disorders, neoplastic conditions, reactive erythemas, vasculitis, other cutaneous conditions, and other systemic diseases.³

Three subtypes have been defined based on etiology: (1) classical (or idiopathic) Sweet syndrome; (2) malignancy-associated Sweet syndrome, which is most often related to acute myelogenous leukemia; and (3) drug-induced Sweet syndrome, which is usually associated with granulocyte colony–­stimulating factor treatment.⁴ Our patient had the most common subtype: classical Sweet syndrome.

Continue to: What you'll see

What you’ll see. Classical Sweet syndrome usually develops approximately 1 to 3 weeks after an infection—usually an upper respiratory tract or gastrointestinal infection.⁵ It may also be associated with inflammatory bowel disease or pregnancy.⁵ Potential symptoms include pyrexia; elevated neutrophil count; papules, nodules, or plaques; and a diffuse infiltrate of predominantly mature neutrophils located in the upper dermis.^1,5

Corticosteroid therapy is the gold standard for treatment of classical Sweet syndrome.Dosing usually starts with prednisone 1 mg/kg/d, which can be tapered to 10 mg/d within 4 to 6 weeks.⁵ If steroid treatment is contraindicated in the patient, alternative treatments are colchicine 0.5 mg 3 times daily for 10 to 21 days or enteric-coated potassium iodide 300 mg 3 times daily until the rash subsides.⁵ Without treatment, symptoms may resolve within weeks to months; with treatment, the rash usually resolves within 2 to 5 days. Some resistant forms may require 2 to 3 months of treatment.

There is a risk of recurrence in approximately one-third of patients after successful treatment of classical Sweet syndrome.⁵ Recurrence can be caused by another inciting factor (ie, irritable bowel disease, upper respiratory tract infection, malignancy, or a new medication), making a new investigation necessary. However, treatment would entail the same medications.⁵

The patient was placed on penicillin V 250 mg twice daily for 5 years due to the significant risk of carditis in the setting of rheumatic fever. She started an oral steroid regimen of a prednisone weekly taper, starting with 60 mg/d, for 4 to 6 weeks. Her papular rash improved soon after initiation of steroid therapy.

THE TAKEAWAY

On presentation, this patient’s symptoms met the Jones criteria for rheumatic fever, but she did not respond to treatment. This led us to revisit her case, order additional tests, and identify a second diagnosis—Sweet syndrome—that responded positively to treatment. This case is a reminder that sometimes the signs and symptoms we are looking at are the result of 2 underlying illnesses, with 1 possibly triggering the other. That was likely what occurred in this case.

CORRESPONDENCE
Farah Leclercq, DO, Department of Family Medicine, University of Florida, 12041 Southwest 1 Lane, Gainesville, FL 32607; [email protected]

THE CASE

A 40-year-old woman with no significant medical history sought care at the emergency department for a fever, rash, and arthralgia. On admission, she had worsening bilateral ankle pain and was having difficulty walking. During the previous 3 months, she’d had 3 episodes of tonsillitis, all of which were presumed to be caused by Streptococcus, although no swabs were obtained. Her primary care physician treated her with antibiotics each time: 1 round of amoxicillin 500 mg twice daily for 10 days and 2 rounds of amoxicillin/clavulanate 875 mg twice daily for 7 to 10 days. During the previous month, she’d experienced intermittent fevers ranging from 100.2 °F to 100.8 °F, with no distinct pattern.

The patient said that 2 weeks prior to her admission to the hospital, she’d developed a rash on her right arm, which was papular, nondraining, nonpruritic, and not painful (FIGURE 1). Six days later, the rash spread to her left arm, chest, and back, with a few lesions on her legs (FIGURE 2). A few days later, she developed arthralgias in her hips, knees, and ankles. These were associated with the appearance of large, flat, erythematous lesions on her anterior lower extremities (FIGURE 2). About 5 days before she was admitted to our hospital, the patient was seen at another hospital and treated for possible cellulitis with cephalexin (500 mg 4 times daily for 5-7 days), but her symptoms persisted.

At this point, she sought care at our hospital for her worsening lower extremity arthralgia, difficulty walking, and the persistent rash. An initial lab report showed a white blood cell (WBC) count of 12.6 × 10³/µL (normal range, 4.0-10.0 × 10³/µL) with an absolute neutrophil count of 9.7 × 10³/µL ­(normal, 1.7-7.0 × 10³/µL). Her C-reactive protein (CRP) level was elevated (194.7 mg/L; normal, 0.0-5.0 mg/L), as was her erythrocyte sedimentation rate (ESR) (102.0 mm/h; normal, 0.0-20.0 mm/h). A rapid pharyngeal strep test was negative. Her anti-­streptolysin O (ASO) titer was elevated (2092.0 IU/mL; normal, < 250.0 IU/mL), and her rheumatic factor was mildly elevated (19.0 IU/mL; normal, 0.0-14.0 IU/mL). An antinuclear antibody panel was positive at 1:80. Further testing was performed, and the patient was found to be negative for Sjögren syndrome A, Sjögren syndrome B, anti-Smith, scleroderma-70, double-stranded DNA, and chromatin AB—making an autoimmune disease unlikely.

THE DIAGNOSIS

The patient met the American Heart Association’s revised Jones criteria for the diagnosis of rheumatic fever: She had a positive ASO titer; polyarthritis and subcutaneous nodules (2 major criteria); and ESR > 60 mm/h and CRP > 3 mg/L (1 minor criterion).¹ She started taking naproxen 500 mg twice per day and was given a penicillin G 1.5-million-unit injection. A transthoracic echocardiogram also was performed during her admission to rule out endocarditis; no abnormalities were found.

A few days after starting treatment for rheumatic fever, the patient’s WBC count returned to within normal limits and her joint swelling and pain improved; however, her rash did not go away, leading us to wonder if there was a second disease at work. Dermatology was consulted, and a punch biopsy was obtained. The results showed acute febrile neutrophilic dermatosis, or Sweet syndrome.

DISCUSSION

Sweet syndrome is considered rare, and incidence numbers are elusive.² It has a worldwide distribution and no racial bias.³ Sweet syndrome usually occurs in women ages 30 to 50 years, although it may also occur in younger adults and children.³ The differentialdiagnosis for Sweet syndrome is broad and includes infectious and inflammatory disorders, neoplastic conditions, reactive erythemas, vasculitis, other cutaneous conditions, and other systemic diseases.³

Three subtypes have been defined based on etiology: (1) classical (or idiopathic) Sweet syndrome; (2) malignancy-associated Sweet syndrome, which is most often related to acute myelogenous leukemia; and (3) drug-induced Sweet syndrome, which is usually associated with granulocyte colony–­stimulating factor treatment.⁴ Our patient had the most common subtype: classical Sweet syndrome.

Continue to: What you'll see

What you’ll see. Classical Sweet syndrome usually develops approximately 1 to 3 weeks after an infection—usually an upper respiratory tract or gastrointestinal infection.⁵ It may also be associated with inflammatory bowel disease or pregnancy.⁵ Potential symptoms include pyrexia; elevated neutrophil count; papules, nodules, or plaques; and a diffuse infiltrate of predominantly mature neutrophils located in the upper dermis.^1,5

Corticosteroid therapy is the gold standard for treatment of classical Sweet syndrome.Dosing usually starts with prednisone 1 mg/kg/d, which can be tapered to 10 mg/d within 4 to 6 weeks.⁵ If steroid treatment is contraindicated in the patient, alternative treatments are colchicine 0.5 mg 3 times daily for 10 to 21 days or enteric-coated potassium iodide 300 mg 3 times daily until the rash subsides.⁵ Without treatment, symptoms may resolve within weeks to months; with treatment, the rash usually resolves within 2 to 5 days. Some resistant forms may require 2 to 3 months of treatment.

