Article

Even with recent pharmacologic treatment advances, narrowband UVB (NB-UVB) phototherapy remains a versatile, safe, and efficacious adjunctive or exclusive treatment for multiple dermatologic conditions, including psoriasis and atopic dermatitis. ^1-9 Some providers choose NB-UVB phototherapy as a first-line treatment for older adult patients who frequently use multiple treatment modalities for more than 1 health condition. Older adults with atopic dermatitis and psoriasis are at higher risk for comorbidities such as autoimmune disorders, diabetes mellitus, dyslipidemia, sleep disorders, neuropsychiatric disorders, and cardiovascular disease that can complicate treatment compared with their peers without these dermatologic diagnoses. ^10-12 Polypharmacy (ie, the use of 5 or more daily medications), frequently associated with these conditions, contributes to prescribers pursuing NB-UVB phototherapy as a nonpharmacologic treatment, but some providers wonder if it is as effective and safe for their older patients compared with younger patients.

In a prior study, Matthews et al¹³ reported that 96% (50/52) of patients older than 65 years achieved medium to high levels of clearance with NB-UVB phototherapy. Nonetheless, 2 other findings in this study related to the number of treatments required to achieve clearance (ie, clearance rates) and erythema rates prompted further investigation. The first finding was higher-than-expected clearance rates. Older adults had a clearance rate with a mean of 33 treatments compared to prior studies featuring mean clearance rates of 20 to 28 treatments.^7,8,14-16 This finding resembled a study in the United Kingdom¹⁷ with a median clearance rate in older adults of 30 treatments. In contrast, the median clearance rate from a study in Turkey¹⁸ was 42 treatments in older adults. We hypothesized that more photosensitizing medications used in older vs younger adults prompted more dose adjustments with NB-UVB phototherapy to avoid burning (ie, erythema) at baseline and throughout the treatment course. These dose adjustments may have increased the overall clearance rates. If true, we predicted that younger adults treated with the same protocol would have cleared more quickly, either because of age-related differences or because they likely had fewer comorbidities and therefore fewer medications.

The second finding from Matthews et al¹³ that warranted further investigation was a higher erythema rate compared to the older adult study from the United Kingdom.¹⁷ We hypothesized that potentially greater use of photosensitizing medications in the United States could explain the higher erythema rates. Although medication-induced photosensitivity is less likely with NB-UVB phototherapy than with UVA, certain medications can cause UVB photosensitivity, including thiazides, quinidine, calcium channel antagonists, phenothiazines, and nonsteroidal anti-inflammatory drugs.^8,19,20 Therefore, photosensitizing medication use either at baseline or during a course of NB-UVB phototherapy could increase the risk for erythema. Age-related skin changes also have been considered as a potential cause for erythema. One study found that the skin of older patients was more sensitive than younger patients, resulting in a lower minimal erythema dose (MED)¹⁴—the lowest UV dose that results in erythema.²¹ Others, however, found similar MEDs across age groups, but older adults experienced more intense erythema in the late phase of NB-UVB treatment.^22,23 Such conflicting findings indicate that questions remain regarding the risk for erythema in older patients and if photosensitizing medications are responsible for an increased risk.

This retrospective study aimed to determine if NB-UVB phototherapy is equally effective in both older and younger adults treated with the same protocol; to examine the association between the use of photosensitizing medications and clearance rates in both older and younger adults; and to examine the association between the use of photosensitizing medications and erythema rates in older vs younger adults.

Methods

Study Design and Patients—This retrospective cohort study used billing records to identify patients who received NB-UVB phototherapy at 3 different clinical sites within a large US health care system in Washington (Group Health Cooperative, now Kaiser Permanente Washington), serving more than 600,000 patients between January 1, 2012, and December 31, 2016. The institutional review board of Kaiser Permanente Washington Health Research Institute approved this study (IRB 1498087-4). Younger adults were classified as those 64 years or younger and older adults as those 65 years and older at the start of their phototherapy regimen. A power analysis determined that the optimal sample size for this study was 250 patients.

Individuals were excluded if they had fewer than 6 phototherapy treatments; a diagnosis of vitiligo, photosensitivity dermatitis, morphea, or pityriasis rubra pilaris; and/or treatment of the hands or feet only.

Phototherapy Protocol—Using a 48-lamp NB-UVB unit, trained phototherapy nurses provided all treatments following standardized treatment protocols¹³ based on previously published phototherapy guidelines.²⁴ Nurses determined each patient’s disease clearance level using a 3-point clearance scale (high, medium, low).¹³ Each patient’s starting dose was determined based on the estimated MED for their skin phototype. If the patient was using photosensitizing medications, the protocol indicated a need for a decreased starting dose—down 25% to 50%—depending on the presumed level of photosensitivity. All clinical sites used the same protocol, but decisions about adjustments within this range were made by individual registered nurses and dermatologists, which could lead to variability across sites. Protocols also directed nurses to query patients about specific treatment responses, including erythema, tenderness, or itching; how their condition was responding; use of photosensitizing medications; missed treatments; and placement of shielding. Doses were adjusted accordingly.

Statistical Analysis—Data were analyzed using Stata statistical software (StataCorp LLC). Univariate analyses were used to examine the data and identify outliers, bad values, and missing data, as well as to calculate descriptive statistics. Pearson χ² and Fisher exact statistics were used to calculate differences in categorical variables. Linear multivariate regression models and logistic multivariate models were used to examine statistical relationships between variables. Statistical significance was defined as P≤.05.

Results

Patient Characteristics—Medical records were reviewed for 172 patients who received phototherapy between 2012 and 2016. Patients ranged in age from 23 to 91 years, with 102 patients 64 years and younger and 70 patients 65 years and older. Tables 1 and 2 outline the patient characteristics and conditions treated.

Phototherapy Effectiveness—Narrowband UVB phototherapy was found to be equally effective in older vs younger adults, with 82.9% of older adults (n=58) achieving a high level of clearance vs 80.4% (n=82) of younger adults, and 5.7% (n=4) of older adults achieved a medium level of clearance vs 10% (n=10) of younger adults (Table 3). Although older adults had slightly faster clearance rates on average (34.6 vs 37.2 treatments), these differences were not significant.

Photosensitizing Medications, Clearance Levels, and Clearance Rates—There was no significant association between clearance levels and number of photosensitizing medications in either younger (Figure 1) or older (Figure 2) adults. There was a wide range of clearance rates in both groups (Table 3), but no relationship was identified between clearance rates and photosensitizing medications or age (Figure 3). Clinic C had higher overall clearance rates for both age groups compared to the other clinics (Figure 4), but the clearance levels were still equivalent. No consistent pattern emerged indicating that age was a factor for the slower clearance at this site, and no relationship was identified between taking photosensitizing medications and clearance levels (Fisher exact test, P=.467) or clearance rates (t[149]=0.75; P=.45).

Frequency of Treatments and Clearance Rates—Older adults more consistently completed the recommended frequency of treatments—3 times weekly—compared to younger adults (74.3% vs 58.5%). However, all patients who completed 3 treatments per week required a similar number of treatments to clear (older adults, mean [SD]: 35.7 [21.6]; younger adults, mean [SD]: 34.7 [19.0]; P=.85). Among patients completing 2 or fewer treatments per week, older adults required a mean (SD) of only 31 (9.0) treatments to clear vs 41.5 (21.3) treatments to clear for younger adults, but the difference was not statistically significant (P=.08). However, even those with suboptimal frequency ultimately achieved similar clearance levels.

Photosensitizing Medications and Erythema Rates—Many patients in both age groups took medications that listed photosensitivity as a potential side effect (77.1% of older adults and 60.8% of younger adults). Of them, most patients took only 1 or 2 photosensitizing medications. However, significantly more older patients took 3 or more photosensitizing medications (28.6% vs 12.7%; P=.01)(Table 3). Asymptomatic (grade 1) erythema was unrelated to medication use and quite common in all adults (48.6% of older adults and 60.8% of younger adults). Most patients had only a few episodes of grade 1 erythema (mean [SD], 1.2 [2.9] in older adults and 1.6 [2.2] in younger adults). More older adults had grade 2 erythema (28.6%) compared to younger adults (17.6%). Patients using 3 or more photosensitizing medications were twice as likely to experience grade 2 erythema. Grades 3 and 4 erythema were extremely rare; none of the patients stopped phototherapy because they experienced erythema.

Overall, phototherapy nurses adjusted the starting dose according to the phototype-based protocol an average of 69% of the time for patients on medications with photosensitivity listed as a potential side effect. However, the frequency depended significantly on the clinic (clinic A, 24%; clinic B, 92%; clinic C, 87%)(P≤.001). Nurses across all clinics consistently decreased the treatment dose when patients reported starting new photosensitizing medications. Patients with adjusted starting doses had slightly but not significantly higher clearance rates compared to those without (mean, 37.8 vs 35.5; t(104)=0.58; P=.56).

Comment

Comparisons to Prior Studies—This study confirmed that phototherapy is equally effective for older and younger adults, with approximately 90% reaching medium to high clearance levels with approximately 35 treatments in both groups. Prior studies of all age groups found that patients typically cleared with an average of 20 to 28 treatments.^7,8,14-16 In contrast, the findings in older adults from this study were similar to the older adult study from the United Kingdom that reported a 91% clear/near clear rate with an average of 30 treatments.¹⁷ The clearance level also was similar to the older adult study in Turkey¹⁸ that reported 73.7% (70/95) of patients with psoriasis achieved a minimum psoriasis area severity index of 75, indicating 75% improvement from baseline.

Impact of Photosensitizing Medications on Clearance—Photosensitizing medications and treatment frequency were 2 factors that might explain the slower clearance rates in younger adults. In this study, both groups of patients used similar numbers of photosensitizing medications, but more older adults were taking 3 or more medications (Table 3). We found no statistically significant relationship between taking photosensitizing medications and either the clearance rates or the level of clearance achieved in either age group.

Impact of Treatment Frequency—Weekly treatment frequency also was examined. One prior study demonstrated that treatments 3 times weekly led to a faster clearance time and higher clearance levels compared with twice-weekly treatment.⁷ When patients completed treatments twice weekly, it took an average of 1.5 times more days to clear, which impacted cost and clinical resource availability. The patients ranged in age from 17 to 80 years, but outcomes in older patients were not described separately.⁷ Interestingly, our study seemed to find a difference between age groups when the impact of treatment frequency was examined. Older adults completed nearly 4 fewer mean treatments to clear when treating less often, with more than 80% achieving high levels of clearance, whereas the younger adults required almost 7 more treatments to clear when they came in less frequently, with approximately 80% achieving a high level of clearance. As a result, our study found that in both age groups, slowing the treatment frequency extended the treatment time to clearance—more for the younger adults than the older adults—but did not significantly change the percentage of individuals reaching full clearance in either group.

Erythema Rates—There was no association between photosensitizing medications and erythema rates except when patients were taking at least 3 medications. Most medications that listed photosensitivity as a possible side effect did not specify their relevant range of UV radiation; therefore, all such medications were examined during this analysis. Prior research has shown UVB range photosensitizing medications include thiazides, quinidine, calcium channel antagonists, phenothiazines, and nonsteroidal anti-inflammatory drugs.¹⁹ A sensitivity analysis that focused only on these medications found no association between them and any particular grade of erythema. However, patients taking 3 or more of any medications listing photosensitivity as a side effect had an increased risk for grade 2 erythema.

Erythema rates in this study were consistent with a 2013 systematic review that reported 57% of patients with asymptomatic grade 1 erythema.²⁵ In the 2 other comparative older adult studies, erythema rates varied widely: 35% in a study from Turkey¹⁸compared to only1.89% in a study from the United Kingdom.¹⁷

The starting dose for NB-UVB may drive erythema rates. The current study’s protocols were based on an estimated MED that is subjectively determined by the dermatology provider’s assessment of the patient’s skin sensitivity via examination and questions to the patient about their response to environmental sun exposure (ie, burning and tanning)²⁶ and is frequently used to determine the starting dose and subsequent dose escalation. Certain medications have been found to increase photosensitivity and erythema,²⁰ which can change an individual’s MED. If photosensitizing medications are started prior to or during a course of NB-UVB without a pretreatment MED, they might increase the risk for erythema. This study did not identify specific erythema-inducing medications but did find that taking 3 or more photosensitizing medications was associated with increased episodes of grade 2 erythema. Similarly, Harrop et al⁸ found that patients who were taking photosensitizing medications were more likely to have grade 2 or higher erythema, despite baseline MED testing, which is an established safety mechanism to reduce the risk and severity of erythema.^14,20,27 The authors of a recent study of older adults in Taiwan specifically recommended MED testing due to the unpredictable influence of polypharmacy on MED calculations in this population.²⁸ Therefore, this study’s use of an estimated MED in older adults may have influenced the starting dose as well as the incidence and severity of erythemic events. Age-related skin changes likely are ruled out as a consideration for mild erythema by the similarity of grade 1 erythema rates in both older and younger adults. Other studies have identified differences between the age groups, where older patients experienced more intense erythema in the late phase of UVB treatments.^22,23 This phenomenon could increase the risk for a grade 2 erythema, which may correspond with this study’s findings.

Other potential causes of erythema were ruled out during our study, including erythema related to missed treatments and shielding mishaps. Other factors, however, may impact the level of sensitivity each patient has to phototherapy, including genetics, epigenetics, and cumulative sun damage. With NB-UVB, near-erythemogenic doses are optimal to achieve effective treatments but require a delicate balance to achieve, which may be more problematic for older adults, especially those taking several medications.

Study Limitations—Our study design made it difficult to draw conclusions about rarer dermatologic conditions. Some patients received treatments over years that were not included in the study period. Finally, power calculations suggested that our actual sample size was too small, with approximately one-third of the required sample missing.

Practical Implications—The goals of phototherapy are to achieve a high level of disease clearance with the fewest number of treatments possible and minimal side effects. Skin phototype–driven standardized doses based on estimated MED may be conservatively low to minimize the risk of side effects (eg, erythema), which could slow the treatment progression. Thus, basing the starting dose on individual MED assessments may improve clearance rates. This study also confirmed that phototherapy is safe with minimal erythema in adults of all ages. The erythema episodes that patients experienced were few and mild, but because of greater rates of grade 2 erythema in patients on 3 or more photosensitizing medications, consideration of MED testing in both age groups might optimize doses at baseline and prompt caution for subsequent dose titration in this subset of patients.

The extra staff training and patient monitoring required for MED testing likely is to add value and preserve resources if faster clearance rates could be achieved and may warrant further investigation. Phototherapy centers require standardized treatment protocols, diligent well-trained staff, and program monitoring to ensure consistent care to all patients. This study highlighted the ongoing opportunity for health care organizations to conduct evidence-based practice inquiries to continually optimize care for their patients.

Even with recent pharmacologic treatment advances, narrowband UVB (NB-UVB) phototherapy remains a versatile, safe, and efficacious adjunctive or exclusive treatment for multiple dermatologic conditions, including psoriasis and atopic dermatitis. ^1-9 Some providers choose NB-UVB phototherapy as a first-line treatment for older adult patients who frequently use multiple treatment modalities for more than 1 health condition. Older adults with atopic dermatitis and psoriasis are at higher risk for comorbidities such as autoimmune disorders, diabetes mellitus, dyslipidemia, sleep disorders, neuropsychiatric disorders, and cardiovascular disease that can complicate treatment compared with their peers without these dermatologic diagnoses. ^10-12 Polypharmacy (ie, the use of 5 or more daily medications), frequently associated with these conditions, contributes to prescribers pursuing NB-UVB phototherapy as a nonpharmacologic treatment, but some providers wonder if it is as effective and safe for their older patients compared with younger patients.

In a prior study, Matthews et al¹³ reported that 96% (50/52) of patients older than 65 years achieved medium to high levels of clearance with NB-UVB phototherapy. Nonetheless, 2 other findings in this study related to the number of treatments required to achieve clearance (ie, clearance rates) and erythema rates prompted further investigation. The first finding was higher-than-expected clearance rates. Older adults had a clearance rate with a mean of 33 treatments compared to prior studies featuring mean clearance rates of 20 to 28 treatments.^7,8,14-16 This finding resembled a study in the United Kingdom¹⁷ with a median clearance rate in older adults of 30 treatments. In contrast, the median clearance rate from a study in Turkey¹⁸ was 42 treatments in older adults. We hypothesized that more photosensitizing medications used in older vs younger adults prompted more dose adjustments with NB-UVB phototherapy to avoid burning (ie, erythema) at baseline and throughout the treatment course. These dose adjustments may have increased the overall clearance rates. If true, we predicted that younger adults treated with the same protocol would have cleared more quickly, either because of age-related differences or because they likely had fewer comorbidities and therefore fewer medications.

The second finding from Matthews et al¹³ that warranted further investigation was a higher erythema rate compared to the older adult study from the United Kingdom.¹⁷ We hypothesized that potentially greater use of photosensitizing medications in the United States could explain the higher erythema rates. Although medication-induced photosensitivity is less likely with NB-UVB phototherapy than with UVA, certain medications can cause UVB photosensitivity, including thiazides, quinidine, calcium channel antagonists, phenothiazines, and nonsteroidal anti-inflammatory drugs.^8,19,20 Therefore, photosensitizing medication use either at baseline or during a course of NB-UVB phototherapy could increase the risk for erythema. Age-related skin changes also have been considered as a potential cause for erythema. One study found that the skin of older patients was more sensitive than younger patients, resulting in a lower minimal erythema dose (MED)¹⁴—the lowest UV dose that results in erythema.²¹ Others, however, found similar MEDs across age groups, but older adults experienced more intense erythema in the late phase of NB-UVB treatment.^22,23 Such conflicting findings indicate that questions remain regarding the risk for erythema in older patients and if photosensitizing medications are responsible for an increased risk.

This retrospective study aimed to determine if NB-UVB phototherapy is equally effective in both older and younger adults treated with the same protocol; to examine the association between the use of photosensitizing medications and clearance rates in both older and younger adults; and to examine the association between the use of photosensitizing medications and erythema rates in older vs younger adults.

Methods

Study Design and Patients—This retrospective cohort study used billing records to identify patients who received NB-UVB phototherapy at 3 different clinical sites within a large US health care system in Washington (Group Health Cooperative, now Kaiser Permanente Washington), serving more than 600,000 patients between January 1, 2012, and December 31, 2016. The institutional review board of Kaiser Permanente Washington Health Research Institute approved this study (IRB 1498087-4). Younger adults were classified as those 64 years or younger and older adults as those 65 years and older at the start of their phototherapy regimen. A power analysis determined that the optimal sample size for this study was 250 patients.

Individuals were excluded if they had fewer than 6 phototherapy treatments; a diagnosis of vitiligo, photosensitivity dermatitis, morphea, or pityriasis rubra pilaris; and/or treatment of the hands or feet only.

Phototherapy Protocol—Using a 48-lamp NB-UVB unit, trained phototherapy nurses provided all treatments following standardized treatment protocols¹³ based on previously published phototherapy guidelines.²⁴ Nurses determined each patient’s disease clearance level using a 3-point clearance scale (high, medium, low).¹³ Each patient’s starting dose was determined based on the estimated MED for their skin phototype. If the patient was using photosensitizing medications, the protocol indicated a need for a decreased starting dose—down 25% to 50%—depending on the presumed level of photosensitivity. All clinical sites used the same protocol, but decisions about adjustments within this range were made by individual registered nurses and dermatologists, which could lead to variability across sites. Protocols also directed nurses to query patients about specific treatment responses, including erythema, tenderness, or itching; how their condition was responding; use of photosensitizing medications; missed treatments; and placement of shielding. Doses were adjusted accordingly.

Statistical Analysis—Data were analyzed using Stata statistical software (StataCorp LLC). Univariate analyses were used to examine the data and identify outliers, bad values, and missing data, as well as to calculate descriptive statistics. Pearson χ² and Fisher exact statistics were used to calculate differences in categorical variables. Linear multivariate regression models and logistic multivariate models were used to examine statistical relationships between variables. Statistical significance was defined as P≤.05.

Results

Patient Characteristics—Medical records were reviewed for 172 patients who received phototherapy between 2012 and 2016. Patients ranged in age from 23 to 91 years, with 102 patients 64 years and younger and 70 patients 65 years and older. Tables 1 and 2 outline the patient characteristics and conditions treated.

Phototherapy Effectiveness—Narrowband UVB phototherapy was found to be equally effective in older vs younger adults, with 82.9% of older adults (n=58) achieving a high level of clearance vs 80.4% (n=82) of younger adults, and 5.7% (n=4) of older adults achieved a medium level of clearance vs 10% (n=10) of younger adults (Table 3). Although older adults had slightly faster clearance rates on average (34.6 vs 37.2 treatments), these differences were not significant.

Photosensitizing Medications, Clearance Levels, and Clearance Rates—There was no significant association between clearance levels and number of photosensitizing medications in either younger (Figure 1) or older (Figure 2) adults. There was a wide range of clearance rates in both groups (Table 3), but no relationship was identified between clearance rates and photosensitizing medications or age (Figure 3). Clinic C had higher overall clearance rates for both age groups compared to the other clinics (Figure 4), but the clearance levels were still equivalent. No consistent pattern emerged indicating that age was a factor for the slower clearance at this site, and no relationship was identified between taking photosensitizing medications and clearance levels (Fisher exact test, P=.467) or clearance rates (t[149]=0.75; P=.45).

Frequency of Treatments and Clearance Rates—Older adults more consistently completed the recommended frequency of treatments—3 times weekly—compared to younger adults (74.3% vs 58.5%). However, all patients who completed 3 treatments per week required a similar number of treatments to clear (older adults, mean [SD]: 35.7 [21.6]; younger adults, mean [SD]: 34.7 [19.0]; P=.85). Among patients completing 2 or fewer treatments per week, older adults required a mean (SD) of only 31 (9.0) treatments to clear vs 41.5 (21.3) treatments to clear for younger adults, but the difference was not statistically significant (P=.08). However, even those with suboptimal frequency ultimately achieved similar clearance levels.

Photosensitizing Medications and Erythema Rates—Many patients in both age groups took medications that listed photosensitivity as a potential side effect (77.1% of older adults and 60.8% of younger adults). Of them, most patients took only 1 or 2 photosensitizing medications. However, significantly more older patients took 3 or more photosensitizing medications (28.6% vs 12.7%; P=.01)(Table 3). Asymptomatic (grade 1) erythema was unrelated to medication use and quite common in all adults (48.6% of older adults and 60.8% of younger adults). Most patients had only a few episodes of grade 1 erythema (mean [SD], 1.2 [2.9] in older adults and 1.6 [2.2] in younger adults). More older adults had grade 2 erythema (28.6%) compared to younger adults (17.6%). Patients using 3 or more photosensitizing medications were twice as likely to experience grade 2 erythema. Grades 3 and 4 erythema were extremely rare; none of the patients stopped phototherapy because they experienced erythema.

Overall, phototherapy nurses adjusted the starting dose according to the phototype-based protocol an average of 69% of the time for patients on medications with photosensitivity listed as a potential side effect. However, the frequency depended significantly on the clinic (clinic A, 24%; clinic B, 92%; clinic C, 87%)(P≤.001). Nurses across all clinics consistently decreased the treatment dose when patients reported starting new photosensitizing medications. Patients with adjusted starting doses had slightly but not significantly higher clearance rates compared to those without (mean, 37.8 vs 35.5; t(104)=0.58; P=.56).

Comment

Comparisons to Prior Studies—This study confirmed that phototherapy is equally effective for older and younger adults, with approximately 90% reaching medium to high clearance levels with approximately 35 treatments in both groups. Prior studies of all age groups found that patients typically cleared with an average of 20 to 28 treatments.^7,8,14-16 In contrast, the findings in older adults from this study were similar to the older adult study from the United Kingdom that reported a 91% clear/near clear rate with an average of 30 treatments.¹⁷ The clearance level also was similar to the older adult study in Turkey¹⁸ that reported 73.7% (70/95) of patients with psoriasis achieved a minimum psoriasis area severity index of 75, indicating 75% improvement from baseline.

Impact of Photosensitizing Medications on Clearance—Photosensitizing medications and treatment frequency were 2 factors that might explain the slower clearance rates in younger adults. In this study, both groups of patients used similar numbers of photosensitizing medications, but more older adults were taking 3 or more medications (Table 3). We found no statistically significant relationship between taking photosensitizing medications and either the clearance rates or the level of clearance achieved in either age group.

Impact of Treatment Frequency—Weekly treatment frequency also was examined. One prior study demonstrated that treatments 3 times weekly led to a faster clearance time and higher clearance levels compared with twice-weekly treatment.⁷ When patients completed treatments twice weekly, it took an average of 1.5 times more days to clear, which impacted cost and clinical resource availability. The patients ranged in age from 17 to 80 years, but outcomes in older patients were not described separately.⁷ Interestingly, our study seemed to find a difference between age groups when the impact of treatment frequency was examined. Older adults completed nearly 4 fewer mean treatments to clear when treating less often, with more than 80% achieving high levels of clearance, whereas the younger adults required almost 7 more treatments to clear when they came in less frequently, with approximately 80% achieving a high level of clearance. As a result, our study found that in both age groups, slowing the treatment frequency extended the treatment time to clearance—more for the younger adults than the older adults—but did not significantly change the percentage of individuals reaching full clearance in either group.

Erythema Rates—There was no association between photosensitizing medications and erythema rates except when patients were taking at least 3 medications. Most medications that listed photosensitivity as a possible side effect did not specify their relevant range of UV radiation; therefore, all such medications were examined during this analysis. Prior research has shown UVB range photosensitizing medications include thiazides, quinidine, calcium channel antagonists, phenothiazines, and nonsteroidal anti-inflammatory drugs.¹⁹ A sensitivity analysis that focused only on these medications found no association between them and any particular grade of erythema. However, patients taking 3 or more of any medications listing photosensitivity as a side effect had an increased risk for grade 2 erythema.

Erythema rates in this study were consistent with a 2013 systematic review that reported 57% of patients with asymptomatic grade 1 erythema.²⁵ In the 2 other comparative older adult studies, erythema rates varied widely: 35% in a study from Turkey¹⁸compared to only1.89% in a study from the United Kingdom.¹⁷

The starting dose for NB-UVB may drive erythema rates. The current study’s protocols were based on an estimated MED that is subjectively determined by the dermatology provider’s assessment of the patient’s skin sensitivity via examination and questions to the patient about their response to environmental sun exposure (ie, burning and tanning)²⁶ and is frequently used to determine the starting dose and subsequent dose escalation. Certain medications have been found to increase photosensitivity and erythema,²⁰ which can change an individual’s MED. If photosensitizing medications are started prior to or during a course of NB-UVB without a pretreatment MED, they might increase the risk for erythema. This study did not identify specific erythema-inducing medications but did find that taking 3 or more photosensitizing medications was associated with increased episodes of grade 2 erythema. Similarly, Harrop et al⁸ found that patients who were taking photosensitizing medications were more likely to have grade 2 or higher erythema, despite baseline MED testing, which is an established safety mechanism to reduce the risk and severity of erythema.^14,20,27 The authors of a recent study of older adults in Taiwan specifically recommended MED testing due to the unpredictable influence of polypharmacy on MED calculations in this population.²⁸ Therefore, this study’s use of an estimated MED in older adults may have influenced the starting dose as well as the incidence and severity of erythemic events. Age-related skin changes likely are ruled out as a consideration for mild erythema by the similarity of grade 1 erythema rates in both older and younger adults. Other studies have identified differences between the age groups, where older patients experienced more intense erythema in the late phase of UVB treatments.^22,23 This phenomenon could increase the risk for a grade 2 erythema, which may correspond with this study’s findings.

Other potential causes of erythema were ruled out during our study, including erythema related to missed treatments and shielding mishaps. Other factors, however, may impact the level of sensitivity each patient has to phototherapy, including genetics, epigenetics, and cumulative sun damage. With NB-UVB, near-erythemogenic doses are optimal to achieve effective treatments but require a delicate balance to achieve, which may be more problematic for older adults, especially those taking several medications.

Study Limitations—Our study design made it difficult to draw conclusions about rarer dermatologic conditions. Some patients received treatments over years that were not included in the study period. Finally, power calculations suggested that our actual sample size was too small, with approximately one-third of the required sample missing.

Practical Implications—The goals of phototherapy are to achieve a high level of disease clearance with the fewest number of treatments possible and minimal side effects. Skin phototype–driven standardized doses based on estimated MED may be conservatively low to minimize the risk of side effects (eg, erythema), which could slow the treatment progression. Thus, basing the starting dose on individual MED assessments may improve clearance rates. This study also confirmed that phototherapy is safe with minimal erythema in adults of all ages. The erythema episodes that patients experienced were few and mild, but because of greater rates of grade 2 erythema in patients on 3 or more photosensitizing medications, consideration of MED testing in both age groups might optimize doses at baseline and prompt caution for subsequent dose titration in this subset of patients.

The extra staff training and patient monitoring required for MED testing likely is to add value and preserve resources if faster clearance rates could be achieved and may warrant further investigation. Phototherapy centers require standardized treatment protocols, diligent well-trained staff, and program monitoring to ensure consistent care to all patients. This study highlighted the ongoing opportunity for health care organizations to conduct evidence-based practice inquiries to continually optimize care for their patients.

Even with recent pharmacologic treatment advances, narrowband UVB (NB-UVB) phototherapy remains a versatile, safe, and efficacious adjunctive or exclusive treatment for multiple dermatologic conditions, including psoriasis and atopic dermatitis. ^1-9 Some providers choose NB-UVB phototherapy as a first-line treatment for older adult patients who frequently use multiple treatment modalities for more than 1 health condition. Older adults with atopic dermatitis and psoriasis are at higher risk for comorbidities such as autoimmune disorders, diabetes mellitus, dyslipidemia, sleep disorders, neuropsychiatric disorders, and cardiovascular disease that can complicate treatment compared with their peers without these dermatologic diagnoses. ^10-12 Polypharmacy (ie, the use of 5 or more daily medications), frequently associated with these conditions, contributes to prescribers pursuing NB-UVB phototherapy as a nonpharmacologic treatment, but some providers wonder if it is as effective and safe for their older patients compared with younger patients.

In a prior study, Matthews et al¹³ reported that 96% (50/52) of patients older than 65 years achieved medium to high levels of clearance with NB-UVB phototherapy. Nonetheless, 2 other findings in this study related to the number of treatments required to achieve clearance (ie, clearance rates) and erythema rates prompted further investigation. The first finding was higher-than-expected clearance rates. Older adults had a clearance rate with a mean of 33 treatments compared to prior studies featuring mean clearance rates of 20 to 28 treatments.^7,8,14-16 This finding resembled a study in the United Kingdom¹⁷ with a median clearance rate in older adults of 30 treatments. In contrast, the median clearance rate from a study in Turkey¹⁸ was 42 treatments in older adults. We hypothesized that more photosensitizing medications used in older vs younger adults prompted more dose adjustments with NB-UVB phototherapy to avoid burning (ie, erythema) at baseline and throughout the treatment course. These dose adjustments may have increased the overall clearance rates. If true, we predicted that younger adults treated with the same protocol would have cleared more quickly, either because of age-related differences or because they likely had fewer comorbidities and therefore fewer medications.