There is a risk of recurrence in approximately one-third of patients after successful treatment of classical Sweet syndrome.⁵ Recurrence can be caused by another inciting factor (ie, irritable bowel disease, upper respiratory tract infection, malignancy, or a new medication), making a new investigation necessary. However, treatment would entail the same medications.⁵

The patient was placed on penicillin V 250 mg twice daily for 5 years due to the significant risk of carditis in the setting of rheumatic fever. She started an oral steroid regimen of a prednisone weekly taper, starting with 60 mg/d, for 4 to 6 weeks. Her papular rash improved soon after initiation of steroid therapy.

THE TAKEAWAY

On presentation, this patient’s symptoms met the Jones criteria for rheumatic fever, but she did not respond to treatment. This led us to revisit her case, order additional tests, and identify a second diagnosis—Sweet syndrome—that responded positively to treatment. This case is a reminder that sometimes the signs and symptoms we are looking at are the result of 2 underlying illnesses, with 1 possibly triggering the other. That was likely what occurred in this case.

CORRESPONDENCE
Farah Leclercq, DO, Department of Family Medicine, University of Florida, 12041 Southwest 1 Lane, Gainesville, FL 32607; [email protected]

Roy Altman, MD, was a father, a husband, a teacher, a physician, an editor, and a mentor. He died November 30 as a result of complications related to Parkinson’s disease.

Altman was an editorial advisory board member for MDedge Rheumatology/Rheumatology News since the publications’ start in 2002. He also treated patients and taught students at the University of Miami and the University of California, Los Angeles. A father of four adult children and a grandfather to nine grandchildren, Altman was also a husband to Linda, “his lifelong partner.”

“[He] had this tremendous editorial expertise to be able to manage different journals at the same time without conflict,” said Marc Hochberg, MD, MPH, a professor of medicine, epidemiology, and public health and head of the division of rheumatology and clinical immunology at the University of Maryland School of Medicine, Baltimore. “This was done in the days before electronic publishing, in the days before everything was being done on the computer.”

Publications where Altman served as editor include Osteoarthritis and Cartilage and Seminars in Arthritis and Rheumatism.

In addition to editing articles, Altman also had an active patient panel, while lecturing and traveling internationally, Hochberg said. Altman accomplished this “while maintaining a very active family life,” remembers Hochberg, who learned from Altman about ways to achieve work-life balance.

“That’s important when you’re a junior faculty member – and you’re trying to develop your academic career – that you prioritize what you need to do to be successful in the world of academic medicine, especially rheumatology,” said Hochberg, who described Altman as a “very close friend.”

Teacher, physician, and mentor

John FitzGerald, MD, PhD, MBA, chief of clinical rheumatology at the University of California, Los Angeles, looks back on the more than 15 years that Altman drove 1 hour each way to teach fellows about topics including osteoarthritis. “He really valued teaching. ... that was a lot of his focus,” said FitzGerald, who adds that Altman also enjoyed his relationships with patients.

Altman joined the University of California, Los Angeles, faculty as a professor of medicine in the division of rheumatology and immunology in 2003. Before arriving at UCLA, he was chief of rheumatology and immunology at the University of Miami for many years.

“His patients loved him because he was providing treatments and services that they really had trouble finding elsewhere,” FitzGerald said. Altman entrusted FitzGerald with giving him injections between patients or during lunch for the arthritis that increasingly bothered him.

“He was very appreciative of having the care provided to him. ... he was also sort of playful and teasing,” FitzGerald said.

Altman also took on the role of teacher at home, according to his daughter, Evie. “My dad loved to diagnose; he enjoyed piecing together the disparate physical and radiologic clues to determine the cause of disease or pain. When I was much younger, he taught me how to spot someone with Paget’s Disease from the other end of the room.”

“He loved teaching, imparting his knowledge to others,” she added, remembering the slide sessions Altman presented to his students at their family home. “We loved [the slide sessions] because we could get pizza for dinner, and we got really good at spotting the biological markers of rheumatoid arthritis.”

Aaron Altman said his father was “impassioned by bringing people alleviation of their pain and suffering. It drove him to his very core.”

Researcher and family man

Evie Altman said in an interview that many people don’t know her father was one of the first practitioners of arthroscopy. “He would bring the then-rigid scopes into our elementary school class for ‘show and tell.’ Also, he traveled to the Bolivian jungles in the late 1970s to gather specific red ants whose venom locals had reported as an arthritic treatment,” she said.

Ultimately, Altman isolated the venom’s active ingredient, said Evie, who remembers that her father studied the effect of the treatment for many years. “This eventually led to his research with capsaicin peppers, which was developed into a cream used widely today.”

“Growing up, our garage freezer always had serum and patient urine in one section, away from the ice cream,” Evie added.

In 2011, Sally Koch Kubetin reported for Rheumatology News on Altman’s habit of donning his wife’s handpainted ties. His motivation? It was “born of the sensible desire to be recognizable in a busy world,” she wrote.

Evie said that her mother started painting ties for her father early in his career. Two of his favorite ties, she said, are the “Lady and the Tramp” tie featuring the two dogs eating spaghetti from the same bowl and the Winnie the Pooh tie. “Mostly, he loved the ties because my mom made them,” she said.

Student and military doctor

Altman received his medical degree from the University of Miami School of Medicine after earning an undergraduate degree from Michigan State University, East Lansing, Kubetin reported. The University of Miami School of Medicine was also where he did his internship, residency, and fellowship in rheumatology.

Kubetin reported that Altman’s military service interrupted his training. During his service as a lieutenant in the U.S. Navy active duty reserve, he was a general medical officer and cared for sailors and officers at Naval Air Station Point Mugu in Oxnard, Calif.

Altman had a second academic appointment as a professor of orthopedics when he was in Miami, according to the Rheumatology News profile. In addition, he was the clinical director of the geriatric research, education, and clinical center, and chief of the arthritis section in the division of medicine at the Miami Veterans Affairs Medical Center.

“Persistence, stubbornness, and all around stick-to-it-iveness defined him in our eyes,” said his daughter, Sarah. His daughter, Ruth, credits her father’s kindness and patience with informing how she practices veterinary medicine. “When I went to rounds with dad on Saturdays, he went to a nearby flower place downtown to get mom flowers almost every week if he could,” she said.

Altman announced at the family’s annual summer reunion in 2021 that he would stop seeing patients, said his daughter, Evie. He continued to present slide sessions and grand rounds to medical students at UCLA until early this year. Altman continued to edit journals and review articles until he died from complications of Parkinson’s disease.

He published articles in medical journals that number in the thousands, according to a website established by Altman’s family that honors his life. Altman was born in Astoria, N.Y., on May 16, 1937, and moved to Miami Beach with his parents when he was young.

Roy Altman, MD, was a father, a husband, a teacher, a physician, an editor, and a mentor. He died November 30 as a result of complications related to Parkinson’s disease.

Altman was an editorial advisory board member for MDedge Rheumatology/Rheumatology News since the publications’ start in 2002. He also treated patients and taught students at the University of Miami and the University of California, Los Angeles. A father of four adult children and a grandfather to nine grandchildren, Altman was also a husband to Linda, “his lifelong partner.”

“[He] had this tremendous editorial expertise to be able to manage different journals at the same time without conflict,” said Marc Hochberg, MD, MPH, a professor of medicine, epidemiology, and public health and head of the division of rheumatology and clinical immunology at the University of Maryland School of Medicine, Baltimore. “This was done in the days before electronic publishing, in the days before everything was being done on the computer.”

Publications where Altman served as editor include Osteoarthritis and Cartilage and Seminars in Arthritis and Rheumatism.