The second finding from Matthews et al¹³ that warranted further investigation was a higher erythema rate compared to the older adult study from the United Kingdom.¹⁷ We hypothesized that potentially greater use of photosensitizing medications in the United States could explain the higher erythema rates. Although medication-induced photosensitivity is less likely with NB-UVB phototherapy than with UVA, certain medications can cause UVB photosensitivity, including thiazides, quinidine, calcium channel antagonists, phenothiazines, and nonsteroidal anti-inflammatory drugs.^8,19,20 Therefore, photosensitizing medication use either at baseline or during a course of NB-UVB phototherapy could increase the risk for erythema. Age-related skin changes also have been considered as a potential cause for erythema. One study found that the skin of older patients was more sensitive than younger patients, resulting in a lower minimal erythema dose (MED)¹⁴—the lowest UV dose that results in erythema.²¹ Others, however, found similar MEDs across age groups, but older adults experienced more intense erythema in the late phase of NB-UVB treatment.^22,23 Such conflicting findings indicate that questions remain regarding the risk for erythema in older patients and if photosensitizing medications are responsible for an increased risk.

This retrospective study aimed to determine if NB-UVB phototherapy is equally effective in both older and younger adults treated with the same protocol; to examine the association between the use of photosensitizing medications and clearance rates in both older and younger adults; and to examine the association between the use of photosensitizing medications and erythema rates in older vs younger adults.

Methods

Study Design and Patients—This retrospective cohort study used billing records to identify patients who received NB-UVB phototherapy at 3 different clinical sites within a large US health care system in Washington (Group Health Cooperative, now Kaiser Permanente Washington), serving more than 600,000 patients between January 1, 2012, and December 31, 2016. The institutional review board of Kaiser Permanente Washington Health Research Institute approved this study (IRB 1498087-4). Younger adults were classified as those 64 years or younger and older adults as those 65 years and older at the start of their phototherapy regimen. A power analysis determined that the optimal sample size for this study was 250 patients.

Individuals were excluded if they had fewer than 6 phototherapy treatments; a diagnosis of vitiligo, photosensitivity dermatitis, morphea, or pityriasis rubra pilaris; and/or treatment of the hands or feet only.

Phototherapy Protocol—Using a 48-lamp NB-UVB unit, trained phototherapy nurses provided all treatments following standardized treatment protocols¹³ based on previously published phototherapy guidelines.²⁴ Nurses determined each patient’s disease clearance level using a 3-point clearance scale (high, medium, low).¹³ Each patient’s starting dose was determined based on the estimated MED for their skin phototype. If the patient was using photosensitizing medications, the protocol indicated a need for a decreased starting dose—down 25% to 50%—depending on the presumed level of photosensitivity. All clinical sites used the same protocol, but decisions about adjustments within this range were made by individual registered nurses and dermatologists, which could lead to variability across sites. Protocols also directed nurses to query patients about specific treatment responses, including erythema, tenderness, or itching; how their condition was responding; use of photosensitizing medications; missed treatments; and placement of shielding. Doses were adjusted accordingly.

Statistical Analysis—Data were analyzed using Stata statistical software (StataCorp LLC). Univariate analyses were used to examine the data and identify outliers, bad values, and missing data, as well as to calculate descriptive statistics. Pearson χ² and Fisher exact statistics were used to calculate differences in categorical variables. Linear multivariate regression models and logistic multivariate models were used to examine statistical relationships between variables. Statistical significance was defined as P≤.05.

Results

Patient Characteristics—Medical records were reviewed for 172 patients who received phototherapy between 2012 and 2016. Patients ranged in age from 23 to 91 years, with 102 patients 64 years and younger and 70 patients 65 years and older. Tables 1 and 2 outline the patient characteristics and conditions treated.

Phototherapy Effectiveness—Narrowband UVB phototherapy was found to be equally effective in older vs younger adults, with 82.9% of older adults (n=58) achieving a high level of clearance vs 80.4% (n=82) of younger adults, and 5.7% (n=4) of older adults achieved a medium level of clearance vs 10% (n=10) of younger adults (Table 3). Although older adults had slightly faster clearance rates on average (34.6 vs 37.2 treatments), these differences were not significant.

Photosensitizing Medications, Clearance Levels, and Clearance Rates—There was no significant association between clearance levels and number of photosensitizing medications in either younger (Figure 1) or older (Figure 2) adults. There was a wide range of clearance rates in both groups (Table 3), but no relationship was identified between clearance rates and photosensitizing medications or age (Figure 3). Clinic C had higher overall clearance rates for both age groups compared to the other clinics (Figure 4), but the clearance levels were still equivalent. No consistent pattern emerged indicating that age was a factor for the slower clearance at this site, and no relationship was identified between taking photosensitizing medications and clearance levels (Fisher exact test, P=.467) or clearance rates (t[149]=0.75; P=.45).

Frequency of Treatments and Clearance Rates—Older adults more consistently completed the recommended frequency of treatments—3 times weekly—compared to younger adults (74.3% vs 58.5%). However, all patients who completed 3 treatments per week required a similar number of treatments to clear (older adults, mean [SD]: 35.7 [21.6]; younger adults, mean [SD]: 34.7 [19.0]; P=.85). Among patients completing 2 or fewer treatments per week, older adults required a mean (SD) of only 31 (9.0) treatments to clear vs 41.5 (21.3) treatments to clear for younger adults, but the difference was not statistically significant (P=.08). However, even those with suboptimal frequency ultimately achieved similar clearance levels.

Photosensitizing Medications and Erythema Rates—Many patients in both age groups took medications that listed photosensitivity as a potential side effect (77.1% of older adults and 60.8% of younger adults). Of them, most patients took only 1 or 2 photosensitizing medications. However, significantly more older patients took 3 or more photosensitizing medications (28.6% vs 12.7%; P=.01)(Table 3). Asymptomatic (grade 1) erythema was unrelated to medication use and quite common in all adults (48.6% of older adults and 60.8% of younger adults). Most patients had only a few episodes of grade 1 erythema (mean [SD], 1.2 [2.9] in older adults and 1.6 [2.2] in younger adults). More older adults had grade 2 erythema (28.6%) compared to younger adults (17.6%). Patients using 3 or more photosensitizing medications were twice as likely to experience grade 2 erythema. Grades 3 and 4 erythema were extremely rare; none of the patients stopped phototherapy because they experienced erythema.

Overall, phototherapy nurses adjusted the starting dose according to the phototype-based protocol an average of 69% of the time for patients on medications with photosensitivity listed as a potential side effect. However, the frequency depended significantly on the clinic (clinic A, 24%; clinic B, 92%; clinic C, 87%)(P≤.001). Nurses across all clinics consistently decreased the treatment dose when patients reported starting new photosensitizing medications. Patients with adjusted starting doses had slightly but not significantly higher clearance rates compared to those without (mean, 37.8 vs 35.5; t(104)=0.58; P=.56).

Comment

Comparisons to Prior Studies—This study confirmed that phototherapy is equally effective for older and younger adults, with approximately 90% reaching medium to high clearance levels with approximately 35 treatments in both groups. Prior studies of all age groups found that patients typically cleared with an average of 20 to 28 treatments.^7,8,14-16 In contrast, the findings in older adults from this study were similar to the older adult study from the United Kingdom that reported a 91% clear/near clear rate with an average of 30 treatments.¹⁷ The clearance level also was similar to the older adult study in Turkey¹⁸ that reported 73.7% (70/95) of patients with psoriasis achieved a minimum psoriasis area severity index of 75, indicating 75% improvement from baseline.

Impact of Photosensitizing Medications on Clearance—Photosensitizing medications and treatment frequency were 2 factors that might explain the slower clearance rates in younger adults. In this study, both groups of patients used similar numbers of photosensitizing medications, but more older adults were taking 3 or more medications (Table 3). We found no statistically significant relationship between taking photosensitizing medications and either the clearance rates or the level of clearance achieved in either age group.

Impact of Treatment Frequency—Weekly treatment frequency also was examined. One prior study demonstrated that treatments 3 times weekly led to a faster clearance time and higher clearance levels compared with twice-weekly treatment.⁷ When patients completed treatments twice weekly, it took an average of 1.5 times more days to clear, which impacted cost and clinical resource availability. The patients ranged in age from 17 to 80 years, but outcomes in older patients were not described separately.⁷ Interestingly, our study seemed to find a difference between age groups when the impact of treatment frequency was examined. Older adults completed nearly 4 fewer mean treatments to clear when treating less often, with more than 80% achieving high levels of clearance, whereas the younger adults required almost 7 more treatments to clear when they came in less frequently, with approximately 80% achieving a high level of clearance. As a result, our study found that in both age groups, slowing the treatment frequency extended the treatment time to clearance—more for the younger adults than the older adults—but did not significantly change the percentage of individuals reaching full clearance in either group.

Erythema Rates—There was no association between photosensitizing medications and erythema rates except when patients were taking at least 3 medications. Most medications that listed photosensitivity as a possible side effect did not specify their relevant range of UV radiation; therefore, all such medications were examined during this analysis. Prior research has shown UVB range photosensitizing medications include thiazides, quinidine, calcium channel antagonists, phenothiazines, and nonsteroidal anti-inflammatory drugs.¹⁹ A sensitivity analysis that focused only on these medications found no association between them and any particular grade of erythema. However, patients taking 3 or more of any medications listing photosensitivity as a side effect had an increased risk for grade 2 erythema.

Erythema rates in this study were consistent with a 2013 systematic review that reported 57% of patients with asymptomatic grade 1 erythema.²⁵ In the 2 other comparative older adult studies, erythema rates varied widely: 35% in a study from Turkey¹⁸compared to only1.89% in a study from the United Kingdom.¹⁷

The starting dose for NB-UVB may drive erythema rates. The current study’s protocols were based on an estimated MED that is subjectively determined by the dermatology provider’s assessment of the patient’s skin sensitivity via examination and questions to the patient about their response to environmental sun exposure (ie, burning and tanning)²⁶ and is frequently used to determine the starting dose and subsequent dose escalation. Certain medications have been found to increase photosensitivity and erythema,²⁰ which can change an individual’s MED. If photosensitizing medications are started prior to or during a course of NB-UVB without a pretreatment MED, they might increase the risk for erythema. This study did not identify specific erythema-inducing medications but did find that taking 3 or more photosensitizing medications was associated with increased episodes of grade 2 erythema. Similarly, Harrop et al⁸ found that patients who were taking photosensitizing medications were more likely to have grade 2 or higher erythema, despite baseline MED testing, which is an established safety mechanism to reduce the risk and severity of erythema.^14,20,27 The authors of a recent study of older adults in Taiwan specifically recommended MED testing due to the unpredictable influence of polypharmacy on MED calculations in this population.²⁸ Therefore, this study’s use of an estimated MED in older adults may have influenced the starting dose as well as the incidence and severity of erythemic events. Age-related skin changes likely are ruled out as a consideration for mild erythema by the similarity of grade 1 erythema rates in both older and younger adults. Other studies have identified differences between the age groups, where older patients experienced more intense erythema in the late phase of UVB treatments.^22,23 This phenomenon could increase the risk for a grade 2 erythema, which may correspond with this study’s findings.

Other potential causes of erythema were ruled out during our study, including erythema related to missed treatments and shielding mishaps. Other factors, however, may impact the level of sensitivity each patient has to phototherapy, including genetics, epigenetics, and cumulative sun damage. With NB-UVB, near-erythemogenic doses are optimal to achieve effective treatments but require a delicate balance to achieve, which may be more problematic for older adults, especially those taking several medications.

Study Limitations—Our study design made it difficult to draw conclusions about rarer dermatologic conditions. Some patients received treatments over years that were not included in the study period. Finally, power calculations suggested that our actual sample size was too small, with approximately one-third of the required sample missing.

Practical Implications—The goals of phototherapy are to achieve a high level of disease clearance with the fewest number of treatments possible and minimal side effects. Skin phototype–driven standardized doses based on estimated MED may be conservatively low to minimize the risk of side effects (eg, erythema), which could slow the treatment progression. Thus, basing the starting dose on individual MED assessments may improve clearance rates. This study also confirmed that phototherapy is safe with minimal erythema in adults of all ages. The erythema episodes that patients experienced were few and mild, but because of greater rates of grade 2 erythema in patients on 3 or more photosensitizing medications, consideration of MED testing in both age groups might optimize doses at baseline and prompt caution for subsequent dose titration in this subset of patients.

The extra staff training and patient monitoring required for MED testing likely is to add value and preserve resources if faster clearance rates could be achieved and may warrant further investigation. Phototherapy centers require standardized treatment protocols, diligent well-trained staff, and program monitoring to ensure consistent care to all patients. This study highlighted the ongoing opportunity for health care organizations to conduct evidence-based practice inquiries to continually optimize care for their patients.

The Diagnosis: Netherton Syndrome

A punch biopsy from the right lower back supported the clinical diagnosis of ichthyosis linearis circumflexa. The patient underwent genetic testing and was found to have a heterozygous mutation in the serine protease inhibitor Kazal type 5 gene, SPINK5, that was consistent with a diagnosis of Netherton syndrome.

Netherton syndrome is an autosomal-recessive genodermatosis characterized by a triad of congenital ichthyosis, hair shaft abnormalities, and atopic diatheses.^1,2 It affects approximately 1 in 200,000 live births^2,3; however, it is considered by many to be underdiagnosed due to the variability in the clinical appearance. Therefore, the incidence of Netherton syndrome may actually be closer 1 in 50,000 live births.¹ The manifestations of the disease are caused by a germline mutation in the SPINK5 gene, which encodes the serine protease inhibitor LEKTI.^1,2 Dysfunctional LEKTI results in increased proteolytic activity of the lipid-processing enzymes in the stratum corneum, resulting in a disruption in the lipid bilayer.¹ Dysfunctional LEKTI also results in a loss of the antiinflammatory and antimicrobial function of the stratum corneum. Clinical features of Netherton syndrome usually present at birth or shortly thereafter.¹ Congenital ichthyosiform erythroderma, or the continuous peeling of the skin, is a common presentation seen at birth and in the neonatal period.² As the patient ages, the dermatologic manifestations evolve into serpiginous and circinate, erythematous plaques with a characteristic peripheral, double-edged scaling.^1,2 This distinctive finding is termed ichthyosis linearis circumflexa and is pathognomonic for the syndrome.² Lesions often affect the trunk and extremities and demonstrate an undulating course.¹ Because eczematous and lichenified plaques in flexural areas as well as pruritus are common clinical features, this disease often is misdiagnosed as atopic dermatitis,^1,3 as was the case in our patient.

Patients with Netherton syndrome can present with various hair abnormalities. Trichorrhexis invaginata, known as bamboo hair, is the intussusception of the hair shaft and is characteristic of the disease.³ It develops from a reduced number of disulfide bonds, which results in cortical softening.¹ Trichorrhexis invaginata may not be present at birth and often improves with age.^1,3 Other hair shaft abnormalities such as pili torti, trichorrhexis nodosa, and helical hair also may be observed in Netherton syndrome.¹ Extracutaneous manifestations also are typical. There is immune dysregulation of memory B cells and natural killer cells, which manifests as frequent respiratory and skin infections as well as sepsis.^1,2 Patients also may have increased levels of serum IgE and eosinophilia resulting in atopy and allergic reactions to various triggers such as foods.¹ The neonatal period also may be complicated by dehydration, electrolyte imbalances, inability to regulate body temperature, and failure to thrive.^1,3

When there is an extensive disruption of the skin barrier during the neonatal period, there may be severe electrolyte imbalances and thermoregulatory challenges necessitating treatment in the neonatal intensive care unit. Cutaneous disease can be treated with topical therapies with variable success.¹ Topical therapies for symptom management include emollients, corticosteroids, calcineurin inhibitors, calcipotriene, and retinoids; however, utmost caution must be employed with these therapies due to the increased risk for systemic absorption resulting from the disturbance of the skin barrier. When therapy with topical tacrolimus is implemented, monitoring of serum drug levels is required.¹ Pruritus may be treated symptomatically with oral antihistamines. Intravenous immunoglobulin has been shown to decrease the frequency of infections and improve skin inflammation. Systemic retinoids have unpredictable effects and result in improvement of disease in some patients but exacerbation in others. Phototherapy with narrowband UVB, psoralen plus UVA, UVA¹, and balneophototherapy also are effective treatments for cutaneous disease.1 Dupilumab has been shown to decrease pruritus, improve hair abnormalities, and improve skin disease, thereby demonstrating its effectiveness in treating the atopy and ichthyosis in Netherton syndrome.⁴

The differential diagnosis includes other figurate erythemas including erythema marginatum and erythrokeratodermia variabilis. Erythema marginatum is a cutaneous manifestation of acute rheumatic fever and is characterized by migratory polycyclic erythematous plaques without overlying scale, usually on the trunk and proximal extremities.⁵ Erythrokeratodermia variabilis is caused by heterozygous mutations in gap junction protein beta 3, GJB3, and gap junction protein beta 4, GJB4, and is characterized by transient geographic and erythematous patches and stable scaly plaques; however, double-edged scaling is not a feature.¹ Acrodermatitis enteropathica is an autosomal-recessive disorder caused by mutations in the zinc transporter SLC39A4. Cutaneous manifestations occur after weaning from breast milk and are characterized by erythematous plaques with erosions, vesicles, and scaling, which characteristically occur in the perioral and perianal locations.6 Neonatal lupus is a form of subacute cutaneous lupus erythematosus. Typical skin lesions are erythematous annular plaques with overlying scaling, which may be present at birth and have a predilection for the face and other sun-exposed areas. Lesions generally resolve after clearance of the pathogenic maternal antibodies.⁷

The Diagnosis: Netherton Syndrome

A punch biopsy from the right lower back supported the clinical diagnosis of ichthyosis linearis circumflexa. The patient underwent genetic testing and was found to have a heterozygous mutation in the serine protease inhibitor Kazal type 5 gene, SPINK5, that was consistent with a diagnosis of Netherton syndrome.