In addition to editing articles, Altman also had an active patient panel, while lecturing and traveling internationally, Hochberg said. Altman accomplished this “while maintaining a very active family life,” remembers Hochberg, who learned from Altman about ways to achieve work-life balance.

“That’s important when you’re a junior faculty member – and you’re trying to develop your academic career – that you prioritize what you need to do to be successful in the world of academic medicine, especially rheumatology,” said Hochberg, who described Altman as a “very close friend.”

Teacher, physician, and mentor

John FitzGerald, MD, PhD, MBA, chief of clinical rheumatology at the University of California, Los Angeles, looks back on the more than 15 years that Altman drove 1 hour each way to teach fellows about topics including osteoarthritis. “He really valued teaching. ... that was a lot of his focus,” said FitzGerald, who adds that Altman also enjoyed his relationships with patients.

Altman joined the University of California, Los Angeles, faculty as a professor of medicine in the division of rheumatology and immunology in 2003. Before arriving at UCLA, he was chief of rheumatology and immunology at the University of Miami for many years.

“His patients loved him because he was providing treatments and services that they really had trouble finding elsewhere,” FitzGerald said. Altman entrusted FitzGerald with giving him injections between patients or during lunch for the arthritis that increasingly bothered him.

“He was very appreciative of having the care provided to him. ... he was also sort of playful and teasing,” FitzGerald said.

Altman also took on the role of teacher at home, according to his daughter, Evie. “My dad loved to diagnose; he enjoyed piecing together the disparate physical and radiologic clues to determine the cause of disease or pain. When I was much younger, he taught me how to spot someone with Paget’s Disease from the other end of the room.”

“He loved teaching, imparting his knowledge to others,” she added, remembering the slide sessions Altman presented to his students at their family home. “We loved [the slide sessions] because we could get pizza for dinner, and we got really good at spotting the biological markers of rheumatoid arthritis.”

Aaron Altman said his father was “impassioned by bringing people alleviation of their pain and suffering. It drove him to his very core.”

Researcher and family man

Evie Altman said in an interview that many people don’t know her father was one of the first practitioners of arthroscopy. “He would bring the then-rigid scopes into our elementary school class for ‘show and tell.’ Also, he traveled to the Bolivian jungles in the late 1970s to gather specific red ants whose venom locals had reported as an arthritic treatment,” she said.

Ultimately, Altman isolated the venom’s active ingredient, said Evie, who remembers that her father studied the effect of the treatment for many years. “This eventually led to his research with capsaicin peppers, which was developed into a cream used widely today.”

“Growing up, our garage freezer always had serum and patient urine in one section, away from the ice cream,” Evie added.

In 2011, Sally Koch Kubetin reported for Rheumatology News on Altman’s habit of donning his wife’s handpainted ties. His motivation? It was “born of the sensible desire to be recognizable in a busy world,” she wrote.

Evie said that her mother started painting ties for her father early in his career. Two of his favorite ties, she said, are the “Lady and the Tramp” tie featuring the two dogs eating spaghetti from the same bowl and the Winnie the Pooh tie. “Mostly, he loved the ties because my mom made them,” she said.

Student and military doctor

Altman received his medical degree from the University of Miami School of Medicine after earning an undergraduate degree from Michigan State University, East Lansing, Kubetin reported. The University of Miami School of Medicine was also where he did his internship, residency, and fellowship in rheumatology.

Kubetin reported that Altman’s military service interrupted his training. During his service as a lieutenant in the U.S. Navy active duty reserve, he was a general medical officer and cared for sailors and officers at Naval Air Station Point Mugu in Oxnard, Calif.

Altman had a second academic appointment as a professor of orthopedics when he was in Miami, according to the Rheumatology News profile. In addition, he was the clinical director of the geriatric research, education, and clinical center, and chief of the arthritis section in the division of medicine at the Miami Veterans Affairs Medical Center.

“Persistence, stubbornness, and all around stick-to-it-iveness defined him in our eyes,” said his daughter, Sarah. His daughter, Ruth, credits her father’s kindness and patience with informing how she practices veterinary medicine. “When I went to rounds with dad on Saturdays, he went to a nearby flower place downtown to get mom flowers almost every week if he could,” she said.

Altman announced at the family’s annual summer reunion in 2021 that he would stop seeing patients, said his daughter, Evie. He continued to present slide sessions and grand rounds to medical students at UCLA until early this year. Altman continued to edit journals and review articles until he died from complications of Parkinson’s disease.

He published articles in medical journals that number in the thousands, according to a website established by Altman’s family that honors his life. Altman was born in Astoria, N.Y., on May 16, 1937, and moved to Miami Beach with his parents when he was young.

Roy Altman, MD, was a father, a husband, a teacher, a physician, an editor, and a mentor. He died November 30 as a result of complications related to Parkinson’s disease.

Altman was an editorial advisory board member for MDedge Rheumatology/Rheumatology News since the publications’ start in 2002. He also treated patients and taught students at the University of Miami and the University of California, Los Angeles. A father of four adult children and a grandfather to nine grandchildren, Altman was also a husband to Linda, “his lifelong partner.”

“[He] had this tremendous editorial expertise to be able to manage different journals at the same time without conflict,” said Marc Hochberg, MD, MPH, a professor of medicine, epidemiology, and public health and head of the division of rheumatology and clinical immunology at the University of Maryland School of Medicine, Baltimore. “This was done in the days before electronic publishing, in the days before everything was being done on the computer.”

Publications where Altman served as editor include Osteoarthritis and Cartilage and Seminars in Arthritis and Rheumatism.

In addition to editing articles, Altman also had an active patient panel, while lecturing and traveling internationally, Hochberg said. Altman accomplished this “while maintaining a very active family life,” remembers Hochberg, who learned from Altman about ways to achieve work-life balance.

“That’s important when you’re a junior faculty member – and you’re trying to develop your academic career – that you prioritize what you need to do to be successful in the world of academic medicine, especially rheumatology,” said Hochberg, who described Altman as a “very close friend.”

Teacher, physician, and mentor

John FitzGerald, MD, PhD, MBA, chief of clinical rheumatology at the University of California, Los Angeles, looks back on the more than 15 years that Altman drove 1 hour each way to teach fellows about topics including osteoarthritis. “He really valued teaching. ... that was a lot of his focus,” said FitzGerald, who adds that Altman also enjoyed his relationships with patients.

Altman joined the University of California, Los Angeles, faculty as a professor of medicine in the division of rheumatology and immunology in 2003. Before arriving at UCLA, he was chief of rheumatology and immunology at the University of Miami for many years.

“His patients loved him because he was providing treatments and services that they really had trouble finding elsewhere,” FitzGerald said. Altman entrusted FitzGerald with giving him injections between patients or during lunch for the arthritis that increasingly bothered him.

“He was very appreciative of having the care provided to him. ... he was also sort of playful and teasing,” FitzGerald said.

Altman also took on the role of teacher at home, according to his daughter, Evie. “My dad loved to diagnose; he enjoyed piecing together the disparate physical and radiologic clues to determine the cause of disease or pain. When I was much younger, he taught me how to spot someone with Paget’s Disease from the other end of the room.”

“He loved teaching, imparting his knowledge to others,” she added, remembering the slide sessions Altman presented to his students at their family home. “We loved [the slide sessions] because we could get pizza for dinner, and we got really good at spotting the biological markers of rheumatoid arthritis.”

Aaron Altman said his father was “impassioned by bringing people alleviation of their pain and suffering. It drove him to his very core.”

Researcher and family man

Evie Altman said in an interview that many people don’t know her father was one of the first practitioners of arthroscopy. “He would bring the then-rigid scopes into our elementary school class for ‘show and tell.’ Also, he traveled to the Bolivian jungles in the late 1970s to gather specific red ants whose venom locals had reported as an arthritic treatment,” she said.