Netherton syndrome is an autosomal-recessive genodermatosis characterized by a triad of congenital ichthyosis, hair shaft abnormalities, and atopic diatheses.^1,2 It affects approximately 1 in 200,000 live births^2,3; however, it is considered by many to be underdiagnosed due to the variability in the clinical appearance. Therefore, the incidence of Netherton syndrome may actually be closer 1 in 50,000 live births.¹ The manifestations of the disease are caused by a germline mutation in the SPINK5 gene, which encodes the serine protease inhibitor LEKTI.^1,2 Dysfunctional LEKTI results in increased proteolytic activity of the lipid-processing enzymes in the stratum corneum, resulting in a disruption in the lipid bilayer.¹ Dysfunctional LEKTI also results in a loss of the antiinflammatory and antimicrobial function of the stratum corneum. Clinical features of Netherton syndrome usually present at birth or shortly thereafter.¹ Congenital ichthyosiform erythroderma, or the continuous peeling of the skin, is a common presentation seen at birth and in the neonatal period.² As the patient ages, the dermatologic manifestations evolve into serpiginous and circinate, erythematous plaques with a characteristic peripheral, double-edged scaling.^1,2 This distinctive finding is termed ichthyosis linearis circumflexa and is pathognomonic for the syndrome.² Lesions often affect the trunk and extremities and demonstrate an undulating course.¹ Because eczematous and lichenified plaques in flexural areas as well as pruritus are common clinical features, this disease often is misdiagnosed as atopic dermatitis,^1,3 as was the case in our patient.

Patients with Netherton syndrome can present with various hair abnormalities. Trichorrhexis invaginata, known as bamboo hair, is the intussusception of the hair shaft and is characteristic of the disease.³ It develops from a reduced number of disulfide bonds, which results in cortical softening.¹ Trichorrhexis invaginata may not be present at birth and often improves with age.^1,3 Other hair shaft abnormalities such as pili torti, trichorrhexis nodosa, and helical hair also may be observed in Netherton syndrome.¹ Extracutaneous manifestations also are typical. There is immune dysregulation of memory B cells and natural killer cells, which manifests as frequent respiratory and skin infections as well as sepsis.^1,2 Patients also may have increased levels of serum IgE and eosinophilia resulting in atopy and allergic reactions to various triggers such as foods.¹ The neonatal period also may be complicated by dehydration, electrolyte imbalances, inability to regulate body temperature, and failure to thrive.^1,3

When there is an extensive disruption of the skin barrier during the neonatal period, there may be severe electrolyte imbalances and thermoregulatory challenges necessitating treatment in the neonatal intensive care unit. Cutaneous disease can be treated with topical therapies with variable success.¹ Topical therapies for symptom management include emollients, corticosteroids, calcineurin inhibitors, calcipotriene, and retinoids; however, utmost caution must be employed with these therapies due to the increased risk for systemic absorption resulting from the disturbance of the skin barrier. When therapy with topical tacrolimus is implemented, monitoring of serum drug levels is required.¹ Pruritus may be treated symptomatically with oral antihistamines. Intravenous immunoglobulin has been shown to decrease the frequency of infections and improve skin inflammation. Systemic retinoids have unpredictable effects and result in improvement of disease in some patients but exacerbation in others. Phototherapy with narrowband UVB, psoralen plus UVA, UVA¹, and balneophototherapy also are effective treatments for cutaneous disease.1 Dupilumab has been shown to decrease pruritus, improve hair abnormalities, and improve skin disease, thereby demonstrating its effectiveness in treating the atopy and ichthyosis in Netherton syndrome.⁴

The differential diagnosis includes other figurate erythemas including erythema marginatum and erythrokeratodermia variabilis. Erythema marginatum is a cutaneous manifestation of acute rheumatic fever and is characterized by migratory polycyclic erythematous plaques without overlying scale, usually on the trunk and proximal extremities.⁵ Erythrokeratodermia variabilis is caused by heterozygous mutations in gap junction protein beta 3, GJB3, and gap junction protein beta 4, GJB4, and is characterized by transient geographic and erythematous patches and stable scaly plaques; however, double-edged scaling is not a feature.¹ Acrodermatitis enteropathica is an autosomal-recessive disorder caused by mutations in the zinc transporter SLC39A4. Cutaneous manifestations occur after weaning from breast milk and are characterized by erythematous plaques with erosions, vesicles, and scaling, which characteristically occur in the perioral and perianal locations.6 Neonatal lupus is a form of subacute cutaneous lupus erythematosus. Typical skin lesions are erythematous annular plaques with overlying scaling, which may be present at birth and have a predilection for the face and other sun-exposed areas. Lesions generally resolve after clearance of the pathogenic maternal antibodies.⁷

The Diagnosis: Netherton Syndrome

A punch biopsy from the right lower back supported the clinical diagnosis of ichthyosis linearis circumflexa. The patient underwent genetic testing and was found to have a heterozygous mutation in the serine protease inhibitor Kazal type 5 gene, SPINK5, that was consistent with a diagnosis of Netherton syndrome.

Netherton syndrome is an autosomal-recessive genodermatosis characterized by a triad of congenital ichthyosis, hair shaft abnormalities, and atopic diatheses.^1,2 It affects approximately 1 in 200,000 live births^2,3; however, it is considered by many to be underdiagnosed due to the variability in the clinical appearance. Therefore, the incidence of Netherton syndrome may actually be closer 1 in 50,000 live births.¹ The manifestations of the disease are caused by a germline mutation in the SPINK5 gene, which encodes the serine protease inhibitor LEKTI.^1,2 Dysfunctional LEKTI results in increased proteolytic activity of the lipid-processing enzymes in the stratum corneum, resulting in a disruption in the lipid bilayer.¹ Dysfunctional LEKTI also results in a loss of the antiinflammatory and antimicrobial function of the stratum corneum. Clinical features of Netherton syndrome usually present at birth or shortly thereafter.¹ Congenital ichthyosiform erythroderma, or the continuous peeling of the skin, is a common presentation seen at birth and in the neonatal period.² As the patient ages, the dermatologic manifestations evolve into serpiginous and circinate, erythematous plaques with a characteristic peripheral, double-edged scaling.^1,2 This distinctive finding is termed ichthyosis linearis circumflexa and is pathognomonic for the syndrome.² Lesions often affect the trunk and extremities and demonstrate an undulating course.¹ Because eczematous and lichenified plaques in flexural areas as well as pruritus are common clinical features, this disease often is misdiagnosed as atopic dermatitis,^1,3 as was the case in our patient.

Patients with Netherton syndrome can present with various hair abnormalities. Trichorrhexis invaginata, known as bamboo hair, is the intussusception of the hair shaft and is characteristic of the disease.³ It develops from a reduced number of disulfide bonds, which results in cortical softening.¹ Trichorrhexis invaginata may not be present at birth and often improves with age.^1,3 Other hair shaft abnormalities such as pili torti, trichorrhexis nodosa, and helical hair also may be observed in Netherton syndrome.¹ Extracutaneous manifestations also are typical. There is immune dysregulation of memory B cells and natural killer cells, which manifests as frequent respiratory and skin infections as well as sepsis.^1,2 Patients also may have increased levels of serum IgE and eosinophilia resulting in atopy and allergic reactions to various triggers such as foods.¹ The neonatal period also may be complicated by dehydration, electrolyte imbalances, inability to regulate body temperature, and failure to thrive.^1,3

When there is an extensive disruption of the skin barrier during the neonatal period, there may be severe electrolyte imbalances and thermoregulatory challenges necessitating treatment in the neonatal intensive care unit. Cutaneous disease can be treated with topical therapies with variable success.¹ Topical therapies for symptom management include emollients, corticosteroids, calcineurin inhibitors, calcipotriene, and retinoids; however, utmost caution must be employed with these therapies due to the increased risk for systemic absorption resulting from the disturbance of the skin barrier. When therapy with topical tacrolimus is implemented, monitoring of serum drug levels is required.¹ Pruritus may be treated symptomatically with oral antihistamines. Intravenous immunoglobulin has been shown to decrease the frequency of infections and improve skin inflammation. Systemic retinoids have unpredictable effects and result in improvement of disease in some patients but exacerbation in others. Phototherapy with narrowband UVB, psoralen plus UVA, UVA¹, and balneophototherapy also are effective treatments for cutaneous disease.1 Dupilumab has been shown to decrease pruritus, improve hair abnormalities, and improve skin disease, thereby demonstrating its effectiveness in treating the atopy and ichthyosis in Netherton syndrome.⁴

The differential diagnosis includes other figurate erythemas including erythema marginatum and erythrokeratodermia variabilis. Erythema marginatum is a cutaneous manifestation of acute rheumatic fever and is characterized by migratory polycyclic erythematous plaques without overlying scale, usually on the trunk and proximal extremities.⁵ Erythrokeratodermia variabilis is caused by heterozygous mutations in gap junction protein beta 3, GJB3, and gap junction protein beta 4, GJB4, and is characterized by transient geographic and erythematous patches and stable scaly plaques; however, double-edged scaling is not a feature.¹ Acrodermatitis enteropathica is an autosomal-recessive disorder caused by mutations in the zinc transporter SLC39A4. Cutaneous manifestations occur after weaning from breast milk and are characterized by erythematous plaques with erosions, vesicles, and scaling, which characteristically occur in the perioral and perianal locations.6 Neonatal lupus is a form of subacute cutaneous lupus erythematosus. Typical skin lesions are erythematous annular plaques with overlying scaling, which may be present at birth and have a predilection for the face and other sun-exposed areas. Lesions generally resolve after clearance of the pathogenic maternal antibodies.⁷

This patient was given a diagnosis of confluent and reticulated papillomatosis (CRP) based on the clinical presentation.

CRP is characterized by centrally confluent and peripherally reticulated scaly brown plaques and papules that are cosmetically disfiguring.¹ CRP is usually asymptomatic and primarily impacts young adults—especially teenagers.^2,3 It affects both males and females and commonly occurs on the trunk.^1-3 CRP is believed to be a disorder of keratinization. Malassezia furfur may induce CRP’s hyperproliferative epidermal changes, but systemic treatment that eliminates this organism does not clear CRP.³

A CRP diagnosis is made based on clinical presentation. The eruption usually begins as verrucous papules in the inframammary or epigastric region that enlarge to 4 to 5 mm in diameter and coalesce to form a confluent plaque with a peripheral reticulated pattern. CRP can extend over the back, chest, and abdomen to the neck, shoulders, and gluteal cleft. CRP does not affect the oral mucosa, and rarely involves flexural areas, which differentiates it from the similar looking acanthosis nigricans.² Although most cases are asymptomatic, mild pruritus may occur.^1,2

A skin biopsy is rarely necessary for making a CRP diagnosis, but histopathologic findings include papillomatosis, hyperkeratosis, variable acanthosis, follicular plugging, and sparse dermal inflammation.^1,3

Systemic antibiotics, most commonly minocycline 100 mg bid for 30 days or doxycycline 100 mg bid for 30 days, are safe and effective for CRP.^1,4 Sometimes treatment is extended for as long as 6 months. Although CRP usually responds to minocycline or doxycycline, it is believed that this is the result of these drugs’ anti-inflammatory—rather than antibiotic—properties.^1,2,4 Azithromycin is an effective alternative therapy.^2,4 There is a high rate of recurrence of CRP in patients after systemic antibiotics are discontinued.² Uniform responses to treatment and retreatment of flares have solidified the belief that antibiotics are an effective suppressive (if not curative) therapy despite a lack of randomized controlled trials.⁴

This patient was treated with minocycline 100 mg bid. After 1 month, the rash had improved by 70%. At 3 months, it was completely clear, and treatment was discontinued.

‌

This case was adapted from: Sessums MT, Ward KMH, Brodell R. Cutaneous eruption on chest and back. J Fam Pract. 2014;63:467-468.

This patient was given a diagnosis of confluent and reticulated papillomatosis (CRP) based on the clinical presentation.

CRP is characterized by centrally confluent and peripherally reticulated scaly brown plaques and papules that are cosmetically disfiguring.¹ CRP is usually asymptomatic and primarily impacts young adults—especially teenagers.^2,3 It affects both males and females and commonly occurs on the trunk.^1-3 CRP is believed to be a disorder of keratinization. Malassezia furfur may induce CRP’s hyperproliferative epidermal changes, but systemic treatment that eliminates this organism does not clear CRP.³

A CRP diagnosis is made based on clinical presentation. The eruption usually begins as verrucous papules in the inframammary or epigastric region that enlarge to 4 to 5 mm in diameter and coalesce to form a confluent plaque with a peripheral reticulated pattern. CRP can extend over the back, chest, and abdomen to the neck, shoulders, and gluteal cleft. CRP does not affect the oral mucosa, and rarely involves flexural areas, which differentiates it from the similar looking acanthosis nigricans.² Although most cases are asymptomatic, mild pruritus may occur.^1,2

A skin biopsy is rarely necessary for making a CRP diagnosis, but histopathologic findings include papillomatosis, hyperkeratosis, variable acanthosis, follicular plugging, and sparse dermal inflammation.^1,3

Systemic antibiotics, most commonly minocycline 100 mg bid for 30 days or doxycycline 100 mg bid for 30 days, are safe and effective for CRP.^1,4 Sometimes treatment is extended for as long as 6 months. Although CRP usually responds to minocycline or doxycycline, it is believed that this is the result of these drugs’ anti-inflammatory—rather than antibiotic—properties.^1,2,4 Azithromycin is an effective alternative therapy.^2,4 There is a high rate of recurrence of CRP in patients after systemic antibiotics are discontinued.² Uniform responses to treatment and retreatment of flares have solidified the belief that antibiotics are an effective suppressive (if not curative) therapy despite a lack of randomized controlled trials.⁴

This patient was treated with minocycline 100 mg bid. After 1 month, the rash had improved by 70%. At 3 months, it was completely clear, and treatment was discontinued.

‌

This case was adapted from: Sessums MT, Ward KMH, Brodell R. Cutaneous eruption on chest and back. J Fam Pract. 2014;63:467-468.

This patient was given a diagnosis of confluent and reticulated papillomatosis (CRP) based on the clinical presentation.