Ultimately, Altman isolated the venom’s active ingredient, said Evie, who remembers that her father studied the effect of the treatment for many years. “This eventually led to his research with capsaicin peppers, which was developed into a cream used widely today.”

“Growing up, our garage freezer always had serum and patient urine in one section, away from the ice cream,” Evie added.

In 2011, Sally Koch Kubetin reported for Rheumatology News on Altman’s habit of donning his wife’s handpainted ties. His motivation? It was “born of the sensible desire to be recognizable in a busy world,” she wrote.

Evie said that her mother started painting ties for her father early in his career. Two of his favorite ties, she said, are the “Lady and the Tramp” tie featuring the two dogs eating spaghetti from the same bowl and the Winnie the Pooh tie. “Mostly, he loved the ties because my mom made them,” she said.

Student and military doctor

Altman received his medical degree from the University of Miami School of Medicine after earning an undergraduate degree from Michigan State University, East Lansing, Kubetin reported. The University of Miami School of Medicine was also where he did his internship, residency, and fellowship in rheumatology.

Kubetin reported that Altman’s military service interrupted his training. During his service as a lieutenant in the U.S. Navy active duty reserve, he was a general medical officer and cared for sailors and officers at Naval Air Station Point Mugu in Oxnard, Calif.

Altman had a second academic appointment as a professor of orthopedics when he was in Miami, according to the Rheumatology News profile. In addition, he was the clinical director of the geriatric research, education, and clinical center, and chief of the arthritis section in the division of medicine at the Miami Veterans Affairs Medical Center.

“Persistence, stubbornness, and all around stick-to-it-iveness defined him in our eyes,” said his daughter, Sarah. His daughter, Ruth, credits her father’s kindness and patience with informing how she practices veterinary medicine. “When I went to rounds with dad on Saturdays, he went to a nearby flower place downtown to get mom flowers almost every week if he could,” she said.

Altman announced at the family’s annual summer reunion in 2021 that he would stop seeing patients, said his daughter, Evie. He continued to present slide sessions and grand rounds to medical students at UCLA until early this year. Altman continued to edit journals and review articles until he died from complications of Parkinson’s disease.

He published articles in medical journals that number in the thousands, according to a website established by Altman’s family that honors his life. Altman was born in Astoria, N.Y., on May 16, 1937, and moved to Miami Beach with his parents when he was young.

In September 2022, the US Preventive Services Task Force (USPSTF) released 2 sets of draft recommendations on screening for 3 mental health conditions in adults: ­anxiety, depression, and suicide risk.^1,2 These draft recommendations are summarized in TABLE 1^1-4 along with finalized recommendations on the same topics for children and adolescents, published in October 2022.^3,4

The recommendations on depression and suicide risk screening in adults are updates of previous recommendations (2016 for depression and 2014 for suicide risk) with no major changes. Screening for anxiety is a topic addressed for the first time this year for adults and for children and adolescents.^1,3

The recommendations are fairly consistent between age groups. A “B” recommendation supports screening for major depression in all patients starting at age 12 years, including during pregnancy and the postpartum period. (See TABLE 1 for grade definitions.) For all age groups, evidence was insufficient to recommend screening for suicide risk. A “B” recommendation was also assigned to screening for anxiety in those ages 8 to 64 years. The USPSTF believes the evidence is insufficient to make a recommendation on screening for anxiety among adults ≥ 65 years of age.

The anxiety disorders common to both children and adults included in the USPSTF recommendations are generalized anxiety disorder, social anxiety disorder, panic disorder, separation anxiety disorder, phobias, selective mutism, and anxiety type not specified. For adults, the USPSTF also includes substance/medication-induced anxiety and anxiety due to other medical conditions.

Adults with anxiety often present with generalized complaints such as sleep disturbance, pain, and other somatic disorders that can remain undiagnosed for years. The ­USPSTF cites a lifetime prevalence of anxiety disorders of 26.4% for men and 40.4% for women, although the data used are 10 years old.⁵ The cited rate of generalized anxiety in pregnancy is 8.5% to 10.5%, and in the postpartum period, 4.4% to 10.8%.⁶

The data on direct benefits and harms of screening for anxiety in adults through age 64 are sparse. Nevertheless, the USPSTF deemed that screening tests for anxiety have adequate accuracy and that psychological interventions for anxiety result in moderate reduction of anxiety symptoms. Pharmacologic interventions produce a small benefit, although there is a lack of evidence for pharmacotherapy in pregnant and postpartum women. There is even less evidence of benefit for treatment in adults ≥ 65 years of age.¹

How anxiety screening tests compare

Screening tests for anxiety in adults reviewed by the USPSTF included the Generalized Anxiety Disorder (GAD) scale and the Edinburgh Postnatal Depression Scale (EPDS) anxiety subscale.¹ The most studied tools are the ­GAD-2 and GAD-7.

Continue to: The sensitivity and specificity...

The sensitivity and specificity of each test depends on the cutoff used. With the GAD-2, a cutoff of 2 or more resulted in a sensitivity of 94% and a specificity of 68% for detecting generalized anxiety.⁷ A cutoff of 3 or more resulted in a sensitivity of 81% and a specificity of 86%.⁷ The GAD-7, using 10 as a cutoff, achieves a sensitivity of 79% and a specificity of 89%.⁷ Given the similar performance of the 2 options, the GAD-2 (TABLE 2^8,9) is probably preferable for use in primary care because of its ease of administration.

The tests evaluated by the USPSTF for anxiety screening in children and adolescents ≥ 8 years of age included the Screen for Child Anxiety Related Disorders (SCARED) and the Patient Health Questionnaire–Adolescent (PHQ-A).³ These tools ask more questions than the adult screening tools do: 41 for the SCARED and 13 for the PHQ-A. The sensitivity of SCARED for generalized anxiety disorder was 64% and the specificity was 63%.¹⁰ The sensitivity of the PHQ-A was 50% and the specificity was 98%.¹⁰

Various versions of all of these screening tools can be easily located on the internet. Search for them using the acronyms.

Screening for major depression

The depression screening tests the USPSTF examined were various versions of the Patient Health Questionnaire (PHQ), the Center for Epidemiologic Studies Depression Scale ­(CES-D), the Geriatric Depression Scale (GDS) in older adults, and the EPDS in postpartum and pregnant persons.⁷

A 2-question version of the PHQ was found to have a sensitivity of 91% with a specificity of 67%. The 9-question PHQ was found to have a similar sensitivity (88%) but better specificity (85%).⁷TABLE 3¹¹ lists the 2 questions in the PHQ-2 and explains how to score the results.

Continue to: The most commonly...

The most commonly studied screening tool for adolescents is the PHQ-A. Its sensitivity is 73% and specificity is 94%.¹²

The GAD-2 and PHQ-2 have the same possible answers and scores and can be combined into a 4-question screening tool to assess for anxiety and depression. If an initial screen for anxiety or depression (or both) is positive, further diagnostic testing and follow-up are needed.

Frequency of screening

The USPSTF recognized that limited information on the frequency of screening for both anxiety and depression does not support any recommendation on this matter. It suggested screening everyone once and then basing the need for subsequent screening tests on clinical judgment after considering risk factors and life events, with periodic rescreening of those at high risk. Finally, USPSTF recognized the many challenges to implementing screening tests for mental health conditions in primary care practice, but offered little practical advice on how to do this.

Suicide risk screening

As for the evidence on benefits and harms of screening for suicide risk in all age groups, the USPSTF still regards it as insufficient to make a recommendation. The lack of evidence applies to all aspects of screening, including the accuracy of the various screening tools and the potential benefits and harms of preventive interventions.^2,7

Next steps

The recommendations on screening for depression, suicide risk, and anxiety in adults have been published as a draft, and the public comment period will be over by the time of this publication. The USPSTF generally takes 6 to 9 months to consider all the public comments and to publish final recommendations. The final recommendations on these topics for children and adolescents have been published since drafts were made available last April. There were no major changes between the draft and final versions.

In September 2022, the US Preventive Services Task Force (USPSTF) released 2 sets of draft recommendations on screening for 3 mental health conditions in adults: ­anxiety, depression, and suicide risk.^1,2 These draft recommendations are summarized in TABLE 1^1-4 along with finalized recommendations on the same topics for children and adolescents, published in October 2022.^3,4

The recommendations on depression and suicide risk screening in adults are updates of previous recommendations (2016 for depression and 2014 for suicide risk) with no major changes. Screening for anxiety is a topic addressed for the first time this year for adults and for children and adolescents.^1,3

The recommendations are fairly consistent between age groups. A “B” recommendation supports screening for major depression in all patients starting at age 12 years, including during pregnancy and the postpartum period. (See TABLE 1 for grade definitions.) For all age groups, evidence was insufficient to recommend screening for suicide risk. A “B” recommendation was also assigned to screening for anxiety in those ages 8 to 64 years. The USPSTF believes the evidence is insufficient to make a recommendation on screening for anxiety among adults ≥ 65 years of age.

The anxiety disorders common to both children and adults included in the USPSTF recommendations are generalized anxiety disorder, social anxiety disorder, panic disorder, separation anxiety disorder, phobias, selective mutism, and anxiety type not specified. For adults, the USPSTF also includes substance/medication-induced anxiety and anxiety due to other medical conditions.

Adults with anxiety often present with generalized complaints such as sleep disturbance, pain, and other somatic disorders that can remain undiagnosed for years. The ­USPSTF cites a lifetime prevalence of anxiety disorders of 26.4% for men and 40.4% for women, although the data used are 10 years old.⁵ The cited rate of generalized anxiety in pregnancy is 8.5% to 10.5%, and in the postpartum period, 4.4% to 10.8%.⁶

The data on direct benefits and harms of screening for anxiety in adults through age 64 are sparse. Nevertheless, the USPSTF deemed that screening tests for anxiety have adequate accuracy and that psychological interventions for anxiety result in moderate reduction of anxiety symptoms. Pharmacologic interventions produce a small benefit, although there is a lack of evidence for pharmacotherapy in pregnant and postpartum women. There is even less evidence of benefit for treatment in adults ≥ 65 years of age.¹

How anxiety screening tests compare

Screening tests for anxiety in adults reviewed by the USPSTF included the Generalized Anxiety Disorder (GAD) scale and the Edinburgh Postnatal Depression Scale (EPDS) anxiety subscale.¹ The most studied tools are the ­GAD-2 and GAD-7.

Continue to: The sensitivity and specificity...

The sensitivity and specificity of each test depends on the cutoff used. With the GAD-2, a cutoff of 2 or more resulted in a sensitivity of 94% and a specificity of 68% for detecting generalized anxiety.⁷ A cutoff of 3 or more resulted in a sensitivity of 81% and a specificity of 86%.⁷ The GAD-7, using 10 as a cutoff, achieves a sensitivity of 79% and a specificity of 89%.⁷ Given the similar performance of the 2 options, the GAD-2 (TABLE 2^8,9) is probably preferable for use in primary care because of its ease of administration.

The tests evaluated by the USPSTF for anxiety screening in children and adolescents ≥ 8 years of age included the Screen for Child Anxiety Related Disorders (SCARED) and the Patient Health Questionnaire–Adolescent (PHQ-A).³ These tools ask more questions than the adult screening tools do: 41 for the SCARED and 13 for the PHQ-A. The sensitivity of SCARED for generalized anxiety disorder was 64% and the specificity was 63%.¹⁰ The sensitivity of the PHQ-A was 50% and the specificity was 98%.¹⁰

Various versions of all of these screening tools can be easily located on the internet. Search for them using the acronyms.

Screening for major depression

The depression screening tests the USPSTF examined were various versions of the Patient Health Questionnaire (PHQ), the Center for Epidemiologic Studies Depression Scale ­(CES-D), the Geriatric Depression Scale (GDS) in older adults, and the EPDS in postpartum and pregnant persons.⁷

A 2-question version of the PHQ was found to have a sensitivity of 91% with a specificity of 67%. The 9-question PHQ was found to have a similar sensitivity (88%) but better specificity (85%).⁷TABLE 3¹¹ lists the 2 questions in the PHQ-2 and explains how to score the results.

Continue to: The most commonly...

The most commonly studied screening tool for adolescents is the PHQ-A. Its sensitivity is 73% and specificity is 94%.¹²

The GAD-2 and PHQ-2 have the same possible answers and scores and can be combined into a 4-question screening tool to assess for anxiety and depression. If an initial screen for anxiety or depression (or both) is positive, further diagnostic testing and follow-up are needed.

Frequency of screening

The USPSTF recognized that limited information on the frequency of screening for both anxiety and depression does not support any recommendation on this matter. It suggested screening everyone once and then basing the need for subsequent screening tests on clinical judgment after considering risk factors and life events, with periodic rescreening of those at high risk. Finally, USPSTF recognized the many challenges to implementing screening tests for mental health conditions in primary care practice, but offered little practical advice on how to do this.

Suicide risk screening

As for the evidence on benefits and harms of screening for suicide risk in all age groups, the USPSTF still regards it as insufficient to make a recommendation. The lack of evidence applies to all aspects of screening, including the accuracy of the various screening tools and the potential benefits and harms of preventive interventions.^2,7

Next steps

The recommendations on screening for depression, suicide risk, and anxiety in adults have been published as a draft, and the public comment period will be over by the time of this publication. The USPSTF generally takes 6 to 9 months to consider all the public comments and to publish final recommendations. The final recommendations on these topics for children and adolescents have been published since drafts were made available last April. There were no major changes between the draft and final versions.

In September 2022, the US Preventive Services Task Force (USPSTF) released 2 sets of draft recommendations on screening for 3 mental health conditions in adults: ­anxiety, depression, and suicide risk.^1,2 These draft recommendations are summarized in TABLE 1^1-4 along with finalized recommendations on the same topics for children and adolescents, published in October 2022.^3,4

The recommendations on depression and suicide risk screening in adults are updates of previous recommendations (2016 for depression and 2014 for suicide risk) with no major changes. Screening for anxiety is a topic addressed for the first time this year for adults and for children and adolescents.^1,3

The recommendations are fairly consistent between age groups. A “B” recommendation supports screening for major depression in all patients starting at age 12 years, including during pregnancy and the postpartum period. (See TABLE 1 for grade definitions.) For all age groups, evidence was insufficient to recommend screening for suicide risk. A “B” recommendation was also assigned to screening for anxiety in those ages 8 to 64 years. The USPSTF believes the evidence is insufficient to make a recommendation on screening for anxiety among adults ≥ 65 years of age.

The anxiety disorders common to both children and adults included in the USPSTF recommendations are generalized anxiety disorder, social anxiety disorder, panic disorder, separation anxiety disorder, phobias, selective mutism, and anxiety type not specified. For adults, the USPSTF also includes substance/medication-induced anxiety and anxiety due to other medical conditions.