CRP is characterized by centrally confluent and peripherally reticulated scaly brown plaques and papules that are cosmetically disfiguring.¹ CRP is usually asymptomatic and primarily impacts young adults—especially teenagers.^2,3 It affects both males and females and commonly occurs on the trunk.^1-3 CRP is believed to be a disorder of keratinization. Malassezia furfur may induce CRP’s hyperproliferative epidermal changes, but systemic treatment that eliminates this organism does not clear CRP.³

A CRP diagnosis is made based on clinical presentation. The eruption usually begins as verrucous papules in the inframammary or epigastric region that enlarge to 4 to 5 mm in diameter and coalesce to form a confluent plaque with a peripheral reticulated pattern. CRP can extend over the back, chest, and abdomen to the neck, shoulders, and gluteal cleft. CRP does not affect the oral mucosa, and rarely involves flexural areas, which differentiates it from the similar looking acanthosis nigricans.² Although most cases are asymptomatic, mild pruritus may occur.^1,2

A skin biopsy is rarely necessary for making a CRP diagnosis, but histopathologic findings include papillomatosis, hyperkeratosis, variable acanthosis, follicular plugging, and sparse dermal inflammation.^1,3

Systemic antibiotics, most commonly minocycline 100 mg bid for 30 days or doxycycline 100 mg bid for 30 days, are safe and effective for CRP.^1,4 Sometimes treatment is extended for as long as 6 months. Although CRP usually responds to minocycline or doxycycline, it is believed that this is the result of these drugs’ anti-inflammatory—rather than antibiotic—properties.^1,2,4 Azithromycin is an effective alternative therapy.^2,4 There is a high rate of recurrence of CRP in patients after systemic antibiotics are discontinued.² Uniform responses to treatment and retreatment of flares have solidified the belief that antibiotics are an effective suppressive (if not curative) therapy despite a lack of randomized controlled trials.⁴

This patient was treated with minocycline 100 mg bid. After 1 month, the rash had improved by 70%. At 3 months, it was completely clear, and treatment was discontinued.

‌

This case was adapted from: Sessums MT, Ward KMH, Brodell R. Cutaneous eruption on chest and back. J Fam Pract. 2014;63:467-468.

EVIDENCE SUMMARY

Race, gender, and other factors are associated with lack of HCV Tx

A retrospective study (N = 894) assessed factors associated with direct-acting antiviral (DAA) initiation.¹ Patients who were HCV+ with at least 1 clinical visit during the study period completed a survey of psychological, behavioral, and social life assessments. The final cohort (57% male; 64% ≥ 61 years old) was divided into patients who initiated DAA treatment (n = 690) and those who did not (n = 204).

In an adjusted multivariable analysis, factors associated with lower odds of DAA initiation included Black race (adjusted odds ratio [aOR] = 0.59 vs White race; 95% CI, 0.36-0.98); perceived difficulty accessing medical care (aOR = 0.48 vs no difficulty; 95% CI, 0.27-0.83); recent intravenous (IV) drug use (aOR = 0.11 vs no use; 95% CI, 0.02-0.54); alcohol use disorder (AUD; aOR = 0.58 vs no AUD; 95% CI, 0.38-0.90); severe depression (aOR = 0.42 vs no depression; 95% CI, 0.2-0.9); recent homelessness (aOR = 0.36 vs no homelessness; 95% CI, 0.14-0.94); and recent incarceration (aOR = 0.34 vs no incarceration; 95% CI, 0.12-0.94).¹

A multicenter, observational prospective cohort study (N = 3075) evaluated receipt of HCV treatment for patients co-infected with HCV and HIV.² The primary outcome was initiation of HCV treatment with DAAs; 1957 patients initiated therapy, while 1118 did not. Significant independent risk factors for noninitiation of treatment included age younger than 50 years, a history of IV drug use, and use of opioid substitution therapy (OST). Other factors included psychiatric comorbidity (odds ratio [OR] = 0.45; 95% CI, 0.27-0.75), incarceration (OR = 0.6; 95% CI, 0.43-0.87), and female gender (OR = 0.80; 95% CI, 0.66-0.98). In a multivariate analysis limited to those with a history of IV drug use, both use of OST (aOR = 0.55; 95% CI, 0.40-0.75) and recent IV drug use (aOR = 0.019; 95% CI, 0.004-0.087) were identified as factors with low odds of treatment implementation.²

A retrospective cohort study (N = 1024) of medical charts examined the barriers to treatment in adults with chronic HCV infection.³ Of the patient population, 208 were treated and 816 were untreated. Patients not receiving DAAs were associated with poor adherence to/loss to follow-up (n = 548; OR = 36.6; 95% CI, 19.6-68.4); significant psychiatric illness (n = 103; OR = 2.02; 95% CI, 1.13-3.71); and coinfection with HIV (n = 188; OR = 4.5; 95% CI, 2.5-8.2).³

A German multicenter retrospective case-control study (N = 793) identified factors in patient and physician decisions to initiate treatment for HCV.⁴ Patients were ≥ 18 years old, confirmed to be HCV+, and had visited their physician at least 1 time during the observation period. A total of 573 patients received treatment and 220 did not. Patients and clinicians of those who chose not to receive treatment completed a survey that collected reasons for not treating. The most prevalent reason for not initiating treatment was patient wish (42%). This was further delineated to reveal that 17.3% attributed their decision to fear of treatment and 13.2% to fear of adverse events. Other factors associated with nontreatment included IV drug use (aOR = 0.31; 95% CI, 0.16-0.62); HIV coinfection (aOR = 0.19; 95% CI, 0.09-0.40); and use of OST (aOR = 0.37; 95% CI, 0.21-0.68). Patient demographics associated with wish not to be treated included older age (20.2% of those ≥ 40 years old vs 6.4% of those < 40 years old; P = .03) and female gender (51.0% of females vs 35.2% of males; P = .019).⁴

An analysis of a French insurance database (N = 22,545) evaluated the incidence of HCV treatment with DAAs in patients who inject drugs (PWID) with a diagnosis of alcohol use disorder (AUD).⁵ All participants (78% male; median age, 49 years) were chronically HCV-infected and covered by national health insurance. Individuals were grouped by AUD status: untreated (n = 5176), treated (n = 3020), and no AUD (n = 14349). After multivariate adjustment, those with untreated AUD had lower uptake of DAAs than those who did not have AUD (adjusted hazard ratio [aHR] = 0.86; 95% CI, 0.78-0.94) and those with treated AUD (aHR = 0.83; 95% CI, 0.74-0.94). There were no differences between those with treated AUD and those who did not have AUD. Other factors associated with lower DAA uptake were access to care (aHR = 0.90; 95% CI, 0.83-0.98) and female gender (aHR = 0.83; 95% CI, 0.76-0.9).⁵

A 2017 retrospective cohort study evaluated predictors and barriers to follow-up and treatment with DAAs among veterans who were HCV+.⁶ Patients (94% > 50 years old; 97% male; 48% white) had established HCV care within the US Department of Veterans Affairs system. Of those who followed up with at least 1 visit to an HCV specialty clinic (n = 47,165), 29% received DAAs. Factors associated with lack of treatment included race (Black vs White: OR = 0.77; 95% CI, 0.72-0.82; Hispanic vs White: OR = 0.88; 95% CI, 0.79-0.97); IV drug use (OR = 0.84; 95% CI, 0.80-0.88); AUD (OR = 0.73; 95% CI, 0.70-0.77); medical comorbidities (OR = 0.71; 95% CI, 0.66-0.77); and hepatocellular carcinoma (OR = 0.73; 95% CI, 0.65-0.83).⁶

Continue to: Providers identify similar barriers to treatment of HCV

Providers identify similar barriers to treatment of HCV

A 2017 prospective qualitative study (N = 24) from a Veterans Affairs health care system analyzed provider-perceived barriers to initiation of and adherence to HCV treatment.⁷ The analysis focused on differences by provider specialty. Primary care providers (PCPs; n = 12; 17% with > 40 patients with HCV) and hepatology providers (HPs; n = 12; 83% with > 40 patients with HCV) participated in a semi-structured telephone-based interview, providing their perceptions of patient-level barriers to HCV treatment. Eight patient-­level barrier themes were identified; these are outlined in the TABLE⁷ along with data for both PCPs and HPs.

Editor’s takeaway

These 7 cohort studies show us the factors we consider and the reasons we give to not initiate HCV treatment. Some of the factors seem reasonable, but many do not. We might use this list to remind and challenge ourselves to work through barriers to provide the best possible treatment.

EVIDENCE SUMMARY

Race, gender, and other factors are associated with lack of HCV Tx

A retrospective study (N = 894) assessed factors associated with direct-acting antiviral (DAA) initiation.¹ Patients who were HCV+ with at least 1 clinical visit during the study period completed a survey of psychological, behavioral, and social life assessments. The final cohort (57% male; 64% ≥ 61 years old) was divided into patients who initiated DAA treatment (n = 690) and those who did not (n = 204).

In an adjusted multivariable analysis, factors associated with lower odds of DAA initiation included Black race (adjusted odds ratio [aOR] = 0.59 vs White race; 95% CI, 0.36-0.98); perceived difficulty accessing medical care (aOR = 0.48 vs no difficulty; 95% CI, 0.27-0.83); recent intravenous (IV) drug use (aOR = 0.11 vs no use; 95% CI, 0.02-0.54); alcohol use disorder (AUD; aOR = 0.58 vs no AUD; 95% CI, 0.38-0.90); severe depression (aOR = 0.42 vs no depression; 95% CI, 0.2-0.9); recent homelessness (aOR = 0.36 vs no homelessness; 95% CI, 0.14-0.94); and recent incarceration (aOR = 0.34 vs no incarceration; 95% CI, 0.12-0.94).¹

A multicenter, observational prospective cohort study (N = 3075) evaluated receipt of HCV treatment for patients co-infected with HCV and HIV.² The primary outcome was initiation of HCV treatment with DAAs; 1957 patients initiated therapy, while 1118 did not. Significant independent risk factors for noninitiation of treatment included age younger than 50 years, a history of IV drug use, and use of opioid substitution therapy (OST). Other factors included psychiatric comorbidity (odds ratio [OR] = 0.45; 95% CI, 0.27-0.75), incarceration (OR = 0.6; 95% CI, 0.43-0.87), and female gender (OR = 0.80; 95% CI, 0.66-0.98). In a multivariate analysis limited to those with a history of IV drug use, both use of OST (aOR = 0.55; 95% CI, 0.40-0.75) and recent IV drug use (aOR = 0.019; 95% CI, 0.004-0.087) were identified as factors with low odds of treatment implementation.²

A retrospective cohort study (N = 1024) of medical charts examined the barriers to treatment in adults with chronic HCV infection.³ Of the patient population, 208 were treated and 816 were untreated. Patients not receiving DAAs were associated with poor adherence to/loss to follow-up (n = 548; OR = 36.6; 95% CI, 19.6-68.4); significant psychiatric illness (n = 103; OR = 2.02; 95% CI, 1.13-3.71); and coinfection with HIV (n = 188; OR = 4.5; 95% CI, 2.5-8.2).³

A German multicenter retrospective case-control study (N = 793) identified factors in patient and physician decisions to initiate treatment for HCV.⁴ Patients were ≥ 18 years old, confirmed to be HCV+, and had visited their physician at least 1 time during the observation period. A total of 573 patients received treatment and 220 did not. Patients and clinicians of those who chose not to receive treatment completed a survey that collected reasons for not treating. The most prevalent reason for not initiating treatment was patient wish (42%). This was further delineated to reveal that 17.3% attributed their decision to fear of treatment and 13.2% to fear of adverse events. Other factors associated with nontreatment included IV drug use (aOR = 0.31; 95% CI, 0.16-0.62); HIV coinfection (aOR = 0.19; 95% CI, 0.09-0.40); and use of OST (aOR = 0.37; 95% CI, 0.21-0.68). Patient demographics associated with wish not to be treated included older age (20.2% of those ≥ 40 years old vs 6.4% of those < 40 years old; P = .03) and female gender (51.0% of females vs 35.2% of males; P = .019).⁴

An analysis of a French insurance database (N = 22,545) evaluated the incidence of HCV treatment with DAAs in patients who inject drugs (PWID) with a diagnosis of alcohol use disorder (AUD).⁵ All participants (78% male; median age, 49 years) were chronically HCV-infected and covered by national health insurance. Individuals were grouped by AUD status: untreated (n = 5176), treated (n = 3020), and no AUD (n = 14349). After multivariate adjustment, those with untreated AUD had lower uptake of DAAs than those who did not have AUD (adjusted hazard ratio [aHR] = 0.86; 95% CI, 0.78-0.94) and those with treated AUD (aHR = 0.83; 95% CI, 0.74-0.94). There were no differences between those with treated AUD and those who did not have AUD. Other factors associated with lower DAA uptake were access to care (aHR = 0.90; 95% CI, 0.83-0.98) and female gender (aHR = 0.83; 95% CI, 0.76-0.9).⁵

A 2017 retrospective cohort study evaluated predictors and barriers to follow-up and treatment with DAAs among veterans who were HCV+.⁶ Patients (94% > 50 years old; 97% male; 48% white) had established HCV care within the US Department of Veterans Affairs system. Of those who followed up with at least 1 visit to an HCV specialty clinic (n = 47,165), 29% received DAAs. Factors associated with lack of treatment included race (Black vs White: OR = 0.77; 95% CI, 0.72-0.82; Hispanic vs White: OR = 0.88; 95% CI, 0.79-0.97); IV drug use (OR = 0.84; 95% CI, 0.80-0.88); AUD (OR = 0.73; 95% CI, 0.70-0.77); medical comorbidities (OR = 0.71; 95% CI, 0.66-0.77); and hepatocellular carcinoma (OR = 0.73; 95% CI, 0.65-0.83).⁶

Continue to: Providers identify similar barriers to treatment of HCV

Providers identify similar barriers to treatment of HCV

A 2017 prospective qualitative study (N = 24) from a Veterans Affairs health care system analyzed provider-perceived barriers to initiation of and adherence to HCV treatment.⁷ The analysis focused on differences by provider specialty. Primary care providers (PCPs; n = 12; 17% with > 40 patients with HCV) and hepatology providers (HPs; n = 12; 83% with > 40 patients with HCV) participated in a semi-structured telephone-based interview, providing their perceptions of patient-level barriers to HCV treatment. Eight patient-­level barrier themes were identified; these are outlined in the TABLE⁷ along with data for both PCPs and HPs.

Editor’s takeaway

These 7 cohort studies show us the factors we consider and the reasons we give to not initiate HCV treatment. Some of the factors seem reasonable, but many do not. We might use this list to remind and challenge ourselves to work through barriers to provide the best possible treatment.

EVIDENCE SUMMARY

Race, gender, and other factors are associated with lack of HCV Tx

A retrospective study (N = 894) assessed factors associated with direct-acting antiviral (DAA) initiation.¹ Patients who were HCV+ with at least 1 clinical visit during the study period completed a survey of psychological, behavioral, and social life assessments. The final cohort (57% male; 64% ≥ 61 years old) was divided into patients who initiated DAA treatment (n = 690) and those who did not (n = 204).