Adults with anxiety often present with generalized complaints such as sleep disturbance, pain, and other somatic disorders that can remain undiagnosed for years. The ­USPSTF cites a lifetime prevalence of anxiety disorders of 26.4% for men and 40.4% for women, although the data used are 10 years old.⁵ The cited rate of generalized anxiety in pregnancy is 8.5% to 10.5%, and in the postpartum period, 4.4% to 10.8%.⁶

The data on direct benefits and harms of screening for anxiety in adults through age 64 are sparse. Nevertheless, the USPSTF deemed that screening tests for anxiety have adequate accuracy and that psychological interventions for anxiety result in moderate reduction of anxiety symptoms. Pharmacologic interventions produce a small benefit, although there is a lack of evidence for pharmacotherapy in pregnant and postpartum women. There is even less evidence of benefit for treatment in adults ≥ 65 years of age.¹

How anxiety screening tests compare

Screening tests for anxiety in adults reviewed by the USPSTF included the Generalized Anxiety Disorder (GAD) scale and the Edinburgh Postnatal Depression Scale (EPDS) anxiety subscale.¹ The most studied tools are the ­GAD-2 and GAD-7.

Continue to: The sensitivity and specificity...

The sensitivity and specificity of each test depends on the cutoff used. With the GAD-2, a cutoff of 2 or more resulted in a sensitivity of 94% and a specificity of 68% for detecting generalized anxiety.⁷ A cutoff of 3 or more resulted in a sensitivity of 81% and a specificity of 86%.⁷ The GAD-7, using 10 as a cutoff, achieves a sensitivity of 79% and a specificity of 89%.⁷ Given the similar performance of the 2 options, the GAD-2 (TABLE 2^8,9) is probably preferable for use in primary care because of its ease of administration.

The tests evaluated by the USPSTF for anxiety screening in children and adolescents ≥ 8 years of age included the Screen for Child Anxiety Related Disorders (SCARED) and the Patient Health Questionnaire–Adolescent (PHQ-A).³ These tools ask more questions than the adult screening tools do: 41 for the SCARED and 13 for the PHQ-A. The sensitivity of SCARED for generalized anxiety disorder was 64% and the specificity was 63%.¹⁰ The sensitivity of the PHQ-A was 50% and the specificity was 98%.¹⁰

Various versions of all of these screening tools can be easily located on the internet. Search for them using the acronyms.

Screening for major depression

The depression screening tests the USPSTF examined were various versions of the Patient Health Questionnaire (PHQ), the Center for Epidemiologic Studies Depression Scale ­(CES-D), the Geriatric Depression Scale (GDS) in older adults, and the EPDS in postpartum and pregnant persons.⁷

A 2-question version of the PHQ was found to have a sensitivity of 91% with a specificity of 67%. The 9-question PHQ was found to have a similar sensitivity (88%) but better specificity (85%).⁷TABLE 3¹¹ lists the 2 questions in the PHQ-2 and explains how to score the results.

Continue to: The most commonly...

The most commonly studied screening tool for adolescents is the PHQ-A. Its sensitivity is 73% and specificity is 94%.¹²

The GAD-2 and PHQ-2 have the same possible answers and scores and can be combined into a 4-question screening tool to assess for anxiety and depression. If an initial screen for anxiety or depression (or both) is positive, further diagnostic testing and follow-up are needed.

Frequency of screening

The USPSTF recognized that limited information on the frequency of screening for both anxiety and depression does not support any recommendation on this matter. It suggested screening everyone once and then basing the need for subsequent screening tests on clinical judgment after considering risk factors and life events, with periodic rescreening of those at high risk. Finally, USPSTF recognized the many challenges to implementing screening tests for mental health conditions in primary care practice, but offered little practical advice on how to do this.

Suicide risk screening

As for the evidence on benefits and harms of screening for suicide risk in all age groups, the USPSTF still regards it as insufficient to make a recommendation. The lack of evidence applies to all aspects of screening, including the accuracy of the various screening tools and the potential benefits and harms of preventive interventions.^2,7

Next steps

The recommendations on screening for depression, suicide risk, and anxiety in adults have been published as a draft, and the public comment period will be over by the time of this publication. The USPSTF generally takes 6 to 9 months to consider all the public comments and to publish final recommendations. The final recommendations on these topics for children and adolescents have been published since drafts were made available last April. There were no major changes between the draft and final versions.

Key clinical point: Patients with moderate-to-severe atopic dermatitis (AD) had the highest incidence rate (IR) per 1000 person-years for major adverse cardiovascular events (MACE), followed by venous thrombotic events (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE).

Major finding: The IR per 1000 person-years for MACE, VTE, DVT, and PE were 2.6 (95% CI 2.1-3.2), 2.0 (95% CI 1.5-2.5), 1.6 (95% CI 1.2-2.1), and 0.7 (95% CI 0.5-1.0), respectively.

Study details: This retrospective cohort study included 8197 patients aged ≥12 years with moderate-to-severe AD.

Disclosures: This study was funded by Pfizer, Inc. Some authors declared receiving grant funding from Pfizer. Two authors declared being current or former employees and shareholders of Pfizer.

Source: Hedderson MM et al. Rates of cardiovascular events among patients with moderate-to-severe atopic dermatitis in an integrated health care system: A retrospective cohort study. PLoS One. 2022;17(11):e0277469 (Nov 17). Doi: 10.1371/journal.pone.0277469

Key clinical point: Patients with moderate-to-severe atopic dermatitis (AD) had the highest incidence rate (IR) per 1000 person-years for major adverse cardiovascular events (MACE), followed by venous thrombotic events (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE).

Major finding: The IR per 1000 person-years for MACE, VTE, DVT, and PE were 2.6 (95% CI 2.1-3.2), 2.0 (95% CI 1.5-2.5), 1.6 (95% CI 1.2-2.1), and 0.7 (95% CI 0.5-1.0), respectively.

Study details: This retrospective cohort study included 8197 patients aged ≥12 years with moderate-to-severe AD.

Disclosures: This study was funded by Pfizer, Inc. Some authors declared receiving grant funding from Pfizer. Two authors declared being current or former employees and shareholders of Pfizer.

Source: Hedderson MM et al. Rates of cardiovascular events among patients with moderate-to-severe atopic dermatitis in an integrated health care system: A retrospective cohort study. PLoS One. 2022;17(11):e0277469 (Nov 17). Doi: 10.1371/journal.pone.0277469

Key clinical point: Patients with moderate-to-severe atopic dermatitis (AD) had the highest incidence rate (IR) per 1000 person-years for major adverse cardiovascular events (MACE), followed by venous thrombotic events (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE).

Major finding: The IR per 1000 person-years for MACE, VTE, DVT, and PE were 2.6 (95% CI 2.1-3.2), 2.0 (95% CI 1.5-2.5), 1.6 (95% CI 1.2-2.1), and 0.7 (95% CI 0.5-1.0), respectively.

Study details: This retrospective cohort study included 8197 patients aged ≥12 years with moderate-to-severe AD.

Disclosures: This study was funded by Pfizer, Inc. Some authors declared receiving grant funding from Pfizer. Two authors declared being current or former employees and shareholders of Pfizer.

Source: Hedderson MM et al. Rates of cardiovascular events among patients with moderate-to-severe atopic dermatitis in an integrated health care system: A retrospective cohort study. PLoS One. 2022;17(11):e0277469 (Nov 17). Doi: 10.1371/journal.pone.0277469

Key clinical point: Baricitinib could serve as an effective treatment option for patients with difficult-to-treat moderate-to-severe atopic dermatitis (AD), including those unresponsive to dupilumab treatment; however, a high discontinuation rate indicates its rather heterogenous efficacy.

Major finding: At week 16, the mean Eczema Area and Severity Index score and numerical rating scale-pruritis significantly decreased from 18.3 to 11.1 (P < .0001) and from 6.6 to 5.3 (P < .0001), respectively. The most frequent adverse events (AE) were nausea (11.8%), urinary tract infection (9.8%), and herpes simplex infections (7.8%). Baricitinib treatment was discontinued by 43.2% of patients due to ineffectiveness or AE.