In an adjusted multivariable analysis, factors associated with lower odds of DAA initiation included Black race (adjusted odds ratio [aOR] = 0.59 vs White race; 95% CI, 0.36-0.98); perceived difficulty accessing medical care (aOR = 0.48 vs no difficulty; 95% CI, 0.27-0.83); recent intravenous (IV) drug use (aOR = 0.11 vs no use; 95% CI, 0.02-0.54); alcohol use disorder (AUD; aOR = 0.58 vs no AUD; 95% CI, 0.38-0.90); severe depression (aOR = 0.42 vs no depression; 95% CI, 0.2-0.9); recent homelessness (aOR = 0.36 vs no homelessness; 95% CI, 0.14-0.94); and recent incarceration (aOR = 0.34 vs no incarceration; 95% CI, 0.12-0.94).¹

A multicenter, observational prospective cohort study (N = 3075) evaluated receipt of HCV treatment for patients co-infected with HCV and HIV.² The primary outcome was initiation of HCV treatment with DAAs; 1957 patients initiated therapy, while 1118 did not. Significant independent risk factors for noninitiation of treatment included age younger than 50 years, a history of IV drug use, and use of opioid substitution therapy (OST). Other factors included psychiatric comorbidity (odds ratio [OR] = 0.45; 95% CI, 0.27-0.75), incarceration (OR = 0.6; 95% CI, 0.43-0.87), and female gender (OR = 0.80; 95% CI, 0.66-0.98). In a multivariate analysis limited to those with a history of IV drug use, both use of OST (aOR = 0.55; 95% CI, 0.40-0.75) and recent IV drug use (aOR = 0.019; 95% CI, 0.004-0.087) were identified as factors with low odds of treatment implementation.²

A retrospective cohort study (N = 1024) of medical charts examined the barriers to treatment in adults with chronic HCV infection.³ Of the patient population, 208 were treated and 816 were untreated. Patients not receiving DAAs were associated with poor adherence to/loss to follow-up (n = 548; OR = 36.6; 95% CI, 19.6-68.4); significant psychiatric illness (n = 103; OR = 2.02; 95% CI, 1.13-3.71); and coinfection with HIV (n = 188; OR = 4.5; 95% CI, 2.5-8.2).³

A German multicenter retrospective case-control study (N = 793) identified factors in patient and physician decisions to initiate treatment for HCV.⁴ Patients were ≥ 18 years old, confirmed to be HCV+, and had visited their physician at least 1 time during the observation period. A total of 573 patients received treatment and 220 did not. Patients and clinicians of those who chose not to receive treatment completed a survey that collected reasons for not treating. The most prevalent reason for not initiating treatment was patient wish (42%). This was further delineated to reveal that 17.3% attributed their decision to fear of treatment and 13.2% to fear of adverse events. Other factors associated with nontreatment included IV drug use (aOR = 0.31; 95% CI, 0.16-0.62); HIV coinfection (aOR = 0.19; 95% CI, 0.09-0.40); and use of OST (aOR = 0.37; 95% CI, 0.21-0.68). Patient demographics associated with wish not to be treated included older age (20.2% of those ≥ 40 years old vs 6.4% of those < 40 years old; P = .03) and female gender (51.0% of females vs 35.2% of males; P = .019).⁴

An analysis of a French insurance database (N = 22,545) evaluated the incidence of HCV treatment with DAAs in patients who inject drugs (PWID) with a diagnosis of alcohol use disorder (AUD).⁵ All participants (78% male; median age, 49 years) were chronically HCV-infected and covered by national health insurance. Individuals were grouped by AUD status: untreated (n = 5176), treated (n = 3020), and no AUD (n = 14349). After multivariate adjustment, those with untreated AUD had lower uptake of DAAs than those who did not have AUD (adjusted hazard ratio [aHR] = 0.86; 95% CI, 0.78-0.94) and those with treated AUD (aHR = 0.83; 95% CI, 0.74-0.94). There were no differences between those with treated AUD and those who did not have AUD. Other factors associated with lower DAA uptake were access to care (aHR = 0.90; 95% CI, 0.83-0.98) and female gender (aHR = 0.83; 95% CI, 0.76-0.9).⁵

A 2017 retrospective cohort study evaluated predictors and barriers to follow-up and treatment with DAAs among veterans who were HCV+.⁶ Patients (94% > 50 years old; 97% male; 48% white) had established HCV care within the US Department of Veterans Affairs system. Of those who followed up with at least 1 visit to an HCV specialty clinic (n = 47,165), 29% received DAAs. Factors associated with lack of treatment included race (Black vs White: OR = 0.77; 95% CI, 0.72-0.82; Hispanic vs White: OR = 0.88; 95% CI, 0.79-0.97); IV drug use (OR = 0.84; 95% CI, 0.80-0.88); AUD (OR = 0.73; 95% CI, 0.70-0.77); medical comorbidities (OR = 0.71; 95% CI, 0.66-0.77); and hepatocellular carcinoma (OR = 0.73; 95% CI, 0.65-0.83).⁶

Continue to: Providers identify similar barriers to treatment of HCV

Providers identify similar barriers to treatment of HCV

A 2017 prospective qualitative study (N = 24) from a Veterans Affairs health care system analyzed provider-perceived barriers to initiation of and adherence to HCV treatment.⁷ The analysis focused on differences by provider specialty. Primary care providers (PCPs; n = 12; 17% with > 40 patients with HCV) and hepatology providers (HPs; n = 12; 83% with > 40 patients with HCV) participated in a semi-structured telephone-based interview, providing their perceptions of patient-level barriers to HCV treatment. Eight patient-­level barrier themes were identified; these are outlined in the TABLE⁷ along with data for both PCPs and HPs.

Editor’s takeaway

These 7 cohort studies show us the factors we consider and the reasons we give to not initiate HCV treatment. Some of the factors seem reasonable, but many do not. We might use this list to remind and challenge ourselves to work through barriers to provide the best possible treatment.

THE CASE

A 57-year-old man with type 2 diabetes, hyperlipidemia, and obesity presented to the emergency department (ED) for bilateral foot blisters, both of which appeared 1 day prior to evaluation. The patient’s history also included right-side Charcot foot diagnosed 4 years earlier and right foot osteomyelitis diagnosed 2 years prior. He had ongoing neuropathy in both feet but denied any significant pain.

The patient wore orthotics daily and he’d had new orthotics made 6 months prior; however, a recent COVID-19 diagnosis and prolonged hospital stay resulted in a 30-pound weight loss and decreased swelling in his ankles. He acquired new shoes 2 weeks prior to ED presentation.

Physical examination revealed large blisters along the medial aspect of the patient’s feet, with both hemorrhagic and serous fluid-filled bullae. The lesions were flaccid but intact, without drainage or surrounding erythema, warmth, or tenderness. The blister on the left foot measured 8 x 5 cm and extended from the great toe to mid-arch (FIGURE), while the one on the right foot measured 8 x 3 cm and extended from the great toe to the base of the proximal arch. Sensation was decreased in the bilateral first and second digits but unchanged from prior documented exams. Bilateral dorsalis pedis pulses were normal.

Work-up included imaging and lab work. The patient’s complete blood count was normal, as were his erythrocyte sedimentation rate and C-reactive protein level. Radiographs of the right foot were normal, but those of the left foot were concerning, although inconclusive, for osteomyelitis. Further evaluation with magnetic resonance imaging of his left foot revealed a deformity of the first digit with some subchondral signal change that was thought to be posttraumatic or degenerative, but unlikely osteomyelitis.

THE DIAGNOSIS

Podiatry was consulted for blister management. Based on atraumatic history, rapid appearance, location of blisters, unremarkable lab work and imaging, and concurrent diabetes, the patient received a diagnosis of bilateral bullous diabeticorum (BD).

DISCUSSION

Roughly one-third of patients with diabetes will experience some cutaneous adverse effect because of the disease.¹ Common iterations include acanthosis nigricans, rash, or even infection.² BD is a rare bullous skin lesion that occurs in patients with diabetes; it has a reported annual incidence of 0.16% and may be underdiagnosed.¹

Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of bullous diabeticorum occurrence.

Cases of BD have been described both in patients with longstanding diabetes and in those newly diagnosed, although the former group is more often affected.¹ BD is reported more frequently in males than females, at a ratio of 2:1.^1,3 Patients ages 17 to 80 years (average age, 55 years) have received a diagnosis of BD.¹ Most affected patients will have a concomitant peripheral neuropathy and sometimes nephropathy or retinopathy.¹

Continue to: The etiology of BD...

The etiology of BD is unclear but appears to be multifactorial. Hypotheses suggest that there’s a link to neuropathy/nephropathy, excessive exposure to ultraviolet light, or a vascular cause secondary to hyaline deposition in the capillary walls.^4,5

What you’ll see at presentation

The typical manifestation of BD is the rapid appearance of tense blisters, which may occur overnight or even within hours.¹ They are usually painless; common locations include the feet, distal legs, hands, and forearms.^1,5 The bullae can be serous or hemorrhagic.¹

Most notable in the patient’s history will be a lack of trauma or injury to the area.¹ Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of occurrence.¹

Other sources of blistering must be ruled out

The diagnosis of BD is clinical and based on history, exam, and exclusion of other bullous diagnoses.⁶ A key clue in the history is the spontaneous and rapid onset without associated trauma in a patient with diabetes.⁶ Direct immunofluorescence, although nonspecific, can be helpful to rule out other disorders (such as porphyria cutanea tarda and bullous pemphigoid) if the history and exam are inconclusive. Direct and indirect immunofluorescence is typically negative in BD.^4,6

The differential diagnosis includes other conditions that involve bullae—such as frictional bullae, bullous pemphigoid, and bullous systemic lupus erythematosus—as well as porphyria, erythema multiforme, insect bites, or even fixed drug eruption.^2,7

Continue to: Porphyria

Porphyria tends to develop on the hands, whereas BD most commonly occurs on the feet.⁵

Erythema multiforme typically includes inflammatory skin changes.⁵

Trauma or fixed drug eruption as a cause of blistering lesions would be revealed during history taking.

Considerations for treatment and follow-up

Without treatment, blisters often self-resolve in 2 to 6 weeks, but there is high likelihood of recurrence.^6,8 There is no consensus on treatment, although a typical course of action is to deroof the blister and examine the area to rule out infection.⁶ The wound is then covered with wet-to-dry gauze that is changed regularly. If there is suspicion for or signs of underlying infection, such as an ulcer or skin necrosis, antibiotics should be included in the treatment plan.⁷

Additional considerations. Patients will often need therapeutic footwear if the blisters are located on the feet. Given the higher prevalence of microvascular complications in patients with diabetes who develop BD, routine ophthalmologic examination and renal function testing to monitor for microalbuminuria are recommended.⁵

Our patient underwent bedside incision and drainage and was discharged home with appropriate wound care and follow-up. 

THE TAKEAWAY

BD cases may be underdiagnosed in clinical practice, perhaps due to patients not seeking help for a seemingly nonthreatening condition or lack of clinician recognition that bullae are related to a patient’s diabetes status. Prompt recognition and proper wound care are important to prevent poor outcomes, such as ulceration or necrosis.

CORRESPONDENCE
Kathleen S. Kinderwater, MD, 101 Heart Drive, Greenville, NC 27834; [email protected]

THE CASE

A 57-year-old man with type 2 diabetes, hyperlipidemia, and obesity presented to the emergency department (ED) for bilateral foot blisters, both of which appeared 1 day prior to evaluation. The patient’s history also included right-side Charcot foot diagnosed 4 years earlier and right foot osteomyelitis diagnosed 2 years prior. He had ongoing neuropathy in both feet but denied any significant pain.

The patient wore orthotics daily and he’d had new orthotics made 6 months prior; however, a recent COVID-19 diagnosis and prolonged hospital stay resulted in a 30-pound weight loss and decreased swelling in his ankles. He acquired new shoes 2 weeks prior to ED presentation.

Physical examination revealed large blisters along the medial aspect of the patient’s feet, with both hemorrhagic and serous fluid-filled bullae. The lesions were flaccid but intact, without drainage or surrounding erythema, warmth, or tenderness. The blister on the left foot measured 8 x 5 cm and extended from the great toe to mid-arch (FIGURE), while the one on the right foot measured 8 x 3 cm and extended from the great toe to the base of the proximal arch. Sensation was decreased in the bilateral first and second digits but unchanged from prior documented exams. Bilateral dorsalis pedis pulses were normal.

Work-up included imaging and lab work. The patient’s complete blood count was normal, as were his erythrocyte sedimentation rate and C-reactive protein level. Radiographs of the right foot were normal, but those of the left foot were concerning, although inconclusive, for osteomyelitis. Further evaluation with magnetic resonance imaging of his left foot revealed a deformity of the first digit with some subchondral signal change that was thought to be posttraumatic or degenerative, but unlikely osteomyelitis.

THE DIAGNOSIS

Podiatry was consulted for blister management. Based on atraumatic history, rapid appearance, location of blisters, unremarkable lab work and imaging, and concurrent diabetes, the patient received a diagnosis of bilateral bullous diabeticorum (BD).

DISCUSSION

Roughly one-third of patients with diabetes will experience some cutaneous adverse effect because of the disease.¹ Common iterations include acanthosis nigricans, rash, or even infection.² BD is a rare bullous skin lesion that occurs in patients with diabetes; it has a reported annual incidence of 0.16% and may be underdiagnosed.¹

Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of bullous diabeticorum occurrence.

Cases of BD have been described both in patients with longstanding diabetes and in those newly diagnosed, although the former group is more often affected.¹ BD is reported more frequently in males than females, at a ratio of 2:1.^1,3 Patients ages 17 to 80 years (average age, 55 years) have received a diagnosis of BD.¹ Most affected patients will have a concomitant peripheral neuropathy and sometimes nephropathy or retinopathy.¹

Continue to: The etiology of BD...

The etiology of BD is unclear but appears to be multifactorial. Hypotheses suggest that there’s a link to neuropathy/nephropathy, excessive exposure to ultraviolet light, or a vascular cause secondary to hyaline deposition in the capillary walls.^4,5

What you’ll see at presentation

The typical manifestation of BD is the rapid appearance of tense blisters, which may occur overnight or even within hours.¹ They are usually painless; common locations include the feet, distal legs, hands, and forearms.^1,5 The bullae can be serous or hemorrhagic.¹

Most notable in the patient’s history will be a lack of trauma or injury to the area.¹ Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of occurrence.¹

Other sources of blistering must be ruled out

The diagnosis of BD is clinical and based on history, exam, and exclusion of other bullous diagnoses.⁶ A key clue in the history is the spontaneous and rapid onset without associated trauma in a patient with diabetes.⁶ Direct immunofluorescence, although nonspecific, can be helpful to rule out other disorders (such as porphyria cutanea tarda and bullous pemphigoid) if the history and exam are inconclusive. Direct and indirect immunofluorescence is typically negative in BD.^4,6

The differential diagnosis includes other conditions that involve bullae—such as frictional bullae, bullous pemphigoid, and bullous systemic lupus erythematosus—as well as porphyria, erythema multiforme, insect bites, or even fixed drug eruption.^2,7

Continue to: Porphyria

Porphyria tends to develop on the hands, whereas BD most commonly occurs on the feet.⁵

Erythema multiforme typically includes inflammatory skin changes.⁵

Trauma or fixed drug eruption as a cause of blistering lesions would be revealed during history taking.

Considerations for treatment and follow-up

Without treatment, blisters often self-resolve in 2 to 6 weeks, but there is high likelihood of recurrence.^6,8 There is no consensus on treatment, although a typical course of action is to deroof the blister and examine the area to rule out infection.⁶ The wound is then covered with wet-to-dry gauze that is changed regularly. If there is suspicion for or signs of underlying infection, such as an ulcer or skin necrosis, antibiotics should be included in the treatment plan.⁷

Additional considerations. Patients will often need therapeutic footwear if the blisters are located on the feet. Given the higher prevalence of microvascular complications in patients with diabetes who develop BD, routine ophthalmologic examination and renal function testing to monitor for microalbuminuria are recommended.⁵

Our patient underwent bedside incision and drainage and was discharged home with appropriate wound care and follow-up. 

THE TAKEAWAY

BD cases may be underdiagnosed in clinical practice, perhaps due to patients not seeking help for a seemingly nonthreatening condition or lack of clinician recognition that bullae are related to a patient’s diabetes status. Prompt recognition and proper wound care are important to prevent poor outcomes, such as ulceration or necrosis.

CORRESPONDENCE
Kathleen S. Kinderwater, MD, 101 Heart Drive, Greenville, NC 27834; [email protected]

THE CASE

A 57-year-old man with type 2 diabetes, hyperlipidemia, and obesity presented to the emergency department (ED) for bilateral foot blisters, both of which appeared 1 day prior to evaluation. The patient’s history also included right-side Charcot foot diagnosed 4 years earlier and right foot osteomyelitis diagnosed 2 years prior. He had ongoing neuropathy in both feet but denied any significant pain.

The patient wore orthotics daily and he’d had new orthotics made 6 months prior; however, a recent COVID-19 diagnosis and prolonged hospital stay resulted in a 30-pound weight loss and decreased swelling in his ankles. He acquired new shoes 2 weeks prior to ED presentation.

Physical examination revealed large blisters along the medial aspect of the patient’s feet, with both hemorrhagic and serous fluid-filled bullae. The lesions were flaccid but intact, without drainage or surrounding erythema, warmth, or tenderness. The blister on the left foot measured 8 x 5 cm and extended from the great toe to mid-arch (FIGURE), while the one on the right foot measured 8 x 3 cm and extended from the great toe to the base of the proximal arch. Sensation was decreased in the bilateral first and second digits but unchanged from prior documented exams. Bilateral dorsalis pedis pulses were normal.

Work-up included imaging and lab work. The patient’s complete blood count was normal, as were his erythrocyte sedimentation rate and C-reactive protein level. Radiographs of the right foot were normal, but those of the left foot were concerning, although inconclusive, for osteomyelitis. Further evaluation with magnetic resonance imaging of his left foot revealed a deformity of the first digit with some subchondral signal change that was thought to be posttraumatic or degenerative, but unlikely osteomyelitis.

THE DIAGNOSIS

Podiatry was consulted for blister management. Based on atraumatic history, rapid appearance, location of blisters, unremarkable lab work and imaging, and concurrent diabetes, the patient received a diagnosis of bilateral bullous diabeticorum (BD).

DISCUSSION

Roughly one-third of patients with diabetes will experience some cutaneous adverse effect because of the disease.¹ Common iterations include acanthosis nigricans, rash, or even infection.² BD is a rare bullous skin lesion that occurs in patients with diabetes; it has a reported annual incidence of 0.16% and may be underdiagnosed.¹

Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of bullous diabeticorum occurrence.

Cases of BD have been described both in patients with longstanding diabetes and in those newly diagnosed, although the former group is more often affected.¹ BD is reported more frequently in males than females, at a ratio of 2:1.^1,3 Patients ages 17 to 80 years (average age, 55 years) have received a diagnosis of BD.¹ Most affected patients will have a concomitant peripheral neuropathy and sometimes nephropathy or retinopathy.¹

Continue to: The etiology of BD...

The etiology of BD is unclear but appears to be multifactorial. Hypotheses suggest that there’s a link to neuropathy/nephropathy, excessive exposure to ultraviolet light, or a vascular cause secondary to hyaline deposition in the capillary walls.^4,5

What you’ll see at presentation

The typical manifestation of BD is the rapid appearance of tense blisters, which may occur overnight or even within hours.¹ They are usually painless; common locations include the feet, distal legs, hands, and forearms.^1,5 The bullae can be serous or hemorrhagic.¹

Most notable in the patient’s history will be a lack of trauma or injury to the area.¹ Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of occurrence.¹

Other sources of blistering must be ruled out

The diagnosis of BD is clinical and based on history, exam, and exclusion of other bullous diagnoses.⁶ A key clue in the history is the spontaneous and rapid onset without associated trauma in a patient with diabetes.⁶ Direct immunofluorescence, although nonspecific, can be helpful to rule out other disorders (such as porphyria cutanea tarda and bullous pemphigoid) if the history and exam are inconclusive. Direct and indirect immunofluorescence is typically negative in BD.^4,6

The differential diagnosis includes other conditions that involve bullae—such as frictional bullae, bullous pemphigoid, and bullous systemic lupus erythematosus—as well as porphyria, erythema multiforme, insect bites, or even fixed drug eruption.^2,7

Continue to: Porphyria

Porphyria tends to develop on the hands, whereas BD most commonly occurs on the feet.⁵

Erythema multiforme typically includes inflammatory skin changes.⁵

Trauma or fixed drug eruption as a cause of blistering lesions would be revealed during history taking.

Considerations for treatment and follow-up

Without treatment, blisters often self-resolve in 2 to 6 weeks, but there is high likelihood of recurrence.^6,8 There is no consensus on treatment, although a typical course of action is to deroof the blister and examine the area to rule out infection.⁶ The wound is then covered with wet-to-dry gauze that is changed regularly. If there is suspicion for or signs of underlying infection, such as an ulcer or skin necrosis, antibiotics should be included in the treatment plan.⁷

Additional considerations. Patients will often need therapeutic footwear if the blisters are located on the feet. Given the higher prevalence of microvascular complications in patients with diabetes who develop BD, routine ophthalmologic examination and renal function testing to monitor for microalbuminuria are recommended.⁵

Our patient underwent bedside incision and drainage and was discharged home with appropriate wound care and follow-up. 

THE TAKEAWAY

BD cases may be underdiagnosed in clinical practice, perhaps due to patients not seeking help for a seemingly nonthreatening condition or lack of clinician recognition that bullae are related to a patient’s diabetes status. Prompt recognition and proper wound care are important to prevent poor outcomes, such as ulceration or necrosis.

CORRESPONDENCE
Kathleen S. Kinderwater, MD, 101 Heart Drive, Greenville, NC 27834; [email protected]

The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

 

 

Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^a https://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; [email protected]

The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

 

 

Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^a https://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; [email protected]

The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

 

 

Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^a https://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; [email protected]

THE CASE

Louise T* is a 42-year-old woman who presented to her family medicine office for a routine annual visit. During the exam, her physician noticed bruises on Ms. T’s arms and back. Upon further inquiry, Ms. T reported that she and her husband had argued the night before the appointment. With some hesitancy, she went on to say that this was not the first time this had happened. She said that she and her husband had been arguing frequently for several years and that 6 months earlier, when he lost his job, he began hitting and pushing her.

● How would you proceed with this patient?

*The patient’s name has been changed to protect her identity.

Intimate partner violence (IPV) includes physical, sexual, or psychological aggression or stalking perpetrated by a current or former relationship partner.¹ IPV affects more than 12 million men and women living in the United States each year.² According to a national survey of IPV, approximately one-third (35.6%) of women and one-quarter (28.5%) of men living in the United States experience rape, physical violence, or stalking by an intimate partner during their lifetime.² Lifetime exposure to psychological IPV is even more prevalent, affecting nearly half of women and men (48.4% and 48.8%, respectively).²

Lifetime prevalence of any form of IPV is higher among women who identify as bisexual (59.8%) and lesbian (46.3%) compared with those who identify as heterosexual (37.2%); rates are comparable among men who identify as heterosexual (31.9%), bisexual (35.3%), and gay (35.1%).³ Preliminary data suggest that IPV may have increased in frequency and severity during the COVID-19 pandemic, particularly in the context of mandated shelter-in-place and stay-at-home orders.^4-6

IPV is associated with numerous negative health consequences. They include fear and concern for safety, mental health disorders such as posttraumatic stress disorder (PTSD), and physical health problems including physical injury, chronic pain, sleep disturbance, and frequent headaches.² IPV is also associated with a greater number of missed days from school and work and increased utilization of legal, health care, and housing services.^2,7 The overall annual cost of IPV against women is estimated at $5.8 billion, with health care costs accounting for approximately $4.1 billion.⁷ Family physicians can play an important role in curbing the devastating effects of IPV by screening patients and providing resources when needed.

Facilitate disclosure using screening tools and protocol

In Ms. T’s case, evidence of violence was clearly visible. However, not all instances of IPV leave physical marks. The US Preventive Services Task Force (USPSTF) recommends that all women of childbearing age be screened for IPV, whether or not they exhibit signs of violence.⁸ While the USPSTF has only published recommendations regarding screening women for IPV, there has been a recent push to screen all patients given that men also experience high rates of IPV.⁹

It’s helpful to ask questions such as: “Do arguments [with your partner] ever result in hitting, kicking, or pushing?” and “How often does your partner scream or curse at you?”

Utilize a brief screening tool. Directly ask patients about IPV; this can help reduce stigma, facilitate disclosure, and initiate the process of connecting patients to potentially lifesaving resources. The USPSTF lists several brief screening measures that can be used in primary care settings to assess exposure to IPV (TABLE 1^8,10-17). The brevity of these screening tools makes them well suited for busy physicians; cutoff scores facilitate the rapid identification of positive screens. While the USPSTF has not made specific recommendations regarding a screening interval, many studies examining the utility of these measures have reported on annual screenings.⁸ While there is limited evidence that brief screening alone leads to reductions in IPV,⁸ discussing IPV in a supportive and empathic manner and connecting patients to resources, such as supportive counseling, does have an important benefit: It can reduce symptoms of depression.¹⁸

Continue to: Screen patients in private; this protocol can help

Screen patients in private; this protocol can help. Given the sensitive nature of IPV and the potential danger some patients may be facing, it is important to screen patients in a safe and supportive environment.^19,20 Screening should be conducted by the primary care clinician, ideally when a trusting relationship already has been formed. Screen patients only when they are alone in a private room; avoid screening in public spaces such as clinic waiting rooms or in the vicinity of the patient’s partner or children older than age 2 years.^19,20

To provide all patients with an opportunity for private and safe IPV screening, clinics are encouraged to develop a clinic-wide policy whereby patients are routinely escorted to the exam room alone for the first portion of their visit, after which any accompanying individuals may be invited to join.²¹ Clinic staff can inform patients and accompanying individuals of this policy when they first arrive. Once in the exam room, and before the screening process begins, clearly state reporting requirements to ensure that patients can make an informed decision about whether to disclose IPV.¹⁹

Set a receptive tone. The manner in which clinicians discuss IPV with their patients is just as important as the setting. Demonstrating sensitivity and genuine concern for the patient’s safety and well-being may increase the patient’s comfort level throughout the screening process and may facilitate disclosures of IPV.^19,22 When screening patients for IPV, sit face to face rather than standing over them, maintain warm and open body language, and speak in a soft tone of voice.²²

Patients may feel more comfortable if you ask screening questions in a straightforward, nonjudgmental manner, as this helps to normalize the screening experience. We also recommend using behaviorally specific language (eg, “Do arguments [with your partner] ever result in hitting, kicking, or pushing?”¹⁶ or “How often does your partner scream or curse at you?”),¹³ as some patients who have experienced IPV will not label their experiences as “abuse” or “violence.” Not every patient who experiences IPV will be ready to disclose these events; however, maintaining a positive and supportive relationship during routine IPV screening and throughout the remainder of the medical visit may help facilitate future disclosures if, and when, a patient is ready to seek support.¹⁹

CRITICAL INTERVENTION ELEMENTS: EMPATHY AND SAFETY

A physician’s response to an IPV disclosure can have a lasting impact on the patient. We encourage family physicians to respond to IPV disclosures with empathy. Maintain eye contact and warm body language, validate the patient’s experiences (“I am sorry this happened to you,” “that must have been terrifying”), tell the patient that the violence was not their fault, and thank the patient for disclosing.²³

Continue to: Assess patient safety

Assess patient safety. Another critical component of intervention is to assess the patient’s safety and engage in safety planning. If the patient agrees to this next step, you may wish to provide a warm handoff to a trained social worker, nurse, or psychologist in the clinic who can spend more time covering this information with the patient. Some key components of a safety assessment include determining whether the violence or threat of violence is ongoing and identifying who lives in the home (eg, the partner, children, and any pets). You and the patient can also discuss red flags that would indicate elevated risk. You should discuss red flags that are unique to the patient’s relationship as well as common factors that have been found to heighten risk for IPV (eg, partner engaging in heavy alcohol use).¹

With the patient’s permission, collaboratively construct a safety plan that details how the patient can stay safe on a daily basis and how to safely leave should a dangerous situation arise (TABLE 2^9,24). The interactive safety planning tool available on the National Domestic Violence Hotline’s website can be a valuable resource (www.thehotline.org/plan-for-safety/).²⁴ Finally, if a patient is experiencing mental health concerns associated with IPV (eg, PTSD, depression, substance misuse, suicidal ideation), consider a referral to a domestic violence counseling center or mental health provider.

Move at the patient’s pace. Even if patients are willing to disclose IPV, they will differ in their readiness to discuss psychoeducation, safety planning, and referrals. Similarly, even if a patient is experiencing severe violence, they may not be ready to leave the relationship. Thus, it’s important to ask the patient for permission before initiating each successive step of the follow-up intervention. You and the patient may wish to schedule additional appointments to discuss this information at a pace the patient finds appropriate.

You may need to spend some time helping the patient recognize the severity of their situation and to feel empowered to take action. In addition, offer information and resources to all patients, even those who do not disclose IPV. Some patients may want to receive this information even if they do not feel comfortable sharing their experiences during the appointment.²⁰ You can also inform patients that they are welcome to bring up issues related to IPV at any future appointments in order to leave the door open to future disclosures.

THE CASE

The physician determined that Ms. T had been experiencing physical and psychological IPV in her current relationship. After responding empathically and obtaining the patient’s consent, the physician provided a warm handoff to the psychologist in the clinic. With Ms. T’s permission, the psychologist provided psychoeducation about IPV, and they discussed Ms. T’s current situation and risk level. They determined that Ms. T was at risk for subsequent episodes of IPV and they collaborated on a safety plan, making sure to discuss contact information for local and national crisis resources.

Continue to: Ms. T saved the phone number...

Ms. T saved the phone number for her local domestic violence shelter in her phone under a false name in case her husband looked through her phone. She said she planned to work on several safety plan items when her husband was away from the house and it was safe to do so. For example, she planned to identify additional ways to exit the house in an emergency and she was going to put together a bag with a change of clothes and some money and drop it off at a trusted friend’s house.

Ms. T and the psychologist agreed to follow up with an office visit in 1 week to discuss any additional safety concerns and to determine whether Ms. T could benefit from a referral to domestic violence counseling services or mental health treatment. The psychologist provided a summary of the topics she and Ms. T had discussed to the physician. The physician scheduled a follow-up appointment with Ms. T in 3 weeks to assess her current safety, troubleshoot any difficulties in implementing her safety plan, and offer additional resources, as needed.

CORRESPONDENCE
Andrea Massa, PhD, 125 Doughty Street, Suite 300, Charleston, SC 29403; [email protected]

THE CASE

Louise T* is a 42-year-old woman who presented to her family medicine office for a routine annual visit. During the exam, her physician noticed bruises on Ms. T’s arms and back. Upon further inquiry, Ms. T reported that she and her husband had argued the night before the appointment. With some hesitancy, she went on to say that this was not the first time this had happened. She said that she and her husband had been arguing frequently for several years and that 6 months earlier, when he lost his job, he began hitting and pushing her.

● How would you proceed with this patient?

*The patient’s name has been changed to protect her identity.

Intimate partner violence (IPV) includes physical, sexual, or psychological aggression or stalking perpetrated by a current or former relationship partner.¹ IPV affects more than 12 million men and women living in the United States each year.² According to a national survey of IPV, approximately one-third (35.6%) of women and one-quarter (28.5%) of men living in the United States experience rape, physical violence, or stalking by an intimate partner during their lifetime.² Lifetime exposure to psychological IPV is even more prevalent, affecting nearly half of women and men (48.4% and 48.8%, respectively).²

Lifetime prevalence of any form of IPV is higher among women who identify as bisexual (59.8%) and lesbian (46.3%) compared with those who identify as heterosexual (37.2%); rates are comparable among men who identify as heterosexual (31.9%), bisexual (35.3%), and gay (35.1%).³ Preliminary data suggest that IPV may have increased in frequency and severity during the COVID-19 pandemic, particularly in the context of mandated shelter-in-place and stay-at-home orders.^4-6

IPV is associated with numerous negative health consequences. They include fear and concern for safety, mental health disorders such as posttraumatic stress disorder (PTSD), and physical health problems including physical injury, chronic pain, sleep disturbance, and frequent headaches.² IPV is also associated with a greater number of missed days from school and work and increased utilization of legal, health care, and housing services.^2,7 The overall annual cost of IPV against women is estimated at $5.8 billion, with health care costs accounting for approximately $4.1 billion.⁷ Family physicians can play an important role in curbing the devastating effects of IPV by screening patients and providing resources when needed.