Study details: This multicenter prospective observational study included 51 adult patients with moderate-to-severe AD from the BioDay registry who received baricitinib over 16 weeks.

Disclosures: This study did not report a source of funding. Some authors declared serving as speakers, consultants, advisory board members, or investigators for various organizations.

Source: Boesjes CM et al. Daily practice experience of baricitinib treatment for patients with difficult-to-treat atopic dermatitis: Results from the BioDay registry. Acta Derm Venereol. 2022;102:adv00820 (Nov 24). Doi: 10.2340/actadv.v102.3978

Key clinical point: Baricitinib could serve as an effective treatment option for patients with difficult-to-treat moderate-to-severe atopic dermatitis (AD), including those unresponsive to dupilumab treatment; however, a high discontinuation rate indicates its rather heterogenous efficacy.

Major finding: At week 16, the mean Eczema Area and Severity Index score and numerical rating scale-pruritis significantly decreased from 18.3 to 11.1 (P < .0001) and from 6.6 to 5.3 (P < .0001), respectively. The most frequent adverse events (AE) were nausea (11.8%), urinary tract infection (9.8%), and herpes simplex infections (7.8%). Baricitinib treatment was discontinued by 43.2% of patients due to ineffectiveness or AE.

Study details: This multicenter prospective observational study included 51 adult patients with moderate-to-severe AD from the BioDay registry who received baricitinib over 16 weeks.

Disclosures: This study did not report a source of funding. Some authors declared serving as speakers, consultants, advisory board members, or investigators for various organizations.

Source: Boesjes CM et al. Daily practice experience of baricitinib treatment for patients with difficult-to-treat atopic dermatitis: Results from the BioDay registry. Acta Derm Venereol. 2022;102:adv00820 (Nov 24). Doi: 10.2340/actadv.v102.3978

Key clinical point: Baricitinib could serve as an effective treatment option for patients with difficult-to-treat moderate-to-severe atopic dermatitis (AD), including those unresponsive to dupilumab treatment; however, a high discontinuation rate indicates its rather heterogenous efficacy.

Major finding: At week 16, the mean Eczema Area and Severity Index score and numerical rating scale-pruritis significantly decreased from 18.3 to 11.1 (P < .0001) and from 6.6 to 5.3 (P < .0001), respectively. The most frequent adverse events (AE) were nausea (11.8%), urinary tract infection (9.8%), and herpes simplex infections (7.8%). Baricitinib treatment was discontinued by 43.2% of patients due to ineffectiveness or AE.

Study details: This multicenter prospective observational study included 51 adult patients with moderate-to-severe AD from the BioDay registry who received baricitinib over 16 weeks.

Disclosures: This study did not report a source of funding. Some authors declared serving as speakers, consultants, advisory board members, or investigators for various organizations.

Source: Boesjes CM et al. Daily practice experience of baricitinib treatment for patients with difficult-to-treat atopic dermatitis: Results from the BioDay registry. Acta Derm Venereol. 2022;102:adv00820 (Nov 24). Doi: 10.2340/actadv.v102.3978

This patient was given a diagnosis of cutaneous mastocytosis. The condition was previously known as urticaria pigmentosa, but in 2016 the World Health Organization reclassified the disease to better suit its pathophysiology as a myeloid cell disorder.¹

As the name suggests, this condition—which involves lesions in a sporadic, truncal distribution—involves overactivation of mastocytes at the tissue level from various stimuli, resulting in histocyte degranulation and hyperpigmentation. The exact cause is unknown. What is known is that it is often associated with other allergic or immunologic conditions and is thought to be related to mutations in the gene for CD-117’s receptor for tyrosine kinase.¹ Incidence is similar to that of asthma, in that it occurs more often in younger patients; a majority of affected individuals will grow out of the disease by adolescence.¹

Although most patients do not experience severe symptomatology, it is still important to differentiate cutaneous vs systemic mastocytosis. If a patient presents with inexplicable systemic symptoms of malaise, vague abdominal pain, heartburn, or flushing, the physician should consider systemic mastocytosis, idiopathic anaphylaxis, or hereditary alpha-tryptasemia.²

The test of choice is a serum tryptase test; levels will be elevated with systemic mastocytosis. Consider obtaining a skin biopsy if lesions are ambiguous or nondistinct.

There is no definitive cure for systemic or cutaneous mastocytosis, so treatment is directed at symptoms. Start by advising patients to avoid triggers and to refrain from scratching the affected areas. Topical antihistamines and oral nonsedating antihistamines can be helpful. If symptoms are more severe, refer the patient to an allergist/immunologist or to a hematologist for further medical management.²

The patient in this case had no systemic symptoms, so she was advised to continue taking oral loratadine 10 mg/d, which had been helpful, and to avoid rubbing her skin.

‌

Image courtesy of Daniel Stulberg, MD. Text courtesy of Murtaza Rizvi, MD, and Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

This patient was given a diagnosis of cutaneous mastocytosis. The condition was previously known as urticaria pigmentosa, but in 2016 the World Health Organization reclassified the disease to better suit its pathophysiology as a myeloid cell disorder.¹

As the name suggests, this condition—which involves lesions in a sporadic, truncal distribution—involves overactivation of mastocytes at the tissue level from various stimuli, resulting in histocyte degranulation and hyperpigmentation. The exact cause is unknown. What is known is that it is often associated with other allergic or immunologic conditions and is thought to be related to mutations in the gene for CD-117’s receptor for tyrosine kinase.¹ Incidence is similar to that of asthma, in that it occurs more often in younger patients; a majority of affected individuals will grow out of the disease by adolescence.¹

Although most patients do not experience severe symptomatology, it is still important to differentiate cutaneous vs systemic mastocytosis. If a patient presents with inexplicable systemic symptoms of malaise, vague abdominal pain, heartburn, or flushing, the physician should consider systemic mastocytosis, idiopathic anaphylaxis, or hereditary alpha-tryptasemia.²

The test of choice is a serum tryptase test; levels will be elevated with systemic mastocytosis. Consider obtaining a skin biopsy if lesions are ambiguous or nondistinct.

There is no definitive cure for systemic or cutaneous mastocytosis, so treatment is directed at symptoms. Start by advising patients to avoid triggers and to refrain from scratching the affected areas. Topical antihistamines and oral nonsedating antihistamines can be helpful. If symptoms are more severe, refer the patient to an allergist/immunologist or to a hematologist for further medical management.²

The patient in this case had no systemic symptoms, so she was advised to continue taking oral loratadine 10 mg/d, which had been helpful, and to avoid rubbing her skin.

‌

Image courtesy of Daniel Stulberg, MD. Text courtesy of Murtaza Rizvi, MD, and Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

This patient was given a diagnosis of cutaneous mastocytosis. The condition was previously known as urticaria pigmentosa, but in 2016 the World Health Organization reclassified the disease to better suit its pathophysiology as a myeloid cell disorder.¹

As the name suggests, this condition—which involves lesions in a sporadic, truncal distribution—involves overactivation of mastocytes at the tissue level from various stimuli, resulting in histocyte degranulation and hyperpigmentation. The exact cause is unknown. What is known is that it is often associated with other allergic or immunologic conditions and is thought to be related to mutations in the gene for CD-117’s receptor for tyrosine kinase.¹ Incidence is similar to that of asthma, in that it occurs more often in younger patients; a majority of affected individuals will grow out of the disease by adolescence.¹

Although most patients do not experience severe symptomatology, it is still important to differentiate cutaneous vs systemic mastocytosis. If a patient presents with inexplicable systemic symptoms of malaise, vague abdominal pain, heartburn, or flushing, the physician should consider systemic mastocytosis, idiopathic anaphylaxis, or hereditary alpha-tryptasemia.²

The test of choice is a serum tryptase test; levels will be elevated with systemic mastocytosis. Consider obtaining a skin biopsy if lesions are ambiguous or nondistinct.

There is no definitive cure for systemic or cutaneous mastocytosis, so treatment is directed at symptoms. Start by advising patients to avoid triggers and to refrain from scratching the affected areas. Topical antihistamines and oral nonsedating antihistamines can be helpful. If symptoms are more severe, refer the patient to an allergist/immunologist or to a hematologist for further medical management.²

The patient in this case had no systemic symptoms, so she was advised to continue taking oral loratadine 10 mg/d, which had been helpful, and to avoid rubbing her skin.

‌

Image courtesy of Daniel Stulberg, MD. Text courtesy of Murtaza Rizvi, MD, and Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Key clinical point: The first exposure of pediatric individuals to general anesthesia (GA) is not associated with an increased or decreased risk of developing atopic dermatitis (AD).

Major finding: Multivariate analysis revealed that individuals who were exposed vs not exposed to GA did not have an increased or decreased risk of developing AD (adjusted hazard ratio 1.03; P  =  .701).

Study details: This retrospective cohort study included pediatric individuals aged ≤18 years who were (n = 7,681) or were not (n = 38,405; control individuals) exposed to GA.

Disclosures: This study was funded by a 2020 Amorepacific (South Korea) grant. The authors declared no  conflicts of interest.

Source: Kim DC et al. No association between first exposure to general anaesthesia and atopic dermatitis in the paediatric population. Acta Derm Venereol. 2022;102:adv00813 (Nov 14). Doi: 10.2340/actadv.v102.2738

Key clinical point: The first exposure of pediatric individuals to general anesthesia (GA) is not associated with an increased or decreased risk of developing atopic dermatitis (AD).

Major finding: Multivariate analysis revealed that individuals who were exposed vs not exposed to GA did not have an increased or decreased risk of developing AD (adjusted hazard ratio 1.03; P  =  .701).

Study details: This retrospective cohort study included pediatric individuals aged ≤18 years who were (n = 7,681) or were not (n = 38,405; control individuals) exposed to GA.

Disclosures: This study was funded by a 2020 Amorepacific (South Korea) grant. The authors declared no  conflicts of interest.

Source: Kim DC et al. No association between first exposure to general anaesthesia and atopic dermatitis in the paediatric population. Acta Derm Venereol. 2022;102:adv00813 (Nov 14). Doi: 10.2340/actadv.v102.2738

Key clinical point: The first exposure of pediatric individuals to general anesthesia (GA) is not associated with an increased or decreased risk of developing atopic dermatitis (AD).

Major finding: Multivariate analysis revealed that individuals who were exposed vs not exposed to GA did not have an increased or decreased risk of developing AD (adjusted hazard ratio 1.03; P  =  .701).

Study details: This retrospective cohort study included pediatric individuals aged ≤18 years who were (n = 7,681) or were not (n = 38,405; control individuals) exposed to GA.

Disclosures: This study was funded by a 2020 Amorepacific (South Korea) grant. The authors declared no  conflicts of interest.

Source: Kim DC et al. No association between first exposure to general anaesthesia and atopic dermatitis in the paediatric population. Acta Derm Venereol. 2022;102:adv00813 (Nov 14). Doi: 10.2340/actadv.v102.2738

Key clinical point: Downtitrated baricitinib treatment was efficacious in most patients with moderate-to-severe atopic dermatitis (AD) through 16 weeks; clinically relevant efficacy was observed in most patients who were readministered the original dose due to downtitration or treatment withdrawal-related efficacy loss.

Major finding: In the 4-mg and 2-mg cohorts, 61% and 71% of patients maintained a validated Investigator’s Global Assessment for AD (vIGA-AD) score of 0/1/2 at downtitration week 16 and 80%/85%/88% and 90%/56%/86% of patients who switched to original dose in the continuous dosing/downtitration/treatment withdrawal group re-achieved vIGA-AD 0/1/2, respectively.

Study details: This BREEZE-AD3 trial substudy included 526 patients with moderate-to-severe AD treated with 4/2 mg baricitinib at trial entry who achieved vIGA-AD 0/1/2 at week 52, with each cohort being re-assigned to continuous dosing, downtitration, or treatment withdrawal.

Disclosures: This study was sponsored by Eli Lilly and Company under license from Incyte Corporation. Some authors reported ties with various sources, including Eli Lilly and Incyte. Three authors declared being current or former employees and shareholders of Eli Lilly.

Source: Reich K et al. Efficacy of downtitration or treatment withdrawal compared to continuous dosing after successful treatment with baricitinib in patients with moderate-to-severe atopic dermatitis in a randomised substudy from the long-term extension study, BREEZE-AD3. Br J Dermatol. 2022 (Nov 17). Doi: 10.1093/bjd/ljac057

Key clinical point: Downtitrated baricitinib treatment was efficacious in most patients with moderate-to-severe atopic dermatitis (AD) through 16 weeks; clinically relevant efficacy was observed in most patients who were readministered the original dose due to downtitration or treatment withdrawal-related efficacy loss.

Major finding: In the 4-mg and 2-mg cohorts, 61% and 71% of patients maintained a validated Investigator’s Global Assessment for AD (vIGA-AD) score of 0/1/2 at downtitration week 16 and 80%/85%/88% and 90%/56%/86% of patients who switched to original dose in the continuous dosing/downtitration/treatment withdrawal group re-achieved vIGA-AD 0/1/2, respectively.

Study details: This BREEZE-AD3 trial substudy included 526 patients with moderate-to-severe AD treated with 4/2 mg baricitinib at trial entry who achieved vIGA-AD 0/1/2 at week 52, with each cohort being re-assigned to continuous dosing, downtitration, or treatment withdrawal.

Disclosures: This study was sponsored by Eli Lilly and Company under license from Incyte Corporation. Some authors reported ties with various sources, including Eli Lilly and Incyte. Three authors declared being current or former employees and shareholders of Eli Lilly.

Source: Reich K et al. Efficacy of downtitration or treatment withdrawal compared to continuous dosing after successful treatment with baricitinib in patients with moderate-to-severe atopic dermatitis in a randomised substudy from the long-term extension study, BREEZE-AD3. Br J Dermatol. 2022 (Nov 17). Doi: 10.1093/bjd/ljac057

Key clinical point: Downtitrated baricitinib treatment was efficacious in most patients with moderate-to-severe atopic dermatitis (AD) through 16 weeks; clinically relevant efficacy was observed in most patients who were readministered the original dose due to downtitration or treatment withdrawal-related efficacy loss.

Major finding: In the 4-mg and 2-mg cohorts, 61% and 71% of patients maintained a validated Investigator’s Global Assessment for AD (vIGA-AD) score of 0/1/2 at downtitration week 16 and 80%/85%/88% and 90%/56%/86% of patients who switched to original dose in the continuous dosing/downtitration/treatment withdrawal group re-achieved vIGA-AD 0/1/2, respectively.

Study details: This BREEZE-AD3 trial substudy included 526 patients with moderate-to-severe AD treated with 4/2 mg baricitinib at trial entry who achieved vIGA-AD 0/1/2 at week 52, with each cohort being re-assigned to continuous dosing, downtitration, or treatment withdrawal.

Disclosures: This study was sponsored by Eli Lilly and Company under license from Incyte Corporation. Some authors reported ties with various sources, including Eli Lilly and Incyte. Three authors declared being current or former employees and shareholders of Eli Lilly.

Source: Reich K et al. Efficacy of downtitration or treatment withdrawal compared to continuous dosing after successful treatment with baricitinib in patients with moderate-to-severe atopic dermatitis in a randomised substudy from the long-term extension study, BREEZE-AD3. Br J Dermatol. 2022 (Nov 17). Doi: 10.1093/bjd/ljac057