Facilitate disclosure using screening tools and protocol

In Ms. T’s case, evidence of violence was clearly visible. However, not all instances of IPV leave physical marks. The US Preventive Services Task Force (USPSTF) recommends that all women of childbearing age be screened for IPV, whether or not they exhibit signs of violence.⁸ While the USPSTF has only published recommendations regarding screening women for IPV, there has been a recent push to screen all patients given that men also experience high rates of IPV.⁹

It’s helpful to ask questions such as: “Do arguments [with your partner] ever result in hitting, kicking, or pushing?” and “How often does your partner scream or curse at you?”

Utilize a brief screening tool. Directly ask patients about IPV; this can help reduce stigma, facilitate disclosure, and initiate the process of connecting patients to potentially lifesaving resources. The USPSTF lists several brief screening measures that can be used in primary care settings to assess exposure to IPV (TABLE 1^8,10-17). The brevity of these screening tools makes them well suited for busy physicians; cutoff scores facilitate the rapid identification of positive screens. While the USPSTF has not made specific recommendations regarding a screening interval, many studies examining the utility of these measures have reported on annual screenings.⁸ While there is limited evidence that brief screening alone leads to reductions in IPV,⁸ discussing IPV in a supportive and empathic manner and connecting patients to resources, such as supportive counseling, does have an important benefit: It can reduce symptoms of depression.¹⁸

Continue to: Screen patients in private; this protocol can help

Screen patients in private; this protocol can help. Given the sensitive nature of IPV and the potential danger some patients may be facing, it is important to screen patients in a safe and supportive environment.^19,20 Screening should be conducted by the primary care clinician, ideally when a trusting relationship already has been formed. Screen patients only when they are alone in a private room; avoid screening in public spaces such as clinic waiting rooms or in the vicinity of the patient’s partner or children older than age 2 years.^19,20

To provide all patients with an opportunity for private and safe IPV screening, clinics are encouraged to develop a clinic-wide policy whereby patients are routinely escorted to the exam room alone for the first portion of their visit, after which any accompanying individuals may be invited to join.²¹ Clinic staff can inform patients and accompanying individuals of this policy when they first arrive. Once in the exam room, and before the screening process begins, clearly state reporting requirements to ensure that patients can make an informed decision about whether to disclose IPV.¹⁹

Set a receptive tone. The manner in which clinicians discuss IPV with their patients is just as important as the setting. Demonstrating sensitivity and genuine concern for the patient’s safety and well-being may increase the patient’s comfort level throughout the screening process and may facilitate disclosures of IPV.^19,22 When screening patients for IPV, sit face to face rather than standing over them, maintain warm and open body language, and speak in a soft tone of voice.²²

Patients may feel more comfortable if you ask screening questions in a straightforward, nonjudgmental manner, as this helps to normalize the screening experience. We also recommend using behaviorally specific language (eg, “Do arguments [with your partner] ever result in hitting, kicking, or pushing?”¹⁶ or “How often does your partner scream or curse at you?”),¹³ as some patients who have experienced IPV will not label their experiences as “abuse” or “violence.” Not every patient who experiences IPV will be ready to disclose these events; however, maintaining a positive and supportive relationship during routine IPV screening and throughout the remainder of the medical visit may help facilitate future disclosures if, and when, a patient is ready to seek support.¹⁹

CRITICAL INTERVENTION ELEMENTS: EMPATHY AND SAFETY

A physician’s response to an IPV disclosure can have a lasting impact on the patient. We encourage family physicians to respond to IPV disclosures with empathy. Maintain eye contact and warm body language, validate the patient’s experiences (“I am sorry this happened to you,” “that must have been terrifying”), tell the patient that the violence was not their fault, and thank the patient for disclosing.²³

Continue to: Assess patient safety

Assess patient safety. Another critical component of intervention is to assess the patient’s safety and engage in safety planning. If the patient agrees to this next step, you may wish to provide a warm handoff to a trained social worker, nurse, or psychologist in the clinic who can spend more time covering this information with the patient. Some key components of a safety assessment include determining whether the violence or threat of violence is ongoing and identifying who lives in the home (eg, the partner, children, and any pets). You and the patient can also discuss red flags that would indicate elevated risk. You should discuss red flags that are unique to the patient’s relationship as well as common factors that have been found to heighten risk for IPV (eg, partner engaging in heavy alcohol use).¹

With the patient’s permission, collaboratively construct a safety plan that details how the patient can stay safe on a daily basis and how to safely leave should a dangerous situation arise (TABLE 2^9,24). The interactive safety planning tool available on the National Domestic Violence Hotline’s website can be a valuable resource (www.thehotline.org/plan-for-safety/).²⁴ Finally, if a patient is experiencing mental health concerns associated with IPV (eg, PTSD, depression, substance misuse, suicidal ideation), consider a referral to a domestic violence counseling center or mental health provider.

Move at the patient’s pace. Even if patients are willing to disclose IPV, they will differ in their readiness to discuss psychoeducation, safety planning, and referrals. Similarly, even if a patient is experiencing severe violence, they may not be ready to leave the relationship. Thus, it’s important to ask the patient for permission before initiating each successive step of the follow-up intervention. You and the patient may wish to schedule additional appointments to discuss this information at a pace the patient finds appropriate.

You may need to spend some time helping the patient recognize the severity of their situation and to feel empowered to take action. In addition, offer information and resources to all patients, even those who do not disclose IPV. Some patients may want to receive this information even if they do not feel comfortable sharing their experiences during the appointment.²⁰ You can also inform patients that they are welcome to bring up issues related to IPV at any future appointments in order to leave the door open to future disclosures.

THE CASE

The physician determined that Ms. T had been experiencing physical and psychological IPV in her current relationship. After responding empathically and obtaining the patient’s consent, the physician provided a warm handoff to the psychologist in the clinic. With Ms. T’s permission, the psychologist provided psychoeducation about IPV, and they discussed Ms. T’s current situation and risk level. They determined that Ms. T was at risk for subsequent episodes of IPV and they collaborated on a safety plan, making sure to discuss contact information for local and national crisis resources.

Continue to: Ms. T saved the phone number...

Ms. T saved the phone number for her local domestic violence shelter in her phone under a false name in case her husband looked through her phone. She said she planned to work on several safety plan items when her husband was away from the house and it was safe to do so. For example, she planned to identify additional ways to exit the house in an emergency and she was going to put together a bag with a change of clothes and some money and drop it off at a trusted friend’s house.

Ms. T and the psychologist agreed to follow up with an office visit in 1 week to discuss any additional safety concerns and to determine whether Ms. T could benefit from a referral to domestic violence counseling services or mental health treatment. The psychologist provided a summary of the topics she and Ms. T had discussed to the physician. The physician scheduled a follow-up appointment with Ms. T in 3 weeks to assess her current safety, troubleshoot any difficulties in implementing her safety plan, and offer additional resources, as needed.

CORRESPONDENCE
Andrea Massa, PhD, 125 Doughty Street, Suite 300, Charleston, SC 29403; [email protected]

THE CASE

Louise T* is a 42-year-old woman who presented to her family medicine office for a routine annual visit. During the exam, her physician noticed bruises on Ms. T’s arms and back. Upon further inquiry, Ms. T reported that she and her husband had argued the night before the appointment. With some hesitancy, she went on to say that this was not the first time this had happened. She said that she and her husband had been arguing frequently for several years and that 6 months earlier, when he lost his job, he began hitting and pushing her.

● How would you proceed with this patient?

*The patient’s name has been changed to protect her identity.

Intimate partner violence (IPV) includes physical, sexual, or psychological aggression or stalking perpetrated by a current or former relationship partner.¹ IPV affects more than 12 million men and women living in the United States each year.² According to a national survey of IPV, approximately one-third (35.6%) of women and one-quarter (28.5%) of men living in the United States experience rape, physical violence, or stalking by an intimate partner during their lifetime.² Lifetime exposure to psychological IPV is even more prevalent, affecting nearly half of women and men (48.4% and 48.8%, respectively).²

Lifetime prevalence of any form of IPV is higher among women who identify as bisexual (59.8%) and lesbian (46.3%) compared with those who identify as heterosexual (37.2%); rates are comparable among men who identify as heterosexual (31.9%), bisexual (35.3%), and gay (35.1%).³ Preliminary data suggest that IPV may have increased in frequency and severity during the COVID-19 pandemic, particularly in the context of mandated shelter-in-place and stay-at-home orders.^4-6

IPV is associated with numerous negative health consequences. They include fear and concern for safety, mental health disorders such as posttraumatic stress disorder (PTSD), and physical health problems including physical injury, chronic pain, sleep disturbance, and frequent headaches.² IPV is also associated with a greater number of missed days from school and work and increased utilization of legal, health care, and housing services.^2,7 The overall annual cost of IPV against women is estimated at $5.8 billion, with health care costs accounting for approximately $4.1 billion.⁷ Family physicians can play an important role in curbing the devastating effects of IPV by screening patients and providing resources when needed.

Facilitate disclosure using screening tools and protocol

In Ms. T’s case, evidence of violence was clearly visible. However, not all instances of IPV leave physical marks. The US Preventive Services Task Force (USPSTF) recommends that all women of childbearing age be screened for IPV, whether or not they exhibit signs of violence.⁸ While the USPSTF has only published recommendations regarding screening women for IPV, there has been a recent push to screen all patients given that men also experience high rates of IPV.⁹

It’s helpful to ask questions such as: “Do arguments [with your partner] ever result in hitting, kicking, or pushing?” and “How often does your partner scream or curse at you?”

Utilize a brief screening tool. Directly ask patients about IPV; this can help reduce stigma, facilitate disclosure, and initiate the process of connecting patients to potentially lifesaving resources. The USPSTF lists several brief screening measures that can be used in primary care settings to assess exposure to IPV (TABLE 1^8,10-17). The brevity of these screening tools makes them well suited for busy physicians; cutoff scores facilitate the rapid identification of positive screens. While the USPSTF has not made specific recommendations regarding a screening interval, many studies examining the utility of these measures have reported on annual screenings.⁸ While there is limited evidence that brief screening alone leads to reductions in IPV,⁸ discussing IPV in a supportive and empathic manner and connecting patients to resources, such as supportive counseling, does have an important benefit: It can reduce symptoms of depression.¹⁸

Continue to: Screen patients in private; this protocol can help

Screen patients in private; this protocol can help. Given the sensitive nature of IPV and the potential danger some patients may be facing, it is important to screen patients in a safe and supportive environment.^19,20 Screening should be conducted by the primary care clinician, ideally when a trusting relationship already has been formed. Screen patients only when they are alone in a private room; avoid screening in public spaces such as clinic waiting rooms or in the vicinity of the patient’s partner or children older than age 2 years.^19,20

To provide all patients with an opportunity for private and safe IPV screening, clinics are encouraged to develop a clinic-wide policy whereby patients are routinely escorted to the exam room alone for the first portion of their visit, after which any accompanying individuals may be invited to join.²¹ Clinic staff can inform patients and accompanying individuals of this policy when they first arrive. Once in the exam room, and before the screening process begins, clearly state reporting requirements to ensure that patients can make an informed decision about whether to disclose IPV.¹⁹

Set a receptive tone. The manner in which clinicians discuss IPV with their patients is just as important as the setting. Demonstrating sensitivity and genuine concern for the patient’s safety and well-being may increase the patient’s comfort level throughout the screening process and may facilitate disclosures of IPV.^19,22 When screening patients for IPV, sit face to face rather than standing over them, maintain warm and open body language, and speak in a soft tone of voice.²²

Patients may feel more comfortable if you ask screening questions in a straightforward, nonjudgmental manner, as this helps to normalize the screening experience. We also recommend using behaviorally specific language (eg, “Do arguments [with your partner] ever result in hitting, kicking, or pushing?”¹⁶ or “How often does your partner scream or curse at you?”),¹³ as some patients who have experienced IPV will not label their experiences as “abuse” or “violence.” Not every patient who experiences IPV will be ready to disclose these events; however, maintaining a positive and supportive relationship during routine IPV screening and throughout the remainder of the medical visit may help facilitate future disclosures if, and when, a patient is ready to seek support.¹⁹

CRITICAL INTERVENTION ELEMENTS: EMPATHY AND SAFETY

A physician’s response to an IPV disclosure can have a lasting impact on the patient. We encourage family physicians to respond to IPV disclosures with empathy. Maintain eye contact and warm body language, validate the patient’s experiences (“I am sorry this happened to you,” “that must have been terrifying”), tell the patient that the violence was not their fault, and thank the patient for disclosing.²³

Continue to: Assess patient safety

Assess patient safety. Another critical component of intervention is to assess the patient’s safety and engage in safety planning. If the patient agrees to this next step, you may wish to provide a warm handoff to a trained social worker, nurse, or psychologist in the clinic who can spend more time covering this information with the patient. Some key components of a safety assessment include determining whether the violence or threat of violence is ongoing and identifying who lives in the home (eg, the partner, children, and any pets). You and the patient can also discuss red flags that would indicate elevated risk. You should discuss red flags that are unique to the patient’s relationship as well as common factors that have been found to heighten risk for IPV (eg, partner engaging in heavy alcohol use).¹

With the patient’s permission, collaboratively construct a safety plan that details how the patient can stay safe on a daily basis and how to safely leave should a dangerous situation arise (TABLE 2^9,24). The interactive safety planning tool available on the National Domestic Violence Hotline’s website can be a valuable resource (www.thehotline.org/plan-for-safety/).²⁴ Finally, if a patient is experiencing mental health concerns associated with IPV (eg, PTSD, depression, substance misuse, suicidal ideation), consider a referral to a domestic violence counseling center or mental health provider.

Move at the patient’s pace. Even if patients are willing to disclose IPV, they will differ in their readiness to discuss psychoeducation, safety planning, and referrals. Similarly, even if a patient is experiencing severe violence, they may not be ready to leave the relationship. Thus, it’s important to ask the patient for permission before initiating each successive step of the follow-up intervention. You and the patient may wish to schedule additional appointments to discuss this information at a pace the patient finds appropriate.

You may need to spend some time helping the patient recognize the severity of their situation and to feel empowered to take action. In addition, offer information and resources to all patients, even those who do not disclose IPV. Some patients may want to receive this information even if they do not feel comfortable sharing their experiences during the appointment.²⁰ You can also inform patients that they are welcome to bring up issues related to IPV at any future appointments in order to leave the door open to future disclosures.

THE CASE

The physician determined that Ms. T had been experiencing physical and psychological IPV in her current relationship. After responding empathically and obtaining the patient’s consent, the physician provided a warm handoff to the psychologist in the clinic. With Ms. T’s permission, the psychologist provided psychoeducation about IPV, and they discussed Ms. T’s current situation and risk level. They determined that Ms. T was at risk for subsequent episodes of IPV and they collaborated on a safety plan, making sure to discuss contact information for local and national crisis resources.

Continue to: Ms. T saved the phone number...

Ms. T saved the phone number for her local domestic violence shelter in her phone under a false name in case her husband looked through her phone. She said she planned to work on several safety plan items when her husband was away from the house and it was safe to do so. For example, she planned to identify additional ways to exit the house in an emergency and she was going to put together a bag with a change of clothes and some money and drop it off at a trusted friend’s house.

Ms. T and the psychologist agreed to follow up with an office visit in 1 week to discuss any additional safety concerns and to determine whether Ms. T could benefit from a referral to domestic violence counseling services or mental health treatment. The psychologist provided a summary of the topics she and Ms. T had discussed to the physician. The physician scheduled a follow-up appointment with Ms. T in 3 weeks to assess her current safety, troubleshoot any difficulties in implementing her safety plan, and offer additional resources, as needed.

CORRESPONDENCE
Andrea Massa, PhD, 125 Doughty Street, Suite 300, Charleston, SC 29403; [email protected]

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).